F L A T H E O F ajho€¦ · Through the incorporation of novel diagnostics, systemic therapies, molecular targeted therapies, immunotherapies, and other biotechnological strategies

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Pharmacology UPdateIdelalisib (Zydelig)Hien C. Tang, PharmD, James YC Shen, MD, and Betty M. Chan, PharmD, BCOP

Prostate cancerThe Changing Landscape of Metastatic Prostate CancerBrian Lewis, MD, MPH, and Oliver Sartor, MD

nsclcPD-(L)1 Inhibitors and CTLA-4 Inhibitors: Rationale for Combinations and Recent Data in Non-Small Cell Lung Cancer Rebecca S. Heist MD, MPH

cancer screeningCurrent Controversies Surrounding MRI Screening for Breast Cancer Sarah A. McLaughlin, MD

sUrgeryContemporary Strategies in Breast ReconstructionMerisa L. Piper, MD, and Hani Sbitany, MD, FACS

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H e m a t o l o g y /

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ajho

www.AJHO.com issn 1939-6163 (print) issn 2334-0274 (online)

Volume 11 Number 8 8.15

mUltiPle myeloma CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLC

Advances in Multiple Myeloma

NOVEMBER 4-6, 2015New York Marriott MarquisNew York, NY

Program Co-ChairsEdward P. Ambinder, MDClinical Professor of Medicine,

Hematology and Medical OncologyClinical Professor Oncological

SciencesIcahn School of Medicine at Mt SinaiNew York, NY

Franco Muggia, MDProfessorDepartment of MedicineNYU Langone Medical CenterNew York, NY

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Table of Contents

Pharmacology UPdate

Idelalisib (Zydelig)

Hien C. Tang, PharmD, James YC Shen, MD, and Betty M. Chan, PharmD, BCOPThis brief pharmacology review covers the uses, side effects, mechanisms of action and resistance, dosing and administration, and place in therapy of idelalisib for relapsed chronic lymphocytic leuke-mia, follicular B-cell non-Hodgkin lymphoma, or small lymphocytic lymphoma .

Prostate cancer

The Changing Landscape of Metastatic Prostate Cancer

Brian Lewis, MD, MPH, and Oliver Sartor, MDIn metastatic castration-resistant prostate cancer, treatment is becoming increasingly complex, with questions arising on how to choose a treatment and how to sequence treatments. The authors explore newer developments in prostate cancer.

nsclc

PD-(L)1 Inhibitors and CTLA-4 Inhibitors: Rationale for Combinations and Recent Data in Non-Small Cell Lung Cancer

Rebecca S. Heist MD, MPHAn exploration of current data on combination strategies for the treatment of non-small cell lung can-cer. Many trials are investigating combinations of checkpoint inhibitors with other immunomodulatory agents, targeted therapies, and chemotherapies.

cancer screening

Current Controversies Surrounding MRI Screening for Breast Cancer

Sarah A. McLaughlin, MDScreening breast MRI serves as an adjunct modality to mammographic screening in women at high risk for breast cancer. Contemporary data regarding MRI screening are reviewed, as are some of the screening controversies. sUrgery

Contemporary Strategies in Breast ReconstructionMerisa L. Piper, MD, and Hani Sbitany, MD, FACSThe authors present current techniques for breast reconstruction following cancer excision, provide an overview of the reconstructive decision tree, and focus on the influence of chemotherapy and radi-ation therapy on reconstruction outcomes.

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26

31

Table of Contents (continued)

cme

CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLCmUltiPle myeloma

Advances in Multiple Myeloma Ola Landgren, MD, PhD, shares his thoughts on the key myeloma-related data presented at the 2015 Amer-ican Society of Clinical Oncology Annual Meeting, along with his perspective regarding where myeloma treatment might be headed in the near future.

39

Patrick I. Borgen, MDChairman, Department of Surgery Maimonides Medical CenterDirector, Brooklyn Breast Cancer ProgramBrooklyn, NY

Julie R. Brahmer, MDAssociate Professor, Oncology Johns Hopkins University School of

MedicineSidney Kimmel Comprehensive Cancer

CenterBaltimore, MD

J. Michael Dixon, MD, OBEProfessor of Surgery and Consultant

SurgeonClinical Director, Breakthrough Research

UnitEdinburgh Breast UnitEdinburgh, UK

David R. Gandara, MDProfessor of MedicineDirector, Thoracic Oncology ProgramSenior Advisor to the DirectorDivision of Hematology/OncologyUC Davis Comprehensive Cancer CenterSacramento, CA

Andre Goy, MD, MSChairman and DirectorChief of LymphomaDirector, Clinical and Translational Cancer ResearchJohn Theurer Cancer Center at Hackensack University Medical CenterHackensack, NJ

Omid Hamid, MDChief, Translational Research and ImmunotherapyDirector, Melanoma TherapeuticsThe Angeles Clinic and Research InstituteLos Angeles, CA

Roy S. Herbst, MD, PhDEnsign Professor of Medicine (Medical

Oncology)Professor of PharmacologyChief of Medical OncologyAssociate Director for Translational ResearchYale Cancer CenterYale School of Medicine New Haven, CT

Thomas J. Lynch, Jr, MDDirector, Yale Cancer CenterPhysician-in-Chief, Smilow Cancer Hospital at Yale-New HavenRichard and Jonathan Sackler Professor of

Internal MedicineNew Haven, CT

Maurie Markman, MDPresident, Medicine and ScienceNational Director, Medical OncologyCancer Treatment Centers of AmericaPhiladelphia, PA

John L. Marshall, MDChief, Hematology and Oncology Director, Otto J. Ruesch Center for the

Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC

Hyman B. Muss, MDProfessor of OncologyUniversity of North CarolinaDirector of Geriatric OncologyLineberger Comprehensive Cancer CenterChapel Hill, NC

Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer

Center Texas Oncology The US Oncology NetworkDallas, TX

Daniel P. Petrylak, MDProfessor of Medicine (Medical Oncology) and of UrologyCo-Director, Signal Transduction Research

ProgramYale Cancer Center and Smilow Cancer

HospitalNew Haven, CT

Heather A. Wakelee, MDAssociate Professor, Medicine (Oncology)Stanford University Medical CenterStanford, CA

Jeffrey S. Weber, MD, PhDSenior Member and DirectorDonald A. Adam Comprehensive Melanoma Research CenterMoffitt Cancer CenterTampa, FL

PER® Executive Board/AJHO Editorial Board

VOL. 11, NO. 8 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 3

Idelalisib the is first agent to target the phosphatidylinositol-3-kinase (PI3K) pathway and the second oral

agent approved by the FDA, in July 2014, for treatment of relapsed/refractory chronic lymphocytic leukemia

(CLL). Idelalisib was also granted accelerated approval for the treatment of relapsed follicular B-cell non-Hod-

gkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL). In this issue of The American Journal of

Hematology/Oncology®, a peer-reviewed resource for oncology education and the official journal of Physicians’

Education Resource®, LLC, Hien C. Tang, PharmD, James YC Shen, MD, and Betty M. Chan, PharmD,

BCOP, provide a brief review of the uses of this new targeted therapy, including dosing, side effects, mecha-

nisms of action and resistance, and place in the treatment of CLL, FL, or SLL.

Choice of treatment for metastatic castration-resistant prostate cancer (mCRPC) has become increasingly

complex. Brian Lewis, MD, MPH, and Oliver Sartor, MD, review data leading to the FDA approval of 5 new

agents for mCRPC since 2014, with a focus on optimizing the sequence of drugs and some of the questions

and shortcomings associated with each agent. Clearly there is need for further and active investigation in this

space.

Much progress has been made in the development of immunotherapeutic agents for various cancers. In

the area of non-small cell lung cancer, Rebecca S. Heist, MD, MPH, describes recent and emerging data on

the use of treatment strategies that combine immunotherapy with other regimens, including other immuno-

modulatory agents, targeted therapies, and chemotherapies.

Sarah A. McLaughlin, MD, reviews contemporary data regarding MRI screening for breast cancer. Lim-

itations of MRI screening include reduced specificity compared with mammography and cost, and there is

controversy over its use in some situations.

The management of breast cancer has changed dramatically over the last 30 years, and improvements in

neoadjuvant therapy and surgical techniques have allowed more women to be candidates for breast-

conserving therapy, while on the other hand, detection of inherited susceptibility has increased the number

of prophylactic mastectomies performed. Merisa L. Piper, MD, and Hani Sbitany, MD, FACS, review the

current state of breast reconstruction, factors that influence the reconstructive algorithm, and the outcomes

of various reconstructive techniques.

Finally, this month our CME article focuses on multiple myeloma, and Ola Landgren, MD, PhD, discusses

advances recently presented at the American Society of Clinical Oncology annual meeting and future direc-

tions in treatment.

Please contact us with comments and suggestions. As always, we also invite you to submit original articles

and commentaries.

Michael J. Hennessy, Sr

Chairman and Chief Executive Officer

Chairman’s Note

the content of this publication is for general information purposes only. the reader is encouraged to confirm the information presented with other sources. American Journal of Hema-tology/Oncology makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. American Journal of Hematology/Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. American Journal of Hematology/Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. the views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of American Journal of Hematology/Oncology.

4 www.ajho.com AUGUST 2015

Editor-in-ChiefDebu Tripathy, MD

Professor and Chair Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston, TX

Managing EditorDevera Pine [email protected] Art Director Marie Graboso

Editorial OfficesPhysicians’ Education Resource®, LLC666 Plainsboro Road, Ste 356Plainsboro, NJ 08536(609) 378-3701

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editorial staFF

This issue of The American Journal of Hematology/Oncology contains a forward-looking review of immunotherapy and future trends in lung cancer, one of several malignancies that have for decades eluded efforts to effectively unleash the immune system for clinical benefit. Breast and lung cancers are among the most common cancers and leading causes of cancer mortality in men and women. In the past few years (and in the case of breast cancer, just in the last year), responses are being seen with the latest revolution in immunological therapy—check-point inhibition—which has allowed the crossing of the barrier from responses in melanoma and renal cell cancer to more common cancers. Malignant cells express foreign antigens, but due to similarities to other human proteins, as well as suppressive factors elicited by the tumor itself, the immune response is dampened. Furthermore, the immune system possesses “checkpoint” mechanisms to tamp down exuberant responses following infections. Attempts to goad the immune system into action with tumor or purified antigens, or nonspecific stimulation with interferons, interleukins, and more recently, activated dendritic cells, have worked only on cancers that are more immunogenic, such as melanoma.

A major breakthrough came with the discovery of checkpoint recep-tors on T-cells—initially the CTLA-4 receptor, and more recently the programmed cell death (PD-1) receptor. Ipilimumab, the first CTLA-4 antibody in the clinic, was approved for melanoma on the basis of enhanced survival, and has also shown modest activity in other tumor types. Antibodies to PD-1 and one of its ligands, PD-L1, have been shown to be even more effective in melanoma, and with fewer autoim-mune side effects. Importantly, these are the first immune therapies to show a clear benefit in lung cancer and responses in early-phase trials for triple-negative breast cancer. Of note: the next issue of AJHO will feature a review of immunotherapeutic options and trends in the area of breast cancer.

Which patients will benefit the most from checkpoint inhibition? Mounting data show that a higher mutational tumor rate and more “neoantigens” may predict better response, consistent with a high degree of environmental DNA damage seen in ultraviolet-driven mela-noma and smoking-related lung cancer. Triple-negative breast cancer is also known to harbor more genomic aberrations, and correspondingly, a higher incidence of naturally occurring immunity evidenced by tumoral lymphocytic infiltrates. Evidence also exists showing that the presence of tumor or stromal PD-L1 expression may predict a better response; however, this varies among tumor types, and optimal indices have not been defined.

Finally, there is much interest in further modulating the overall im-munological thrust with combination therapies that include vaccines, hematopoietic and other cytokines, and alternate immunostimulatory pathways. As pointed out in our immunotherapy feature article on lung cancer in this issue, we are at the dawn of a new era of immu-notherapy that holds promise for more sustainable responses across a spectrum of malignancies yet to be defined.

corPorate oFFicers Chairman and CEOMichael J. Hennessy, Sr

Vice Chairman Jack Lepping

Senior Vice President, Operations and Clinical Affairs Jeff Prescott, PharmD, RPh

Chief Creative Officer Jeff Brown

Debu Tripathy, MD Editor-in-Chief

From the Editor


Pharmacology Update

IntroductionIn 2015, newly diagnosed chronic lymphocytic leukemia (CLL) is estimated to reach 14,620 cases, with 4650 deaths occurring in the United States.1 The age-adjusted annual incidence rate in 2007 to 2011 was 4.4 per 100,000 in all age groups, and reaching 25.3 per 100,000 in those 65 years or older. The 5-year survival of patients younger than 65 years reached 89.7% compared with 74.5% for those age 65 years or older.2

The most current guideline published by the National Com-prehensive Cancer Network (NCCN) recommends chemoim-

munotherapy for patients younger than age 70 years, and who do not have significant comorbidities. The combination of chemoimmunotherapy for these patients includes fludarabine, cyclophosphamide, and rituximab as the first-line option. In re-lapsed/refractory patients, the next line of treatment is depen-dent on length of response to initial treatments. For patients able to maintain a long response, retreatment with first-line ther-apy is recommended until short response. In those with short responses to chemoimmunotherapy, the NCCN recommends use of oral agents. One potential option is the use of idelalisib in combination with rituximab.3

In July 2014, idelalisib was approved by the US Food and Drug Administration (FDA) for the treatment of relapsed CLL in combination with rituximab after failure of 2 prior therapies. In addition, it was granted accelerated approval for treatment of relapsed follicular B-cell non-Hodgkin lymphoma (FL) and re-lapsed small lymphocytic lymphoma (SLL). The FDA-approved dose and schedule for idelalisib is 150 mg orally twice daily for patients with FL/SLL and in combination with rituximab for patients with CLL.4

CLL, RelapsedAn initial phase I, dose-ranging trial evaluated 54 patients with relapsed/refractory CLL treated with idelalisib (GS-1101, CAL-101) at dosages of 50 mg to 350 mg once daily or twice daily. Treatment with idelalisib demonstrated an overall response rate (ORR) of 72%, with 39% of patients with partial responses (PRs; International Workshop on Chronic Lymphocytic Leukemia 2008 criteria5) and 33% with PRs in the presence of treatment-in-duced lymphocytosis.6 For those patients who responded, the median time to response was 1 month, with a median duration of response of 16.2 months. The median progression-free surviv-al (PFS) for all patients was 15.8 months.7

A phase III, multicenter, double-blind, placebo-controlled study randomized patients (N = 220) to idelalisib 150 mg twice daily in combination with rituximab (375 mg/m2 once, then 500 mg/m2 every 2 weeks for 4 doses, then every 4 weeks for 3 doses, for a total of 8 doses; Table 1). There was a statistically signifi-cant longer rate of PFS at 24 weeks: 93% in the treatment group versus 46% in the control group (P <.001). The median duration of PFS in the treatment group was not reached at the time of analysis compared with 5.5 months in the control group. The

Idelalisib (Zydelig)

Hien C. Tang, PharmD, James YC Shen, MD, and Betty M. Chan, PharmD, BCOP

Abstract

In 2015, newly diagnosed chronic lymphocytic leukemia

(CLL) is estimated to reach 14,620 cases, with 4650 deaths

in the United States. First-line options typically include

chemoimmunotherapy; however, in patients who re-

lapse or are refractory, oral agents offer a new and safe

alternative. Idelalisib is the first agent to target the phos-

phatidylinositol-3-kinase (PI3K) pathway, and the second

oral agent approved by the US Food and Drug Adminis-

tration (FDA), in July 2014, for the treatment of relapsed/

refractory CLL. In addition, idelalisib was granted accel-

erated approval for treatment of relapsed follicular B-cell

non-Hodgkin lymphoma (FL) and relapsed small lympho-

cytic lymphoma (SLL). In a phase III study of idelalisib in

combination with rituximab in 220 patients with relapsed

CLL, the overall response rate (ORR) was 81%, with a sta-

tistically significant overall survival (OS) of 92% versus

80% at 12 months (P = .02). In a phase II study in patients

with indolent non-Hodgkin lymphoma, the median dura-

tion of response was 12.5 months, median overall sur-

vival was 20.3 months, and 1-year survival was 80%. The

most common adverse events (≥10%) reported in clinical

trials included fever, chills, nausea, cough, infusion reac-

tion, and gastrointestinal symptoms. The FDA-approved

labeling of idelalisib includes black box warnings for fatal

and/or serious diarrhea or colitis, gastrointestinal perfo-

ration, pneumonitis, and hepatotoxicity.

Key words: idelalisib review, CLL, FL, SLL, toxicity

management


Pharmacology Update

ORR was 81% in the treatment group compared with 13% in the control group (P <.001); all responses were PRs. Overall sur-vival (OS) at 12 months in the treatment group was 92% versus 80% in the control group (P = .02).8

Indolent Lymphoma, RelapsedA phase I study of idelalisib evaluated 64 patients with relapsed indolent non-Hodgkin lymphoma (NHL) at dosages ranging from 50 mg to 350 mg once daily or twice daily.9 Treatment with idelalisib resulted in an ORR of 47%, with 1 patient achieving complete response (CR). The median time to response for the 30 patients was 1.3 months, with a median duration of response of 18.4 months. The median PFS was 7.6 months in all patients.

In a phase II, multicenter, open-label study of 125 patients with relapsed indolent NHL treated with idelalisib 150 mg twice daily, the reported response rate was 57%, including 6% CRs (Table 1).10 In addition, the median time to response was 1.9 months, with a median duration of response of 12.5 months. At 48 weeks, 47% of patients remained progression-free, with a median PFS of 11 months. Median OS was 20.3 months, and OS at 1 year was estimated at 80%.

Side Effects and Management of ToxicitiesIn patients being treated with idelalisib in combination with rit-uximab, the most common adverse events (AEs; ≥10%) reported

in clinical trials included fever, chills, nausea, cough, infusion re-action, and gastrointestinal (GI) symptoms (Table 2). Grade 3 or higher serious AEs included fever, sepsis, pneumonitis, diarrhea, neutropenia, Pneumocystis jiroveci pneumonia, and febrile neu-tropenia. The AEs that led to discontinuation in the treatment group included GI and skin disorders. Laboratory abnormali-ties included neutropenia, hepatic transaminitis, and electrolyte disturbances. Although no patients discontinued idelalisib due to elevations in aspartate transaminase (AST) and alanine trans-aminase (ALT) in clinical trials, the FDA-approved labeling of idelalisib recommends interruption of therapy if AST/ALT reaches greater than 5 times the upper limit of normal (ULN).8,11

In indolent NHL where idelalisib is used as a single agent, common reported AEs included fever, fatigue, cough, dyspnea, GI symptoms, decreased appetite, weight loss, rash, insomnia, and night sweats. Serious AEs included fever, pneumonia, diar-rhea, colitis, febrile neutropenia, acute renal failure, and pneu-monitis. Laboratory abnormalities included hematological cyto-penias and hepatic transaminitis.10,11

Black box warnings on the idelalisib approved label include fatal and/or serious diarrhea or colitis, GI perforation, pneu-monitis, and hepatotoxicity. Severe diarrhea or colitis (grade ≥3) have been reported in clinical trials, with median onset of 1.9 months for any grade, 1.5 months for grade 1/2, and 7.1 months for grade 3/4. During clinical trials, 2 types of diarrhea

Table 1. Pivotal Published Trials

Trial Phase Study Design Treatment Results

Furman et al8 III Multicenter, randomized, double-blind, placebo-con-trolled study in relapsed CLL (N = 220)

Treatment: Rituximab (IV 375 mg/m2 x 1, then 500 mg/m2 every 2 weeks for 4 doses, then every 4 weeks for 3 doses) + idelalisib 150 mg twice daily

Control: Rituximab alone

PFS:Treatment vs control: not reached vs 5.5 monthsORR:Treatment: 81%Control: 13%P <.001

CR: None

OS at 12 months:Treatment: 92%Control: 80% P = .02

Gopal et al10 II Multicenter, open label, single-group study in relapsed NHL (N = 125)

Idelalisib 150 mg twice daily ORR: 57%, (CR, 6%; PR, 50%; minor response 1%)

Time to response: median 1.9 months

Duration of response: median 12.5 months

PFS: median 11 months

OS: median 20.3 months (at time of data analysis)

CLL indicates chronic lymphocytic leukemia; CR, complete response; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.


IdelalIsIb

were observed. The first was a self-limiting type that occurs with-in 8 weeks of idelalisib initiation, which was typically mild or moderate and responsive to common antidiarrheal medication. The second type of diarrhea observed typically occurred late in treatment and responded poorly to antimotility medications and

empiric antibiotics. Corticosteroids were used in some cases to manage this toxicity in clinical trials, with enteric budesonide used most commonly. If severe idelalisib-associated diarrhea or colitis is suspected (≥7 stools/day over baseline), initiation of budesonide and interruption of idelalisib is recommended un-

Table 2. Adverse Events With Idelalisib

Treatment Group8,10,11

adverse events and Serious adverse events

Rituximab + Idelalisib (Cll)N (%)

Idelalisib (NHl)N (%)

ae Sae ae Sae

Pyrexia 32 (29) Pneumonia 7 (6) Diarrhea 54 (43) Pyrexia 13 (10)

Fatigue 26 (24) Pyrexia 7 (6) Nausea 37 (30) Pneumonia 9 (7)

Nausea 26 (24) Febrile neutropenia 5 (5) Fatigue 37 (30) Diarrhea 9 (7)

Chills 24 (22) Sepsis 4 (4) Cough 36 (29) Colitis 5 (4)

Infusion reaction 17 (15) Pneumonitis 4 (4) Pyrexia 35 (28) Dehydration 4 (3)

Cough 16 (15) Diarrhea 3 (3) Decreased appetite 22 (18) Febrile neutropenia 4 (3)

Constipation 13 (12) Neutropenia 3 (3) Dyspnea 22 (18) Acute renal failure 3 (2)

Decreased appetite 13 (12) PJP 3 (3) Abdominal pain 20 (16) Pneumonitis 3 (2)

Vomiting 13 (12) Neutropenic sepsis 3 (3) Vomiting 19 (15)

Dyspnea 12 (11) Dyspnea 1 (1) URTI 18 (14)

Night sweats 11 (10) Cellulitis 1 (1) Weight decreased 17 (14)

Rash 11 (10) Rash 16 (13)

Asthenia 14 (11)

Night sweats 14 (11)

Pneumonia 14 (11)

Peripheral edema 13 (10)

Headache 13 (10)

lab abnormalities lab abnormalities

Neutropenia 60 (55) AST/ALT elevation 103 (82)

Hypertriglyceridemia 62 (56) Neutrophils decreased 78 (53)

Hyperglycemia 59 (54) Hemoglobin decreased 41 (28)

AST/ALT elevation 38 (35) Platelets decreased 38 (26)

GGT increased 29 (26) Alkaline phosphatase elevation 28 (22)

Anemia 28 (25) Bilirubin elevation 13 (10)

Thrombocytopenia 19 (17)

Lymphocyte decrease 22 (20)

Lymphocyte increase 27 (25)

Hypoglycemia 12 (11)

Hyponatremia 22 (20)

Any grade (≥10%) or serious adverse events; AE indicates adverse event; AST/ALT, aspartate aminotransferase/alanine aminotransferase; GGT, gamma-glutamyl transferase; PJP, Pneumocystis jiroveci pneumonia; SAE, serious adverse event; URTI, upper respiratory tract infection.


Pharmacology Update

til complete resolution of diarrhea. Recommended dosage of budesonide is 9 mg orally once daily or prednisolone 1 mg/kg orally or intravenously (if unable to tolerate oral), with tapering when diarrhea returns to grade 1.11,12

Fatal cases of pneumonitis have occurred in patients treated with idelalisib. The FDA-approved labeling of idelalisib recom-mends prompt evaluation for symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates, or oxygen saturation decrease of more than 5%. Idelalisib therapy should be interrupted for sus-pected pneumonitis, and if confirmed, corticosteroids should be initiated, as appropriate.11

Elevations of AST/ALT greater than 5 times ULN have oc-curred and were typically observed within 12 weeks of initiating therapy. Interruption of idelalisib therapy results in transam-inase normalizations; however, hepatotoxicity may recur when rechallenging with reduced dosages. The FDA-approved labeling of idelalisib recommends monitoring liver function tests (LFTs) weekly for those with AST/ALT greater than 3 to 5 times ULN or bilirubin greater than 1.5 to 3 times ULN, until AST/ALT and/or bilirubin is 1 or less times ULN. Temporary interruption of idelalisib is recommended for AST/ALT greater than 5 to 20 times ULN or bilirubin greater than 3 to 10 times ULN. Liv-er function should be monitored weekly until AST/ALT and/or bilirubin is 1 or less times ULN, at which time therapy may be reinitiated at 100 mg twice daily. Idelalisib should be discon-tinued permanently if AST/ALT is greater than 20 times ULN, bilirubin is greater than 10 times ULN, or if the patient develops recurrent hepatotoxicity.11

Renal excretion of idelalisib is 14%. In patients with renal impairment, no dosage adjustment is necessary in patients with creatinine clearance (CrCl) greater than or equal to 15 ml/min. Renal adjustment data are not available in patients with CrCl less than 15 ml/min.11

Place in TherapyCurrently, first-line therapy for the treatment of CLL includes a combination of chemotherapeutic agents and monoclonal an-tibodies that target cell-surface antigens. In patients with treat-ment-naïve CLL, the combination of fludarabine, cyclophospha-mide, and rituximab (FCR) results in ORR greater than 90% and complete responses of 44% to 70%.13,14 However, if patients have relapsed/refractory disease and are unable to tolerate addi-tional courses of chemotherapy, idelalisib offers an alternative, effective, and safe treatment option secondary to ibrutinib. Ibru-tinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), is an alternative agent recently approved by the FDA for patients with previously treated CLL. Ibrutinib was initially granted ac-celerated approval for the treatment of relapsed mantle cell lym-phoma (MCL) in November 2013; in February 2014, the FDA granted accelerated approval of ibrutinib for the treatment of patients with CLL that has recurred after at least 1 prior ther-

apy.15 In July 2014, ibrutinib gained expanded approval for the treatment of CLL in patients with chromosome 17p deletion, based on a phase III study of 391 patients.16 In this multicenter, open-label study of ibrutinib compared with ofatumumab in patients with previously treated CLL, ibrutinib significantly im-proved PFS (not reached vs median 8.1 months; P <.001) and OS rates (42.6% vs 4.1%; P <.001).17 At 12 months, the OS rate was 90% with ibrutinib compared with 81% with ofatumumab. A to-tal of 63% (122/195) PRs were seen in the ibrutinib group versus 4% (8/196) in the ofatumumab group. In addition, a subgroup analysis of patients with chromosome 17p13.1 deletion showed similar results with ibrutinib.

Similarly, in patients with FL, first-line treatment options in-clude the use of chemotherapy with rituximab, such as benda-mustine plus rituximab (BR); cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (R-CHOP); or cyclophos-phamide, vincristine, prednisone plus rituximab (RCVP). In addition to relapsed CLL/SLL indications, idelalisib has also obtained accelerated approval for relapsed FL. Currently, the use of idelalisib is limited to second-line treatment of FL after failure of 2 prior therapies, including rituximab and an alkylating agent.

Preclinical data in MCL have shown that specific BTK mu-tations that led to ibrutinib resistance also enhanced PI3K dysregulation.18 PI3K inhibition in the same ibrutinib-resistant model was able to restore the cell-line cytotoxicity. In a separate experiment, ibrutinib in combination with idelalisib produced strongly synergistic inhibition of the lymphoma cell line.19 The likely rationale for the synergistic effect is because ibrutinib and idelalisib both target the B-cell receptor signaling through dif-ferent mechanisms. These data taken together suggest that in ibrutinib-resistant patients, idelalisib may still prove to be an ef-fective therapy, and that combination idelalisib-ibrutinib might be explored in the future.

Mechanism of Action and ResistancePI3K phosphorylation activates the serine/threonine kinase AKT, which then activates mammalian target of rapamycin (mTOR). PI3Kδ (isoform p110δ) is a central lipid kinase in the development and function of normal B cells. Overactive signal-ing of PI3Kδ has been shown to increase proliferation, survival, and migration of malignant B cells into lymphoid tissues.20 Ide-lalisib is a selective small-molecule inhibitor of PI3Kδ compared with α, β, and γ isoforms.11,21

Better knowledge and familiarity with targeted therapy have led to increased understanding of the development of resistance. Idelalisib resistance has not yet been fully characterized, although research is currently under way to explore this subject. Proposed mechanisms include upregulation of alternative PI3K isoform enzymatic cascade through p110α,22 activation of an “escape” on-cogenic pathway such as RAS–RAF–MEK–ERK-MAPK cascade and amplification of MYC,23 and increased upstream signaling


IdelalIsIb

that overwhelms the competitive inhibition.24 Rational combina-tion therapy with agents of different mechanisms of action may ultimately be necessary to improve efficacy and overcome resis-tance. Future directions for overcoming resistance may also in-clude patient selection using predictive biomarkers of response.

Dosing and AdministrationIdelalisib is approved for relapsed CLL in combination with rit-uximab; for FL in patients who have received at least 2 prior systemic therapies; and for SLL in patients who have received at least 2 prior systemic therapies. The FDA-approved, recommend-ed starting dosage is 150 mg orally twice daily without regard to food. Tablets should be taken whole and within 6 hours of scheduled dose if missed. If a dose of idelalisib is missed by more than 6 hours, patients should skip the dose and restart at the next scheduled administration time. Dosing of idelalisib should be adjusted for any toxicities, and permanently discontinued for anaphylaxis, life-threatening diarrhea, or other life-threatening toxicities that recur during rechallenging. Toxicities that require dosing adjustments or interruption of idelalisib include neutro-penia or thrombocytopenia, diarrhea, symptomatic pneumoni-tis, or hepatotoxicity. Idelalisib should be stored in its original container at room temperature (68°F to 86°F) and away from the reach of children. In addition, idelalisib should not be cut, crushed, or altered.11

Idelalisib is a substrate of hepatic enzyme CYP3A, and con-comitant administration should be avoided with strong CYP3A inducers, such as rifampin, phenytoin, St. John’s wort, and car-bamazepine. When administering with strong CYP3A inhib-itors, closely monitor for signs of toxicity due to idelalisib. In addition, idelalisib is a strong CYP3A inhibitor, therefore avoid concomitant use of idelalisib with CYP3A substrates.

ConclusionIdelalisib is the second oral agent approved for the treatment of relapsed/refractory CLL, and the first to target the PI3K pathway (in fact, the first in this class of drugs to be approved overall). Idelalisib in combination with rituximab offers an effective and safe alternative to chemotherapy in relapsed/refractory CLL, sec-ondary to ibrutinib, especially in patients without 17p or 11q deletions. In addition, idelalisib is indicated for use in patients with FL who have failed 2 prior therapies. Ongoing studies reg-istered at http://clinicaltrials.gov for treatment of newly diag-nosed or treatment-naïve patients include registration numbers NCT01980888 (idelalisib in combination with bendamustine and rituximab) and NCT02044822 (idelalisib in combination with rituximab in patients with 17p deletion). However, until data are released for patients with untreated CLL, FDA indica-tions for the use of idelalisib are limited to relapsed/refractory CLL, SLL, and FL.

Affiliations: Hien Chung Tang, PharmD, is adjunct assistant professor of Pharmacy Practice at the University of Southern California School of Pharmacy, USC/Norris Comprehensive Cancer Center & Hospital; James Yu Chang Shen, MD, is from the department of Internal Medicine, Jane Anne Nohl Division of Hematology, and a fellow in the Division of Hematology-On-cology, Keck School of Medicine of University of Southern Cal-ifornia, Los Angeles; Betty M. Chan, PharmD, BCOP, is assis-tant professor of Clinical Pharmacy, residency program director, PGY2 Oncology Pharmacy Practice, and ambulatory pharmacy manager at USC/Norris Comprehensive Cancer Center & Hos-pital, University of Southern California School of Pharmacy, Los Angeles.Disclosures: The authors report no relevant financial conflicts of interest to disclose. Address correspondence to: Betty M. Chan, PharmD, BCOP, USC/Norris Comprehensive Cancer Center & Hospital, Uni-versity of Southern California School of Pharmacy, Los Angeles, CA 90033. Email: [email protected] or [email protected].

REfEREnCES1. American Cancer Society. Cancer Facts & Figures 2015. At-lanta, GA: American Cancer Society; 2015.2. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Sta-tistics Review, 1975-2011. Bethesda, MD: National Cancer In-stitute. April 2014. http://seer.cancer.gov/csr/1975_2011/. Ac-cessed July 21, 2015.3. National Comprehensive Cancer Network. Non-Hodgkin’s Lymphomas (Version 2.2015). http://www.nccn.org/profession-als/physician_gls/pdf/nhl.pdf. Accessed July 21, 2015.4. US Food and Drug Administration. Idelalisib. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm406410.htm. Accessed July 21, 2015.5. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a re-port from the International Workshop on Chronic Lymphocyt-ic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. 6. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820-2822. 7. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397. 8. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rit-uximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.9. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood.


Pharmacology Update

2014;123(22):3406-3413. 10. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. 11. Zydelig [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014.12. Coutré SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert pan-el opinion [published online May 19, 2015]. Leuk Lymphoma. doi:10.3109/10428194.2015.1022770.13. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophospha-mide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4079-4088. 14. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174.15. US Food and Drug Administration. Approved Drugs - Ibru-tinib (IMBRUVICA). http://www.fda.gov/Drugs/Information-OnDrugs/ApprovedDrugs/ucm385878.htm. Accessed May 13, 2015.16. US Food and Drug Administation. FDA expands approved use of Imbruvica for chronic lymphocytic leukemia [news re-lease]. http://www.fda.gov/NewsEvents/Newsroom/PressAn-nouncements/ucm406916.htm. Accessed May 13, 2015.17. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatu-mumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.18. Chiron D, Di Liberto M, Martin P, et al. Cell-cycle repro-gramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Disc. 2014;4(9):1022-1035.19. De Rooij MF, Kuil A, Kater AP, et al. Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for combination therapy. Blood. 2015;125(14):2306-2309.20. Bilancio A, Okkenhaug K, Camps M, et al. Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signal-ing: comparative analysis of genetic and pharmacologic interfer-ence with p110δ function in B cells. Blood. 2006;107(2):642-650. 21. Lannutti BJ, Meadows SA, Herman SEM, et al. CAL-101, a p110 selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cel-lular viability. Blood. 2011;117(2):591-594. 22. Iyengar S, Clear A, Bodor C, et al. P110α-mediated constitu-tive PI3K signaling limits the efficacy of p110δ-selective inhibi-tion in mantle cell lymphoma, particularly with multiple relapse. Blood. 2013;121(12):2274-2284.23. Sos ML, Fischer S, Ullrich R, et al. Identifying geno-type-dependent efficacy of single and combined PI3K- and

MAPK-pathway inhibition in cancer. Proc Natl Acad Sci USA. 2009;106(43):18351-18356.24. Yap TA, Bjerke L, Clarke PA, Workman P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr Opin Pharmacol. 2015;23:98-107.


· Prostate CanCer ·

The Changing Landscape of Metastatic Prostate Cancer

Brian Lewis, MD, MPH, and Oliver Sartor, MD

IntroductionGiven the advances in metastatic castration-resistant prostate cancer (mCRPC) in the last 5 years, it is appropriate to review the data and take stock of where we have been and where we need to go. There is no doubt that tremendous progress has been

made, and that new trials have changed the way we approach this disease. While we laud this progress, it is sometimes easy to forget the shortcomings and how much further we need to go. No one with mCRPC will be cured, and our efforts as a whole have been modest. No comparative trials have been published, and few are in progress. No combination is known to be superior to a single agent, and no sequence is known to be superior to any other sequence. This article will review the data leading to reg-ulatory approvals, but also highlight some of the questions and shortcomings associated with each agent. Clearly there is a need for further and active investigation in this space.

Chemotherapy in Newly Diagnosed mCRPCTen years after the publication of 2 seminal articles detailing the survival advantage of docetaxel over mitoxantrone for pa-tients with mCRPC1,2 and its US Food and Drug Administration (FDA) approval for use in mCRPC, docetaxel has found another potential place in the treatment of prostate cancer. The ECOG CHAARTED trial3 randomized in a 1:1 fashion 790 men with hormone-sensitive mCRPC to usual treatment consisting of an-drogen-deprivation therapy (ADT) or to ADT plus 6 cycles of docetaxel chemotherapy given at 75 mg/m2 every 3 weeks. The primary endpoint was overall survival (OS). The median age was 63 years, and the majority of the patients had an ECOG per-formance status (PS) of 0 or 1. Median OS in the ADT group was 42.3 months and in the ADT-plus-docetaxel group it was 52.7 months, giving a 10.4-month survival advantage to the use of chemotherapy. Patients were stratified based on having high-volume disease (visceral disease and/or ≥4 bone lesions, with at least 1 outside of the pelvis and vertebral column) or low-volume disease. Patients in the high-volume group had a median OS of 32.2 months compared with 49.2 months in the ADT-plus-docetaxel group (hazard ratio [HR], 0.6; P = .0006). In the low-volume group, the median OS was not met, so further follow-up will be required.3

It is important to note that the GETUG-15 trial4 was conduct-ed in a similar patient population, but without demonstrating a benefit to added docetaxel. Differences in the 2 trials are readily apparent. The GETUG-15 trial was much smaller (N = 385 vs 790), utilized up to 9 cycles of docetaxel (vs ≤6), and had 176

Abstract

October 2014 marked the 10th anniversary of the publi-

cation of 2 seminal articles detailing the survival advan-

tage of docetaxel over mitoxantrone for patients with

metastatic castration-resistant prostate cancer (mCRPC).

Since that time, the US Food and Drug Administration

(FDA) has approved 5 additional agents for the treat-

ment of mCRPC based on an increased overall survival

advantage. These agents include a chemotherapeutic

(cabazitaxel), 2 hormonal agents (abiraterone and en-

zalutamide), an alpha-emitting bone-seeking radioiso-

tope (radium-223), and an immunotherapy (sipuleucel-T).

Increasing complexity has been added to the use of these

agents in individual patients, as new pivotal trials have

not reported comparative data for any of the new agents.

Control groups have consisted of agents such as place-

bos, prednisone, mitoxantrone/prednisone, and standard

of care. Sequencing of agents has been explored only in

the post-docetaxel space. The most recent FDA approval

is for use of enzalutamide in mCRPC in patients who are

chemotherapy-naïve, whereas previously this medica-

tion was relegated to use in patients previously treated

with docetaxel. This article will explore the newer devel-

opments in prostate cancer, with an emphasis on both

the progress and pitfalls of the newer data. In particular,

questions have now arisen as to how we should chose

treatments for individual patients, and the sequence of

therapies remains a problematic and thorny issue. Pre-

dictive biomarkers would provide potential insights, but

more work is needed in prospective multi-institutional

trials before clinical practice should change.

Key words: Prostate cancer, treatment, metastatic, se-

quencing, biomarker



death events versus 237 for CHAARTED. The GETUG-15 con-trol group had a median survival of 54 months compared with 44 months for CHAARTED, and the overall GETUG-15 study had a median prostate-specific antigen (PSA) at entry of 26 ng/mL versus 53 ng/mL in CHAARTED. Taken together, the small-er GETUG-15 trial coupled with the better prognosis of enrolled patients may account for the differences in the trial results. More follow-up is needed for both trials.

STAMPEDE5 is a third trial that has recently reported re-sults. In this trial, 2962 men with high-risk, locally advanced or mCRPC who had started ADT were randomized to standard of care (SOC), which was at least 3 years of ADT; SoC plus docetaxel given at a dosage of 75 mg/m2 every 3 weeks for 6 cycles; SOC plus zoledronic acid; or SOC plus zoledronic acid and docetaxel. The proportion of patients with metastatic disease was 61%. In the overall trial, the median OS was increased by 10 months (67 months vs 77 months), favoring the use of docetaxel with an HR for OS of 0.76. For those with metastatic disease, the HR was 0.73, and for those with nonmetastatic disease, the HR was 1.01 (with many fewer events in the nonmetastatic arm). In the met-astatic subset, the docetaxel-plus-ADT subset median survival was 65 months compared with 43 months for those treated with ADT alone. In other words, those with metastatic disease receiv-ing docetaxel in the hormone-sensitive setting had a 22-month longer median survival.

The STAMPEDE results confirm the results of the CHAART-ED trial and will change the standard of care for newly diagnosed mCRPC. Regardless, not all patients are appropriate for chemo-therapy, and not all patients will consent to chemotherapy. How-ever, in patients who present with metastatic disease, particular-ly those with visceral disease and 4 or more bone metastases, chemotherapy should be offered. Although the standards should change, what should become of patients who are chemo-intol-erant or otherwise not candidates for chemotherapy? There is a strong rationale for combining ADT with nonchemotherapeutic agents. ADT combined with radium-223, enzalutamide, ARN-509, ODM-201, or abiraterone may also be effective, and even better tolerated. New trials to address these issues are either on-going or proposed. Regardless, the possibility that ADT mono-therapy will remain the SoC is remote. Times are changing.

DocetaxelDocetaxel was approved for use in men with mCRPC in 2004 as a result of 2 studies published in the same issue of The New En-gland Journal of Medicine that year (Table 1). The TAX 3271 study randomized 1006 men with mCRPC to receive either docetaxel or mitoxantrone. The primary endpoint of OS was met with a 2.4-month improvement in OS favoring docetaxel. All patients were given prednisone 5 mg twice a day and were premedicated with dexamethasone in the following way: 8 mg orally given 12 hours, 3 hours, and 1 hour prior to chemotherapy for the every-

3-week regimen, and 8 mg orally given 1 hour prior to chemo-therapy for the weekly regimen. PSA response, defined as a 50% decline in PSA, was also superior in the docetaxel groups, with 45% in the 3-weekly regimen, 48% in the weekly regimen, and 32% in the mitoxantrone group.

SWOG 99162 randomized 770 men with mCRPC to a com-bination of docetaxel and estramustine or to mitoxantrone. The primary endpoint was met with an improvement in OS of 1.9 months favoring docetaxel.

Docetaxel 75 mg/m2 every 3 weeks is the FDA-approved dos-ing, and given that estramustine was associated with toxicity without clear additional efficacy, estramustine is rarely used to-day. An alternate docetaxel dosing regimen of 50 mg/m2 given every 14 days was evaluated in a randomized trial involving 361 patients.6 In this trial, 184 patients were randomized to docetaxel 75 mg/m2 every 3 weeks, and 170 patients were randomized to docetaxel 50 mg/m2 every 2 weeks. Both regimens were given in combination with oral prednisolone 10 mg daily. The primary endpoint was time to treatment failure (TTF). The TTF in the ev-ery-2-week regimen was 5.6 months compared with 4.9 months for the every-3-week regimen, with an HR of 1.3 for the 3-week arm (P = .014). OS was a secondary endpoint. Interestingly, the HR for OS was 1.4 (P = .021) for the 3-week group, indicating a worse survival for the standard FDA-approved schedule. There were also more adverse events (AEs) in the 3-weekly regimen in-cluding neutropenia (53% vs 36%) and neutropenic fever (14% vs 4%), and infection with neutropenia (24% vs 6%). This is another reasonable dosing schedule for patients designated to receive docetaxel, and we note that this is the only trial with a head-to-head comparison of 2-weekly versus 3-weekly docetaxel that demonstrates a survival advantage. Although the limitations of OS being a secondary endpoint are apparent, this trial demon-strates a provocative result, and the AE profile in the 2-weekly arm at 50 mg/m2 demonstrates clear tolerability. Docetaxel plays a key role in prostate cancer, but many patients die without hav-ing seen docetaxel, and thus many men will never benefit from this therapy.

Sipuleucel-T Sipuleucel-T is an immune-modulating agent best described as an autologous cellular immunotherapy generated after apher-esis of the patient’s own immune cells. The patient’s periph-eral blood mononuclear cells are treated with a prostatic acid phosphatase–granulocyte macrophage colony-stimulating factor (PAP-GM-CSF) fusion protein in addition to various other cy-tokines to generate the final product. The administered dose for the patient consists of a minimum of 50 × 106 CD54+ cells given intravenously. This treatment was FDA-approved in 2010 for use in patients with mCRPC, based in part on the results of the pivotal IMPACT study7 that randomized 512 men to ei-ther sipuleucel-T or placebo consisting of blood mononuclear


Changing LandsCape of MetastatiC prostate CanCer

Table 1. Phase III Trials With a Survival Benefit in mCRPC

Trial agent(FDa approval)

Intervention Overall Survival (months)

TAX 3271

Docetaxel(2004)

1006 men with mCRPCPrimary endpoint: OS

Docetaxel 75 mg/m2 every 3 weeks vsdocetaxel 30 mg/m2 weekly for 5 out of 6 weeks vs mitoxantrone 12 mg/m2 ev-ery 3 weeks and prednisone 5 mg twice daily to everyone

Docetaxel every 3 weeks: 18.9 months Docetaxel weekly: 17.4 monthsMitoxantrone:16.5 monthsDocetaxel every 3 weeks vs mitoxantrone: HR, 0.76; P = .009Docetaxel weekly vs mitoxantrone: HR, 0.91; P = .36

SWOG 99162

Docetaxel(2004)

770 men with mCRPCPrimary endpoint: OS

Docetaxel 60 mg/m2 every 3 weeks + estramustine 280 mg 3 times daily on days 1-5 vs mitoxantrone 12 mg/m2 every 3 weeks + prednisone 5 mg twice daily

Docetaxel: 17.5 months Mitoxantrone + prednisone: 15.6 monthsHR, 0.80; P = .02

IMPACT7

Sipuleucel-T(2010)

512 men with asymptomatic or mini-mally symptomatic mCRPC2:1 ramdomizationPrimary endpoint: OS

Sipuleucel-T given every 2 weeks for 3 doses vs placebo

Sipuleucel-T: 25.8 months Placebo: 21.7 monthsHR, 0.78; P = .03

TROPIC8

Cabazitaxel(2010)

755 men who progressed on or after docetaxelPrimary endpoint: OS

Cabazitaxel 25 mg/m2 every 3 weeks + prednisone 5 mg twice daily vs mitoxantrone 12 mg/m2 every 3 weeks + prednisone 5 mg twice daily

Cabazitaxel: 15.1 months Mitoxantrone: 12.7 monthsHR, 0.70; P <.0001

COU-AA-30110

Abiraterone(2011)

1195 men previously treated with docetaxel2:1 randomizationPrimary endpoint: OS

Abiraterone 1000 mg daily given on an empty stomach + prednisone 5 mg twice daily vsplacebo + prednisone 5 mg twice daily

Abiraterone: 14.8 monthsPlacebo: 10.9 months HR, 0.74; P <.001

COU-AA-30211

Abiraterone(2012)

1088 chemotherapy-naïve men with mCRPC1:1 randomizationPrimary endpoints: OS and radio-graphic PFS

Abiraterone 1000 mg daily given on an empty stomach + prednisone 5 mg twice daily vsplacebo + prednisone 5 mg twice daily

Abiraterone 34.7 monthsPlacebo: 30.3 monthsa

HR, 0.81; P <.0033Radiographic PFS:Abiraterone: 16.5 monthsPlacebo: 8.3 months HR, 0.53; P <.001

AFFIRM15

Enzalutamide(2012)

1199 men previously treated with docetaxel2:1 randomizationPrimary endpoint: OS

Enzalutamide 160 mg daily vs placebo Enzalutamide: 18.4 monthsPlacebo: 13.6 monthsHR, 0.63; P <.001

ALSYMPCA17

Radium-223(2013)

921 men with mCRPC with at least 2 bone metastases, no visceral metas-tasis, no lymph nodes >3 cm2:1 randomizationPrimary endpoint: OS

Radium-223 every 4 weeks for total of 6 doses + BSC vs placebo + BSC

Radium: 14.9 monthsPlacebo: 11.3 monthsHR, 0.70; P <.001

PREVAIL16

Enzalutamide(2014)

1717 asymptomatic or minimally symptomatic menChemotherapy-naïve No prior abiraterone or ketoconazole1:1 randomizationPrimary endpoints: OS and radio-graphic PFS

Enzalutamide 160 mg vs placebo Enzalutamide: 32.4 monthsPlacebo: 30.4 monthsHR, 0.70; P <.0112-month radiographic PFS:Enzalutamide: 65%Placebo: 14%HR, 0.19; P <.001

aFinal analysis. BSC indicates best standard of care; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival.



cells untreated with PAP-GM-CSF. The sipuleucel-T arm had a 4.1-month OS advantage compared with placebo. There was, however, no progression-free survival (PFS) advantage for the use of sipuleucel-T, with the median time to objective disease pro-gression of 3.7 months in the sipuleucel-T group and 3.6 months in the placebo group. There was similarly very little difference in the PSA response, with 2.6% in the sipuleucel-T group and 1.3% in the placebo group having at least a 50% reduction in PSA. A total of 65.2% of the patients had a grade 1 or 2 AE, most of which occurred within 1 day of the infusion. The most common AEs were chills, fever, headache, flu-like illness, myalgia, hyper-tension, hyperhidrosis, and groin pain (likely related to infusion catheter placement). Only 0.9% of patients were unable to get all 3 infusions as a result of infusion-related AEs.7

Sipuleucel-T has been relatively underutilized compared with initial projections, and only rarely does a patient respond to therapy. Underutilization may be due to the cumbersome nature of the administration, which requires 3 apheresis infusions in a month, the not-infrequent requirement for placement of an apheresis catheter, the low PSA response rate, or a combination of these and other factors. The exact reasons for low utilization of this agent is unclear.

CabazitaxelCabazitaxel is a tubulin-binding taxane that was FDA-approved in 2010 for the treatment of men with mCRPC who progressed on docetaxel. Its efficacy was evaluated in the TROPIC trial,8 in which 755 patients with mCRPC who progressed on or after docetaxel were randomized to either cabazitaxel or to mitoxan-trone. Both arms received prednisone 5 mg orally twice daily. The study met its primary endpoint of OS, with an improvement in median OS of 2.4 months. The most common toxicity was hematologic, with 82% of patients developing grade 3 or greater neutropenia and 8% developing febrile neutropenia. A total of 47% of patients developed diarrhea; 6% developed grade 3 or greater diarrhea. Grade 3 or greater peripheral neuropathy was reported in the cabazitaxel arm in 1% of patients, but 14% for all grades. Patients with grade 2 or greater peripheral neuropathy on entry were excluded from the study.8

Two trials are currently evaluating the use of cabazitaxel at 20 mg/m2 or 25 mg/m2. One of these trials utilizes this dosing schema in the post-docetaxel space (PROSELICA), and the oth-er does so in the chemotherapy-naïve population, with a con-trol group consisting of docetaxel every 3 weeks at 75 mg/m2 (FIRSTANA). As a result of the toxicities encountered with the 25-mg/m2 dosage and the fact that phase I studies suggested ei-ther a 20 mg/m2 or 25 mg/m2 dosing schema,9 the FDA required the sponsor to conduct these trials. In the TROPIC trial, de-spite the relatively high rate of febrile neutropenia, prophylactic granulocyte colony-stimulating factor (G-CSF) was not allowed in the first cycle.8 In the FDA-approved package insert, a black box warning states: “Neutropenic deaths have been reported.

Obtain frequent blood counts to monitor for neutropenia. Do not give JEVTANA if neutrophil counts are ≤1500 cells/mm3.” In addition, there is a statement that prophylactic G-CSF should be considered for patients with high-risk features (age >65 years, poor PS, previous episodes of febrile neutropenia, extensive pri-or radiation ports, poor nutritional status, or other serious co-morbidities) that predispose patients to increased complications from prolonged neutropenia. Cabazitaxel is now 1 of 4 drugs approved after conducting phase III studies in patients with pri-or docetaxel treatment. These drugs also include abiraterone, enzalutamide, and radium-223.

Cabazitaxel today is the only drug relegated to the post-docetaxel space, as abiraterone, radium-223, and enzalutamide do not require (from a regulatory perspective) prior chemothera-py treatments. The use of cabazitaxel may or may not be superi-or to docetaxel in the frontline CRPC setting. The FIRSTANA study will address this issue, and likely report top-line results in 2015.

AbirateroneAbiraterone is a very potent inhibitor of P450 c17 (CYP17), an enzyme that has 2 distinct activities: 17-20 lyase and 17-alpha hydroxylase. This enzymatic action is used in the conversion of pregnenolone and progesterone to 17-OH pregnenolone and 17-OH progesterone, and from there to dehydroepiandrosterone (DHEA) and androstenedione, which is the penultimate step in testosterone production. Abiraterone was approved by the FDA in 2011 for use in patients with mCRPC who have been previ-ously treated with docetaxel. In 2012, this indication was expand-ed to include patients who were chemotherapy-naïve.

Two pivotal, randomized phase III trials demonstrated im-provement in OS compared with placebo. In the COU-AA-301 trial,10 1195 patients previously treated with docetaxel were ran-domized to abiraterone plus prednisone or placebo plus predni-sone. The primary endpoint of OS was met with an improvement in OS of 3.9 months compared with placebo. All secondary end-points also favored abiraterone, with a PSA response rate of 29% vs 6%. The most common AE was fatigue, which was similar in both groups. There were more mineralocorticoid symptoms consisting of fluid retention in the abiraterone group, and more hypokalemia in the abiraterone group, although the majority of these side effects were grade 1 in nature.

In the COU-AA-302 trial,11 1088 chemotherapy-naïve pa-tients were randomized to abiraterone plus prednisone or to placebo plus prednisone. The primary endpoints were OS and radiographic PFS. There was an 8.2-month improvement in ra-diographic PFS favoring abiraterone. The OS in in the initial evaluation did not pass the prespecified value for the interim analysis; however, the final OS results reveal an improvement in OS of 4.4 months.12

Overall, this is a well-tolerated and effective medication. In both studies, the rate of discontinuation of the drug was about



20% in both the treatment and placebo arms. The initial COU-AA-302 trial was stopped at an interim analysis by the data mon-itoring committee (DMC), and at that time OS differences were not apparent between the arms. Only later did an OS difference emerge (which was a co-primary endpoint).

The dosing of abiraterone is subject to discussion by some. Consuming food can result in better absorption of abiraterone, and using smaller dosages could likely result in cost savings that are not currently being utilized.13 A single-institution retrospec-tive analysis by Leibowitz-Amit and colleagues14 compared low-dose abiraterone with food to full-dose abiraterone after fasting, and found no difference in OS or PSA response rate, except in chemotherapy-naïve patients, where there was a trend to reduced PSA response rate in the lower-dose group. Considerable cost savings with respect to abiraterone could be obtained with ei-ther dose reduction or a generic drug. Patent protection may expire within the next several years. Should this occur, there are considerable implications for the mCRPC space, particularly with drugs that are currently priced far in excess of a generic abiraterone price.

EnzalutamideEnzalutamide is an androgen receptor (AR) antagonist with a strong antagonist effect in binding the AR. This antagonism in-hibits the DNA binding of the AR, and thereby inhibits cofac-tor recruitment that otherwise would have significant effects on transcription. Enzalutamide received FDA approval in 2012 for the treatment of patients with mCRPC who had been previous-ly treated with a docetaxel-containing chemotherapy regimen; in 2014, this approval was extended to patients who were che-motherapy-naïve. Two large phase III trials have demonstrated the efficacy of enzalutamide in the treatment of patients with mCRPC.

In the AFFIRM trial,15 1199 patients who were previously treated with a docetaxel-containing chemotherapy regimen were randomized to enzalutamide or placebo. The primary endpoint of OS was met with an improvement in OS of 4.8 months favor-ing enzalutamide. There was also improvement in the second-ary endpoints of radiographic PFS (8.3 months vs 2.9 months; HR, 0.40; P <.001) and the time to the first skeletal-related event (SRE; 16.7 months vs 13.3 months; HR, 0.69; P <.001).

In the PREVAIL trial,16 1717 patients with asymptomatic or minimally symptomatic mCRPC who had not received che-motherapy, abiraterone, or ketoconazole were randomized to enzalutamide or placebo. The 2 primary endpoints were radio-graphic PFS and OS. The median radiographic PFS had not been reached in the enzalutamide group and was 3.9 months in the placebo group, with an HR of 0.19 (P <.001). At 12 months, the radiographic PFS was 65% in the enzalutamide group versus 14% in the placebo group. The median OS was estimated at 32.4 months in the enzalutamide arm and 30 months in the placebo

group, with an HR of 0.71 (P <.001). The most common AEs in both trials were fatigue, hot flash-

es, and headache. In the AFFIRM trial, there were 5 seizures in the enzalutamide arm and none in the placebo arm. This has resulted in a warning against the use of enzalutamide in patients with a history of seizures. In the PREVAIL trial, only 1 seizure was noted in each arm; patients with a history of seizure or a condition that could confer a predisposition to seizure were spe-cifically excluded.

Though generally well tolerated, some patients have experi-enced substantial fatigue. Given that many men currently receiv-ing enzalutamide are in the pre-docetaxel space and are otherwise asymptomatic, drug-induced fatigue may be the only symptom in some patients receiving this drug. No prospective trials have been conducted head to head against abiraterone/prednisone to date. The price is considered high by many, and many countries cannot afford to use this new drug. This is an issue common to all of the new life-prolonging agents.

Radium-223Radium-223 is a bone-targeted, alpha-emitting radiopharmaceu-tical that was FDA-approved in 2013 for the treatment of pa-tients with mCRPC. Radium (Ra), like calcium (Ca), strontium (Sr), and barium (Ba), is an alkaline earth metal in the periodic table of the elements, which, as a family, localize to areas of os-teoblastic metastasis. The FDA approval came from the results of ALSYMPCA,17 a phase III trial in which 921 patients received radium-223 or placebo, and all patients received SOC. SOC was confined to nonchemotherapeutics and older hormonal therapies such as flutamide, bicalutamide, and dexamethasone. Enzalutamide and abiraterone were not yet approved when the phase III study was performed. Patients received a total of 6 in-jections, each of which was administered at 4-week intervals at a dosage of 50kBq/kg. The becquerel (Bq) is an SI unit for radioac-tivity defined as the activity of a quantity of radioactive material in which 1 nucleus decays per second.

The primary endpoint was OS, with secondary endpoints in-cluding time to first symptomatic skeletal event (SSE). No radio-graphic monitoring was proscribed as a part of the trial. The pa-tients included in the trial had to have mCRPC, at least 2 bone metastases as detected on bone scan, no visceral metastasis, and no lymph nodes in excess of 3 cm. Patients must also have had symptomatic disease, as defined as regular use of any analgesic medications or radiation therapy for bone pain in the preceding 12 weeks; 55% of the patients were taking opioids for palliation of pain. Patients were required to have docetaxel pretreatment, refuse docetaxel, be considered unfit for docetaxel, or not have docetaxel available.17

The trial met both its primary and secondary endpoints at an interim analysis, and the trial was stopped by the DMC as a con-sequence of the prespecified statistical analysis plan. There was



an OS advantage of 3.6 months (14.9 months for radium-223 and 11.3 months for placebo), with an HR of 0.70 (P <.001). Time to first SSE was 15.6 months for radium-223 and 9.8 months for placebo, giving an almost 6-month advantage with an HR of 0.66 (P <.001).17 However, the analysis was not performed with an endpoint of SSE or death, which are preferred by the FDA.

There were fewer total AEs in the radium-223 arm (93%) compared with the placebo arm (96%), including fewer people stopping the medication as a result of an AE (16% vs 21%). There were more thrombocytopenia and neutropenia in the ra-dium-223 arm. However, a subgroup analysis of disease burden revealed that patients with fewer than 6 lesions on bone scan did not do better than the placebo group, with an HR for OS of 0.95 (95% CI, 0.46-1.95), while patients with 6 to 20 lesions had an HR for OS of 0.71 (95% CI, 0.54-0.92), and those with >20 lesions had an HR for OS of 0.64 (95% CI, 0.47-0.88).17

There is not a large PSA response in patients treated with radi-um-223, as seen in only 14% of patients in the radium-223 group who had a 30% or greater reduction in PSA 4 weeks after the last injection compared with 4% in the placebo arm. The time to PSA rise was statistically significant (P <.001), but clinically not significant: 3.6 months in the radium-223 arm and 3.4 months in the placebo arm. Of note, in the subset analysis looking at pre-vious docetaxel exposure, the HR for OS in chemotherapy-naïve patients was 0.74 (95% CI, 0.56-0.99) and the HR for chemo-therapy-experienced patients was 0.71 (95% CI, 0.56-0.89). In neither case did the 95% CIs overlap 1.0.17 The FDA approved radium-223 without regard to prior docetaxel use.

Controversies in current radium-223 use include the fact that those individuals with no prior docetaxel use had refused docetaxel or were considered unfit for it. These data were not captured in the ALSYMPCA case report form, and some investi-gators have contended that radium-223 use in the pre-docetaxel space is controversial. Although there are limited data to sug-gest that docetaxel post-radium-223 is safe, no prospective trials have demonstrated this to be the case. There is also the ques-tion of safety/efficacy when radium-223 is used in combination with abiraterone or enzalutamide. Initial reports18 indicate no safety concerns, but the question of efficacy awaits prospective randomized trials. Considering exactly how radium-223 fits into the current treatment paradigm is controversial, and no radio-pharmaceutical has achieved widespread use. Administration of radium-223 is restricted to nuclear medicine physicians and se-lected properly licensed radiation oncologists. These physicians are referral specialists, and rarely do they make treatment deci-sions in the complex current mCRPC landscape.

DenosumabMen on long-term ADT are at increased risk for SREs, which are typically defined as pathologic fracture, need for radiation or sur-gery to bone, and spinal cord compression. The use of zoledronic

acid given monthly at a dosage of 4 mg IV has been shown to reduce the rate of developing SREs by 25%; however, the treat-ment had no effect on OS.19 Denosumab is a monoclonal anti-body that binds to RANKL, which is a mediator of osteoclast formation. In a subsequent randomized trial, 1904 men were randomized to either denosumab 120 mg monthly or zoledronic acid 4 mg every 3 weeks.20 The primary endpoint was the time to first on-study SRE, which was assessed for noninferiority and for superiority as a secondary endpoint. Denosumab demonstrated a benefit of 20.7 months compared with 17.1 months for zole-dronic acid (HR, 0.82; P = .0002 for noninferiority and P = .008 for superiority). Any AE was similar in both groups, but there were more grade 3-4 AEs in the denosumab arm (66% vs 72%; P = .01). More hypocalcemia was seen in the denosumab arm (6% vs 13%; P <.0001). The rate of osteonecrosis of the jaw (ONJ) was similar in both groups.20 That said, it was not clear that denos-umab would add additional value to the use of newer agents such as radium-223, enzalutamide, or abiraterone. In each case, these agents have independently been shown to reduce rates of SREs.

In patients with nonmetastatic CRPC, denosumab was shown to slightly delay the development of metastatic bone disease. In a large phase III trial, 1432 patients were randomized 1:1 to ei-ther denosumab 120 mg every 4 weeks or placebo.21 Bone me-tastasis-free survival was greater in the denosumab group, with a median duration of 29.5 months versus 25.2 months for placebo (HR, 0.85; P = .028). There was no survival advantage, howev-er, with a median OS of 43.9 months for denosumab and 44.8 months for placebo (HR, 1.01; P = .91). The only difference in AEs was in ONJ, which occurred in 5% of patients taking de-nosumab versus none in the placebo group, and hypocalcemia, which occurred in 2% in the denosumab arm versus less than 1% in the placebo group. The FDA reviewed this trial and did not issue a label for this indication. Thus, denosumab in the nonmetastatic disease setting is not considered to be SOC.

It is not completely clear how much an agent such as denos-umab will contribute if patients are under treatment with newer agents such as abiraterone or enzalutamide. Denosumab does not prolong survival. Trials have not addressed this question.

Sequencing of Agents in mCRPCThe past 5 years have witnessed an explosion of new therapies in the treatment of mCRPC, with 5 new agents gaining FDA ap-proval for an improvement in OS. While exciting and certainly good for patients, these approvals have generated much discus-sion and debate about what the best agent is and when it should be used. As docetaxel was first approved in 2004, and it took 6 years for another agent to demonstrate that it improved OS, it was certainly natural that the next step was to look for an agent that could be used when docetaxel fails. This set up the schema of the post-docetaxel and pre-docetaxel spaces, although now this segmentation into pre- and post-docetaxel is blurring as 3 agents



(radium-223, abiraterone, and enzalutamide) have now shown a survival benefit both prior to chemotherapy and after docetaxel.

No one sequence can be endorsed over any other at this time. Trials will never address all of the alternatives, nor should they, given the huge number of potential options. It is not clear how long the field will remain in a sequencing paradigm, and the need for evidence for combination therapies and better patient selection seem to be higher priorities. Treating patients with mul-tiple agents seems intuitively correct, but the data are not present to support a strong view.

Cross-ResistanceWith the use of single agents in sequence, evidence is emerging that cross-resistance can be conferred by one agent to the next, and that responses may diminish after the use of multiple thera-pies. Although formal studies are lacking, the retrospective data with abiraterone and enzalutamide in sequence are compelling. With enzalutamide, for example, we see a PSA response rate of 78% in the pre-docetaxel setting and a response rate of 54% in the post-docetaxel setting, whereas retrospective studies have shown a response rate of 23% to 39% post-docetaxel, post-abi-raterone.22-24 This is similar to the response rate of 62% seen with abiraterone in the pre-docetaxel setting and a PSA response rate of 38% (29% confirmed) in the post-docetaxel setting. Ret-rospective studies have shown a response rate for abiraterone of 3% to 8% in the post-docetaxel, post-enzalutamide setting25-26 and of 17% in the post-docetaxel, post-cabazitaxel setting.27 Tak-en together, there is clear evidence for cross-resistance between enzalutamide and abiraterone when these drugs are used sequen-tially.

Optimizing Patient SelectionNone of these newer agents have been compared with one anoth-er; the newer therapies to date are compared with placebo, pred-nisone, mitoxantrone, or best SoC. No level 1 evidence will be available for treatment choices until there are head-to-head trials. Until then, clinicians will speculate and discuss, but no one will truly know what course of action might be best for a patient. Pre-dictive biomarkers would be tremendously helpful in this regard, though none are currently accepted in general clinical practice.

Currently, the evaluation for the initial treatment of mCRPC focuses on 2 aspects. The first is the disease, and the import-ant issues here include: the pace of the disease (PSA doubling time); the location of the disease (visceral involvement, bone involvement); the burden of disease (larger vs smaller extent of metastasis); and degree of symptomatology. The second evalua-tion regards the patient, which includes the patient’s PS, various laboratories related to organ/marrow function, willingness to undergo chemotherapy, and willingness or ability to tolerate the financial toxicity associated with some of the treatments.

In a patient with no visceral disease and a relatively slowly ris-ing PSA and who is asymptomatic or minimally symptomatic, ini-

tial therapy with sipuleucel-T is reasonable. Thus, both low pace and low burden of disease might be considered in the treatment selection. The therapy can be given in 4 weeks’ time, and then the patient can move to other therapies. Two phase II studies are evaluating the use of sipuleucel-T and either abiraterone or en-zalutamide in combination or in sequence.28-29 Both abiraterone and enzalutamide appear to be safe when given simultaneously, but whether efficacy will be affected has yet to be determined.

If a patient has bone-only disease and is symptomatic, radi-um-223 is a reasonable approach. The benefit for radium-223 was best appreciated in patients with 6 or more metastatic bone lesions. A patient with a single bone lesion may or may not achieve maximum benefit from radium-223. In clinical trials, only 16% of patients had a 30% decline in PSA, so the tempo of the disease is also important to consider. Unlike sipuleucel-T, a full course of radium-223 is given over 6 months, so it is critical to select patients whose disease will allow a 6-month “runway” to complete the therapy. Two phase III trials are currently under way evaluating the combination of radium-223 with abiraterone and enzalutamide (Table 2).

The other special case would be the situation in which a pa-tient has visceral involvement. Here, the level 1 evidence would support enzalutamide or docetaxel. The COU-302 trial excluded patients with visceral involvement, so abiraterone has not been

Table 2. Selected Trials in mCRPC

Study Intervention Control arm Patient Population

Tasquinimod Placebo mCRPC

Ipilimumab Placebo Chemo-naïve mCRPC

ODM201 Placebo Non-metastatic CRPC

Galeterone Enzalutamide AR-V7 positive mCRPC

Enzalutamide Placebo Non-metastatic CRPC

ARN-509 Placebo Non-metastatic CRPC

DCVAC + chemotherapy

Placebo + chemo-therapy

mCRPC

Enzalutamide + abiraterone + prednisone

Abiraterone + prednisone

Chemo-naïve mCRPC

JNJ-56021927 + abiraterone + prednisone

Abiraterone + prednisone

Chemo-naïve mCRPC

Abiraterone + prednisone + radium-223

Abiraterone + prednisone + placebo

Chemo-naïve mCRPC

Radium-223 + abiraterone or enzalutamide

Radium-223 + standard of care

Chemo-naïve mCRPC

Chemo indicates chemotherapy; mCRPC, metastatic castration-resistant prostate cancer.



formally tested in the pre-docetaxel setting with visceral disease. However, clear evidence of activity for abiraterone in patients with visceral disease is seen in the post-docetaxel space.

Selected Potential Predictive Biomarkers Resistance to abiraterone and enzalutamide was reported as a result of a variant of the AR, specifically the isoform encoded by the AR splice variant 7 (AR-V7).30 This transcript encodes for a cryptic exon associated with a premature stop codon, thereby de-leting the C-terminal portion of the AR. This truncated AR can serve as a ligand-independent transcription factor, and is capable of stimulating expression of a series of genes associated with cellu-lar proliferation. Table 3 lists predictive biomarkers. Antonarakis et al30 evaluated the impact of this variant on resistance to newer hormonal therapy. The study used an assay that utilized circulat-ing tumor cells (CTCs) isolated by immunomagnetic beads and a RT-PCR assay specifically designed to detect AR-V7 mRNA.Of the 62 patients evaluated, 31 received enzalutamide and 31 received abiraterone. A total of 39% of the enzalutamide-treat-ed patients and 19% of the abiraterone-treated patients had de-tectable AR-V7. In the patients receiving enzalutamide, the PSA response rate among the AR-V7-positive patients was 0% versus 53% among AR-V7-negative patients. In the patients receiving abiraterone, the PSA response rate among the AR-V7-positive pa-tients was 0% versus 68% in the AR-V7-negative population. In a follow-up study separately reported, Antonarakis et al31 evalu-ated taxane-treated patients who were prospectively enrolled and evaluated for the AR-V7 isoform via CTCs. The PSA response in both AR-V7-negative and -positive patients was not statistical-ly significant, nor was the median PFS.31 Taken together, these studies indicate that the AR-V7 mutation induces resistance to enzalutamide and abiraterone, but not to chemotherapy with docetaxel.

Cell-free DNA collected from peripheral blood is an area of active investigation. Azad et al32 collected tumor cell-free DNA

from the serum of 53 patients who were starting therapy with enzalutamide. They showed that having AR amplification/gain was more common in patients progressing on enzalutamide com-pared with abiraterone or other agents (53% vs 17% vs 21%, respectively; P = .02). In addition, patients who also had an AR copy number gain and/or an exon 8 mutation had a lower re-sponse rate to enzalutamide (P = .013) and had a shorter median PFS (4.6 months vs 2.3 months; P = .01). These data suggest that cell-free DNA may serve as a predictive biomarker for patients with mCRPC being treated with enzalutamide.

An AR-V7 detection methodology that uses a monoclonal an-tibody to a unique AR-V7 epitope was presented at the 2015 an-nual meeting of the American Association for Cancer Research.33 The methodology utilized this antibody in CTCs evaluated by the Epic Sciences CTC detection platform. The expression of V7 was associated with a high rate of resistance to new hormonal agents, but some docetaxel-treated patients responded.

Another recent report yet to appear in peer-reviewed format involves AR-V7 detection using RNA isolation followed by RT-PCR without CTC isolation.34 Such an assay has obvious advan-tages in that it avoids the CTC isolation step, which can compli-cate assessments and requires immunomagnetic cell-based CTC assays. Preliminary work suggests that patients resistant to new-er-generation hormonal agents commonly express AR-V7, but prospective assessments on these assays have yet to be performed.

Olaparib acts as an inhibitor of the enzyme poly(ADP-ribose) polymerase (PARP), which functions as a DNA repair enzyme. It is currently FDA-approved for the treatment of patients with BRCA-positive, advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. The TOPARP study35 evaluated the efficacy of olaparib in 50 patients with mCRPC who had failed previous docetaxel therapy. In this study, present-ed only in abstract form, 96% had also received abiraterone and 58% received cabazitaxel. Of the 49 evaluable patients, 16 had a response to the olaparib therapy, defined as a greater than 50%

decline in PSA. The investigators then performed DNA sequencing of the patients’ tumors to identify a possible genetic biomarker. Mu-tations in DNA repair genes were found in 15 of the 49 evaluable pa-tients (30.6%) enrolled in the study. Of the 15 patients with mutations, 13 of them responded to olaparib, with 7 of 7 patients with a BRCA2 mutation responding to olaparib. DNA-repair defects may be a pow-erful biomarker for olaparib action, and these defects may be more com-mon than previously appreciated in patients with mCRPC. A larger trial is now being planned.

Table 3. Predictive Biomarkers in Experimental Use

assay Tissue Source

Material Substrate Methods Therapeuticagent(s)

Prediction

AR-V732 Blood CTCs RNA RT-PCR AbirateroneEnzalutamide

Resistance

AR-V733 Blood CTCs Protein Antibody AbirateroneEnzalutamide

Resistance

AR-V734 Blood Mononuclear cells

RNA RT-PCR AbirateroneEnzalutamide

Resistance

DNA repair genes35

Tumor Tumor DNA DNA sequencing

Olaparib Sensitivity

AR-V7 indicates androgen receptor splice variant 7; CTCs, circulating tumor cells; RT-PCR, reverse transcription and polymerase chain reaction.



Selected New AgentsThere are now myriad options for the treatment of patients with mCRPC, and more are being studied (Table 2). ARN509 is an AR inhibitor; galeterone is an AR inhibitor that also has activ-ity as an inhibitor of CYP17 and downregulates AR variants in preclinical studies. PROSTVAC-VF/TRICOM and DCVAC/PCa are vaccine therapies in clinical trials. ODM201 is an AR inhibitor, and tasquinimod is a small-molecule inhibitor that al-ters the tumor microenvironment. Ipilimumab, FDA-approved for melanoma, is also being tested in advanced prostate cancer.

SynopsisRight now, there is the enviable problem of having many ther-apies available to our patients, but a lack of level 1 evidence comparing these new agents to one another. In the future, com-mercial assays for predictive biomarkers will likely be available to help guide therapeutic decisions (much like cetuximab for KRAS wild-type colon cancer or erlotinib for EGFR-positive non-small cell lung cancer). Imatinib was FDA-approved for Bcr-Abl-trans-located leukemia in 2001, marking the beginning of personalized cancer therapy. Now 14 years after that milestone, progress in the area of personalized prostate cancer therapy is being made, but much more progress is needed before the survival curves bend in a more meaningful manner.

Affiliations: Brian Lewis, MD, MPH, is assistant professor of Clinical Medicine, and Oliver Sartor, MD, is Laborde Professor for Cancer Research, Departments of Medicine and Urology, Tu-lane University School of Medicine, New Orleans, LA.Disclosures: Dr Lewis reports no relevant financial conflicts of interest to disclose. Dr Sartor has been a consultant or advisory board member for Bayer, Algeta, Sanofi, Bellicum Pharmaceuti-cals, and Dendreon; he has received grant support from Bayer, Sanofi, Janssen, and Dendreon.Address correspondence to: Oliver Sartor, MD, Box SL-42, 1430 Tulane Ave, New Orleans, LA 70112. Phone: 504-355-7970; fax: 504-988-1813; email: [email protected].

REfERENCES1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus pred-nisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512.2. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and es-tramustine compared with mitoxantrone and prednisone for ad-vanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520.3. Sweeney C, Chen Y, Carducci M, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol.

2014;32:5s(suppl; abstr LBA2).4. Gravis G1, Fizazi K, Joly F, et al. Androgen-deprivation ther-apy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomized, open-label, phase 3 trial. Lancet Oncol. 2013;14(2):149-158.5. Medical Press. Adding chemotherapy to standard prostate can-cer treatment may extend life expectancy. http://medicalxpress.com/news/2015-05-adding-chemotherapy-standard-prostate-can-cer.html. Accessed May 14, 2015.6. Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, et al. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomized, phase 3 trial. Lancet Oncol. 2013;14(2):117-124.7. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immu-notherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.8. De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a random-ized open-label trial. Lancet. 2010;376:1147-1154.9. Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and phar-macokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15:723-730. 10. De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.11. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in met-astatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-148.12. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemothera-py-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomized, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152-160.13. Ryan C, Rosenberg J, Lin A, et al. Effect of concomitant food intake on pharmacokinetics of abiraterone acetate, a 17 α hy-droxylase C17,20-lyase inhibitor in castration-resistant prostate cancer (CRPC). Presented at: AACR-NCI-EORTC International Conference; October 22-26, 2007; San Francisco, CA. Abstract C214. Leibowitz-Amit R, Atenafu E, Seah J, et al. Low-dose abi-raterone (abi) with food in men with metastatic castration-resis-tant prostate cancer (mCRPC): the Princess Margaret Cancer Centre experience. J Clin Oncol. 2014;32(suppl 5s; abstr 5077).15. Scher HI, Fizazi K, Saad F, et al. Increased survival with en-zalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 16. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med.



2014;371:424-433.17. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radi-um-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-223.18. Dan TD, Eldredge-Hindy HB, Hoffman-Censits J, et al. He-matologic toxicity of concurrent administration of radium-223 and next-generation antiandrogen therapies [published online February 25, 2015]. Am J Clin Oncol.19. Saad F, Gleason DM, Murray R, et al. A randomized, pla-cebo-controlled trial of zoledronic acid in patients with hor-mone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.20. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. Lancet. 2011;377:813-822.21. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomized, placebo-con-trolled trial. Lancet. 2012;379:39-46.22. Thomson D, Charnley N, Parikhet O. Enzalutamide after failure of docetaxel and abiraterone in metastatic castrate resis-tant prostate cancer: results from an expanded access program. J Clin Oncol. 2014;32(suppl 4; abstr 188).23. Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalut-amide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65:30-36.24. Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer pretreated with docetaxel and abiraterone. Eur J Cancer. 2014;50:78-84. 25. Loriot Y, Bianchini D, Ileana E, et al. Antitumor activity of abiraterone acetate against metastatic castration-resistant pros-tate cancer prgressing after docetaxel and enzalutamide. Ann Oncol. 2013;24:1807-1812.26. Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24:1802-1807.27. Wissing MD, Coenen JL, Van den Berg P, et al. CAST: a retrospective analysis of cabazitaxel and abi-raterone acetate sequential treatment in patients with met-astatic castrate-resistant prostate cancer previously treat-ed with docetaxel. Int J Cancer. 2015;136:E760-E762. 28. Petrylak D, Quinn DI, Dreicer R, et al. 774P - STRIDE, a randomized, phase 2, open-label study of sipuleucel-T with con-current vs sequential enzalutamide in metastatic castration-re-sistant prostate cancer (mCRPC). Ann Oncol. 2014;25(sup-pl_4):iv255-iv279. doi:10.1093/annonc/mdu336.29. Small E, Lance R, Redfernet C, et al. A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone

acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2013;31(suppl; abstr 5047).30. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028-1038.31. Antonarakis ES, Lu C, Chen Y, et al. AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-re-sistant prostate cancer (mCRPC). J Clin Oncol. 2015;33(suppl 7; abstr 138).32. Azad A, Wyatt A, Volik S, et al. Genomic analysis of cir-culating cell-free DNA (cfDNA) to investigate mechanisms of resistance to enzalutamide (ENZ) in metastatic castration-re-sistant prostate cancer (mCRPC) patients (pts). J Clin Oncol. 2015;33(suppl 7; abstr 157).33. Kelvin J, Lu D, Packer D, et al. Single cell analysis of AR N terminal, AR C terminal and the ARV7 splice variant in the CTCs of metastatic castration-resistant prostate cancer (mCRPC) patients. Presented at: 106th Annual Meeting of the American Association for Cancer Research; April 18-22, 2015; Philadel-phia, PA. Abstract 1588. 34. Liu X, Ledet E, Qi Y, et al. A novel blood-based assay for detecting androgen receptor splice variants in patients with ad-vanced prostate cancer. Presented at: 21st Annual PCF Scientific Retreat; October 23-25, 2014; Carlsbad, CA. 35. Mateo1 J, Sandhu1 S, Miranda S, et al. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration-resistant prostate can-cer. Presented at: 106th Annual Meeting of the American Associ-ation for Cancer Research; April 18-22, 2015; Philadelphia, PA. Abstract CT322.


· NSCLC ·

PD-(L)1 Inhibitors and CTLA-4 Inhibitors: Rationale for Combinations and Recent Data

in Non-Small Cell Lung Cancer

Rebecca S. Heist, MD, MPH

IntroductionWhile lung cancer historically has not been thought of as being susceptible to immunomodulation, the recent success of PD-1 and PD-L1 checkpoint inhibitors in non-small cell lung cancer (NSCLC) has overturned the conventional wisdom. The FDA recently approved nivolumab for the treatment of squamous NSCLC, based on the results of Checkmate-063 and Check-mate-017. Checkmate-063 was a multicenter phase II study of nivolumab in patients with squamous cell lung cancer; of 117 patients, 17 (14.5%) had an objective response and 30 (26%) had stable disease (SD).1 Checkmate-017 was a phase III trial com-paring nivolumab with docetaxel in previously treated squamous lung cancer; this study showed an overall survival (OS) benefit of 9.2 versus 6.0 months in favor of nivolumab.2 With the report of a survival benefit in the similarly designed Checkmate-057 trial, a phase III trial of nivolumab versus docetaxel in nonsquamous lung cancer,3 we can expect that this approval will likely be broad-ened in the near future to encompass nonsquamous NSCLC, as well. While nivolumab is the first PD-1 inhibitor to gain FDA approval for NSCLC, multiple other PD-1 and PD-L1 inhibitors are in development.4,5 Although no head-to-head comparisons exist, in early-phase trials the response rates of these agents have been broadly similar, suggesting a similar range of single-agent activity in this class of drugs.

Multiple ongoing studies are investigating the question of whether one of the following 3 immunotherapy combinations can yield additional benefit: (1) immunotherapies combined with each other; (2) immunotherapy combined with targeted therapy; or (3) immunotherapy combined with chemotherapy. The rationale for combining therapies is perhaps best illustrated by the cancer-immunity cycle proposed by Chen and Mellman.6 This cycle details the series of cyclical steps needed for an an-ticancer immune response to lead to effective killing of cancer cells. These steps include: the release of cancer cell antigens; antigen presentation by dendritic cells and antigen-presenting cells; priming and activation of T-cell responses against the can-cer-specific antigens; trafficking of T cells to tumors; infiltration of T cells into tumors; recognition of cancer cells by T cells; and, finally, killing of the cancer cells, which then leads to further release of antigens and continues the cycle.6

Combining agents that target different parts of this cycle may lead to synergistic effects. CTLA-4 and PD-1/PD-L1 inhibitors act at different parts of this cycle, CTLA-4 primarily at the level of T-cell activation and PD-1/PD-L1 at the level of the tumor microenvironment; this, therefore, is the rationale for combin-ing these different checkpoints.7 Conventional chemotherapy and targeted therapies can result in tumor regression and trig-ger immunogenic cancer cell death, and immune checkpoint blockade can consolidate this response by inducing long-lasting, immune-mediated tumor control.8 The ways in which chemo-therapies and targeted therapies may affect the immune system are varied and complex in their interactions. Some therapies may elicit immunogenic tumor cell death, which results in specific signals that trigger activation of antitumor immune responses.9-11 Other therapies may stimulate the immune system in a variety of ways, by modulating the interplay of immunosuppressive and immunostimulatory effector cells.8-12

Potential immunomodulatory effects of targeted therapies and chemotherapies include attenuating the activity of specific im-mune cell populations that restrain cytotoxic T cells, augmenting tumor antigen presentation by dendritic cells, enhancing prim-ing and activation of tumor-specific T cells, and sensitizing tumor cells to immune-mediated destruction.8-12 For example, paclitaxel

Abstract

The recent success of PD-1 and PD-L1 inhibitors in the

treatment of non-small cell lung cancer (NSCLC) has

opened a new era of immunotherapy for lung cancer.

Combinatorial strategies are increasingly being pursued,

with many trials investigating combinations of check-

point inhibitors with other immunomodulatory agents,

targeted therapies, and chemotherapies. This review de-

scribes recent and emerging data regarding combinatori-

al strategies in NSCLC.

Key words: lung cancer, immune therapy, combination

strategies


· NSCLC ·

and gemcitabine may enhance T-cell activation, and taxanes may modulate dendritic cells.8 Bevacizumab may increase priming to T cells by stimulating dendritic cell maturation and inhibition of myeloid-derived suppressor cells (MDSCs).8,12 EGFR activation has been shown to lead to an immunosuppressive environment, including upregulation of PD-L1 expression, and mice with EGFR-mutated tumors treated with a PD-1 inhibitor had decreas-es in tumor volumes and increased survival.13 However, prelimi-nary data from the phase III trial of nivolumab versus docetaxel in a limited number of patients with EGFR mutation-positive tumors did not suggest an OS benefit from nivolumab when compared with docetaxel (hazard ratio [HR], 1.18),3 and the best strategy for treating patients with EGFR mutations with immu-notherapy remains an ongoing question under active investiga-tion.

It is also becoming increasingly clear that different tumors display different immunophenotypes. Patients with a T-cell in-flamed tumor microenvironment with robust, spontaneous, an-titumor T-cell response and patients with a noninflamed tumor microenvironment and minimal spontaneous antitumor T-cell

response likely will require different strategies for optimal re-sponsiveness to immunotherapy.14 Interventions that can induce immune inflammation at the tumor site likely will be required to convert those with a noninflamed phenotype into an inflamed phenotype.14 Indeed, combinatorial strategies may be required in order to yield best responses in this setting. How best to combine chemotherapy, targeted therapy, and immunotherapy remains an ongoing area of active investigation, and multiple clinical tri-als are testing these concepts in patients.

Clinical Experience: Immunotherapy and ChemotherapyAn early signal of possible effectiveness of combining chemo-therapy with immunotherapy came from a randomized phase II study of ipilimumab and chemotherapy. Patients with previously untreated NSCLC were treated with carboplatin and paclitaxel with placebo, concurrent ipilimumab (4 doses of ipilimumab plus chemotherapy, followed by 2 doses of placebo plus chemo-therapy), or phased ipilimumab (2 doses of chemotherapy plus placebo, followed by 4 doses of ipilimumab plus chemothera-py).15 The phased-ipilimumab group had improved immune-re-lated progression-free survival (irPFS) and PFS compared with the control group, with a median irPFS of 5.7 months for the phased group versus 4.6 months for the control group, and a me-dian PFS of 5.1 months for the phased group versus 4.2 months for the control group.

Multiple ongoing studies are now investigating the combina-tion of the PD-1/PD-L1 checkpoint inhibitors with chemother-apy in the first-line setting in NSCLC. It should be noted that reported results are all preliminary and in abstract form, so no definitive data or conclusions are possible. However, in the ag-gregate they do show the feasibility of this approach, and further study is warranted.

Antonia et al16 reported on the experience with nivolumab combined with chemotherapy at the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO). Patients received nivolumab with cisplatin/gemcitabine, cisplatin/peme-trexed, or carboplatin/paclitaxel. In this preliminary report, response rates ranged from 33% to 47% in the various combi-nation arms. Treatment-related, grade 3-4 adverse events (AEs) were reported in 45% of patients, with the most common being pneumonitis (n = 4, 7%), renal failure (n = 3, 5%), and fatigue (n = 3, 5%).

Liu et al17 reported data at ASCO 2015 on the combination of atezolizumab (MPDL3280A) with carboplatin/paclitaxel (arm C), carboplatin/pemetrexed (arm D), or carboplatin/nab-pa-clitaxel (arm E). Among 37 safety-evaluable patients, the most common treatment-related, grade 3-4 AEs included anemia, neu-tropenia, and thrombocytopenia; no pneumonitis was seen. The overall response rate (ORR) in 30 evaluable patients was 67%: 60% in arm C (95% CI, 15%-95%), including 3 partial respons-es [PRs]; 75% in arm D (95% CI, 43%-95%), including 9 PRs;

Table. Selected Ongoing Combinatorial Trials With Immunotherapy in NSCLC

agent Combination Phase

MPDL3280A Bevacizumab Carboplatin/pemetrexed Carboplatin/paclitaxel Carboplatin/nab-paclitaxel

Ib

Cobimetinib Ib

Erlotinib Ib

Ipilimumab Ib

MEDI4736 Tremelimumab Ib

Gefitinib AZD9291Selumetinib Tremelimumab

IIa

Nivolumab Cisplatin/gemcitabine Cisplatin/pemetrexed Carboplatin/paclitaxel Ipililumab Erlotinib Bevacizumab

Ib

Lirilumab anti-KIR Ib

BMS-986016 anti-LAG3 Ib

Pembrolizumab Carboplatin/paclitaxel +/- bevacizumab Carboplatin/pemetrexed Ipililumab Erlotinib Gefitinib

I/II


PD-(L)1 anD CTLa-4 InhIbITors

and 62% in arm E (95%CI, 32%-86%), including 5 PRs and 3 complete responses (CRs). Responses were seen independent of PD-L1 expression.

Papadimitrakopoulou et al18 reported data on the combina-tion of pembrolizumab and chemotherapy (carboplatin/pacli-taxel [cohort A] or carboplatin/pemetrexed [cohort C]) at ASCO 2015, with results from 49 patients reported. The treatment-re-lated, grade 3-4 AE rate was 32% to 38%. Potentially immune-re-lated AEs were reported in 2 patients (8%) in cohort A (grade 3 rash and grade 2 colitis), and 4 patients (17%) in cohort C (grade 3 colitis, grade 2 hypothyroidism, and grade 1 colitis and hyperthyroidism). The preliminary response rate was 28% for the combination with carboplatin/paclitaxel and 58% for the combination with carboplatin/pemetrexed.

In general, these studies as reported thus far have shown the feasibility of combining chemotherapy with immunotherapy, with some intriguing signals of efficacy and potentially durable responses.

Clinical Experience: Combining Checkpoint Inhibitors The fact that CTLA-4 inhibitors and PD-1/PD-L1 inhibitors act at different points in the cancer immunity cycle highlights the logic of combining these checkpoint inhibitors in the hope of achieving a synergistic effect. In melanoma, the combination of nivolumab and ipilimumab has shown impressive clinical activ-ity, with a 40% ORR and rapid tumor regression seen in many of the responders. This came at a cost of significant toxicity, with 53% of patients experiencing grade 3-4 AEs.19

Multiple studies are ongoing combining CTLA-4 inhibitors with the various PD-1 and PD-L1 inhibitors in lung cancer. As with the chemotherapy and immunotherapy combination stud-ies, these studies are all generally ongoing, and preliminary re-sults have been reported thus far.

Antonia et al20 reported preliminary data at ASCO 2014 on 49 patients treated with the combination of nivolumab plus ipilimumab. Patients received either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg for 4 cycles, followed by nivolumab alone. Treatment-re-lated, grade 3-4 AEs occurred in 49% of patients, and 35% of patients discontinued study drugs due to treatment-related AEs. The most common grade 3-4 treatment-related AEs included di-arrhea (n = 5, 10%), ALT elevation (n = 4, 8%), AST elevation (n = 4, 8%), colitis (n = 4, 8%), lipase elevation (n = 4, 8%), fatigue (n = 3, 6%), and pneumonitis (n = 3, 6%). The discontinuation rate due to drug-related AEs was highest in the nivolumab-1-mg/kg/ipilimumab 3-mg/kg-nonsquamous arm, and most discon-tinuations occurred during the concurrent phase of treatment. The response rate ranged from 11% to 33%, with some patients having prolonged duration of response.

Antonia et al21 reported at ASCO 2015 on the combination of tremelimumab plus MEDI4736. Of 102 patients treated with

MEDI4736-plus-tremelimumab combination therapy in the dose-escalation phase, 40% had grade 3 or higher treatment-re-lated AEs, with the most common treatment-related, grade 3-4 events being colitis (n = 9, 9%), diarrhea (n = 8, 8%), pneumoni-tis (n = 4, 4%), AST increase (n = 4, 4%), and ALT increase (n = 3, 3%). The observed response rate was 27% across all cohorts, with a 41% rate exhibiting disease control (CR, PR, and SD of at least 16 weeks).

Patnaik et al22 reported at ASCO 2015 on the combination of pembrolizumab plus ipilimumab. Dosages of pembrolizum-ab and ipilimumab were reduced in this study (from 10 mg/kg to 2 mg/kg for pembrolizumab, and from 3 mg/kg to 1 mg/kg for ipilimumab), based on emerging data from the nivolumab/ipilimumab experience. Of 18 patients enrolled, no dose-limit-ing toxicities (DLTs) or dose modifications were reported. Treat-ment-related, grade 3 AEs occurred in 17% of patients. The ORR was 39% in this preliminary group, with a DCR of 83%. The use of lower pembrolizumab and ipilimumab dosages did not appear to negatively impact efficacy.

Clinical Experience: Immunotherapy and Targeted TherapyMultiple trials of targeted therapy and immunotherapy are in progress, but the data are very early. Rivzi et al23 reported pre-liminary data on the combination of erlotinib plus nivolumab among patients with EGFR-mutated lung cancer who were che-motherapy-naïve. Of 21 patients, all but 1 had had prior treat-ment with erlotinib, although it is unclear whether this was immediately preceding treatment. The ORR was 15% and SD 45%. Treatment-related AEs were seen in 24% of patients, with diarrhea (n = 2), increased AST (n = 2), and increased ALT (n = 1) being most common.

Creelan et al24 reported results from a phase I study combin-ing gefitinib with MEDI4736. Ten patients were treated in the dose-escalation phase, which allowed both EGFR wild-type and mutant lung cancer. No DLTs were observed, and a maximum tolerated dose was not reached. The recommended dosages mov-ing forward were 250 mg once daily of gefitinib and 10 mg/kg every 2 weeks of MEDI4736. Fifteen patients were enrolled in a dose-expansion phase at the time of this preliminary report; a sensitizing EGFR mutation is required to enroll in the dose-ex-pansion phase. Patients are enrolled into 2 arms: gefitinib 250 mg once daily plus MEDI4736 10 mg/kg every 2 weeks, or gefi-tinib 250 mg once daily for 1 month followed by the combina-tion of gefitinib 250 mg once daily plus MEDI4736 10 mg/kg every 2 weeks. Of 11 evaluable patients in dose expansion, 8 have had PRs and 3 SD thus far.

Oxnard et al25 reported preliminary results at ASCO 2015 of the TATTON trial. In this phase Ib study, the third-generation EGFR inhibitor AZD9291 is combined with the PD-L1 inhibitor MEDI4736, the MET inhibitor AZD6094, or the MEK inhibitor selumetinib in patients with EGFR mutations with T790M re-


· NSCLC ·

sistance and progression on prior EGFR therapy. In this prelim-inary report, 23 patients had been enrolled in the combination arm of AZD9291 plus MEDI4736. AZD9291 was given at 80 mg once daily, and MEDI4736 was dose-escalated up to its mono-therapy phase III dosage. There was 1 DLT of grade 3 neutrope-nia at the MEDI4736 dosage of 10 mg/kg every 2 weeks. There was 1 CR and 8 PRs among 14 evaluable patients. Expansion cohorts to further evaluate efficacy are ongoing.

Multiple other studies are in progress combining targeted therapies with PD-1 and PD-L1 inhibitors, and data from these studies are awaited.

ConclusionImmunotherapy is the newest frontier in lung cancer treatment. Single-agent activity of PD-1 and PD-L1 inhibitors has been promising with activity across multiple histologies, and among responders, a quality and duration of response that is markedly different from that of conventional chemotherapy. Combina-torial strategies are being actively investigated to build on the single-agent activity. Much of the data regarding combination therapies are preliminary in nature, and we await the final results of the multiple, ongoing combinatorial studies to determine best strategies moving forward. While there is much hope and promise with the activity of PD-1 inhibitors in NSCLC, clearly there is much more work to be done. The next great challenge is to increase the response rate from approximately 20% for sin-gle-agent PD-1 therapy. One of the areas of greatest hope lies in trying to augment or potentiate the immune response so that more patients can benefit from this overarching strategy. While the CTLA-4 and PD-1 combinations have been beleaguered by toxicity, other combinations acting at different points in the im-mune cycle are being explored and also hold great interest. With further investigation, combinations that have manageable toxici-ty profiles while augmenting the immune response are expected and eagerly awaited.

Affiliations: Rebecca S. Heist, MD, MPH, is from the Massachu-setts General Hospital, Boston. Disclosure: Dr Heist has served as a consultant or on a paid advisory board for Boehringer Ingelheim.Address correspondence to: Rebecca S. Heist, MD, MPH, Mas-sachusetts General Hospital, Yawkey 7B, 32 Fruit St, Boston MA 02114. Email: [email protected].

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2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer [published online May 31, 2015]. N Engl J Med. 2015;373(2):123-135. doi:10.1056/NEJMoa1504627.3. Paz-Ares L, Horn L, Borgahaei H, et al. Phase III random-ized trial (Checkmate 057) of nivolumab versus docetaxel in ad-vanced non-squamous non-small cell lung cancer. J Clin Oncol. 2015;33(suppl; abstr: LBA109).4. Spira AI, Park K, Mazières J, et al. Efficacy, safety and predic-tive biomarker results from a randomized phase II study compar-ing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;33(suppl; abstr 8010). 5. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treat-ment of non-small cell lung cancer. N Engl J Med. 2015;372:2018-2028.6. Chen DS, Mellman I. Oncology meets immunology: the can-cer-immunity cycle. Immunity. 2013;39:1-10.7. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264. 8. Champiat S, Ileana E, Giaccone G, et al. Incorporating im-mune checkpoint inhibitors into systemic therapy of NSCLC. J Thorac Oncol. 2014;9(2):144-153.9. Zitvogel L, Apetoh L, Ghringhelli F, Kroemer G. Immu-nological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8(1):59-73.10. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the de-sign of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21:15-25.11. Bezu L, Gomes-da-Silva LC, Dewitte H, et al. Combinato-rial strategies for the induction of immunogenic cell death [published online April 24, 2015]. Front Immunol. 2015;6:187. doi:org/10.3389/fimmu.2015.00187.12. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237-251.13. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3(12):1355-1363.14. Spranger S, Gajewski T. Rational combinations of immuno-therapeutics that target discrete pathways. J Immunother Cancer. 2013;1:16.15. Lynch TJ, Bondarenko I, Luft A, et al. ipilimumab in com-bination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small cell lung cancer: results from a ran-domized double-blind multicenter phase 2 study. J Clin Oncol. 2012;30(17):2046-2054.16. Antonia SJ, Brahmer JR, Gettinger SN, et al. Nivolumab in combination with platinum based doublet chemotherapy in ad-vanced NSCLC. J Clin Oncol. 2014;32(5s suppl; abstr 8113).17. Liu SV, Powderly JD, Camidge DR, et al. Safety and efficacy of


PD-(L)1 anD CTLa-4 InhIbITors

MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr 8030).18. Papadimitrakopoulou V, Patnaik A, Borghaei H, et al. Pem-brolizumab (pembro; MK-3475) plus platinum doublet chemo-therapy (PDC) as front-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 Cohorts A and C. J Clin Oncol. 2015;33(suppl; abstr 8031).19. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.20. Antonia SJ, Gettinger SN, Chow LQM, et al. Nivolumab and ipilimumab in first-line NSCLC: interim phase I results. J Clin Oncol. 2014;32(5s suppl; abstr 8023).21. Antonia SJ, Goldberg S, Balmanoukian AS, et al. Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lym-phocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC. J Clin Oncol. 2015;33(suppl; abstr 3014).22. Patnaik A, Socinski MA, Gubens MA, et al. Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NS-CLC): KEYNOTE-021 cohort D. J Clin Oncol. 2015;33(suppl; abstr 8011).23. Rizvi NA, Chow LQM, Borghaei H, et al. Safety and re-sponse with nivolumab plus erlotinib in patients with epidermal growth factor receptor mutant advanced NSCLC. J Clin Oncol. 2014;32(5s suppl; abstr 8022).24. Creelan BC, Chow LQ, Kim DW, et al. Safety and tolerabili-ty results from a phase I study of MEDI4736, a human IgG1 an-ti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr 3047).25. Oxnard GR, Ramalingam SS, Ahn MJ, et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 com-bined with MEDI4736, AZD6094 or selumetinib in EGFR-mu-tant lung cancer. J Clin Oncol. 2015;33(suppl; abstr 2509).

26 www.ajho.com august 2015

· SCREENING ·

Current Controversies surrounding MRI screening for Breast Cancer

sarah a. McLaughlin, MD

screening mammography remains the only clinically proven im-aging modality shown to reduce mortality from breast cancer.1 Current recommendations on when breast cancer screening should commence in women with average risk varies between guidelines. the american Cancer society (aCs) as well as the joint position of the american College of Radiology (aCR) and the society of Breast Imaging support annual screening mam-mography starting at age 40 years.2 the us Preventative services task Force and the International agency for Research on Can-cer (IaRC) recommend that screening begin at age 50 years and could be biennial.3,4 they acknowledge some data demonstrat-ing screening benefits in women ages 40 to 49 years, but find these data to be limited or insufficient in quality, and therefore recommend screening in women younger than age 40 years to be performed on an individualized basis. While screening mam-mography has improved the detection of breast cancer, it still has several limitations as a screening test in young women, women with dense breasts, and in BRCA mutation carriers, where mam-mography sensitivity can be lower. In addition, interval breast

cancers still occur in 10% to 35% of women despite adequate screening.5

Multiple studies have evaluated screening breast magnetic res-onance imaging (MRI) in women at the highest risk of breast cancer in an effort to address some of these mammographic lim-itations. a recent meta-analysis reviewed the 11 prospective, non-randomized, MRI screening studies in high-risk women, finding that the sensitivity of MRI exceeds that of mammography (75% vs 32%, respectively), with the combination of mammography and MRI demonstrating the highest sensitivity, at 84%.6

It is important to acknowledge the difference in the mam-mographic and MRI screening populations. MRI screening studies included only women with a significant family history or proven genetic mutation, producing an inherent, albeit pur-poseful, selection bias. this is meaningful in interpretation, but caution is needed for the extrapolation of the MRI screening data to the average-risk screening population. Currently, the lower specificity of MRI compared with mammography, even in the highest-risk populations, results in limitations that include higher call-back rates, increased biopsy rates, increased costs, and the need for intravenous (IV) contrast.7 Furthermore, unlike the nationally accepted mammography standards set by the Mam-mography Quality standards act and Program (MQsa), MRI guidelines beyond minimum imaging requirements are lacking, which allows for variations in institutional protocols regarding image acquisition and sequences. these variations may affect image interpretation or transfer of patient information between institutions and lead to additional imaging recommendations.

Breast Cancer Screening GuidelinesIn an effort to streamline MRI screening, aCs published the first set of screening-MRI guidelines in 2007.8 these guidelines support MRI screening in addition to mammography in women at the highest risk for breast cancer, including women or the first-degree relatives of women with BRCA, p53, or PTEN mu-tations, women with a lifetime risk of breast cancer greater than 20%,9,10 and women with a history of therapeutic chest radiation before age 30. Recent population-based data have shown a rise in the use of screening MRI related to these guidelines; screen-

Abstract

Screening breast magnetic resonance imaging (MRI)

serves as an adjunct modality to mammographic screen-

ing in women at high risk for breast cancer. Current

guidelines published in 2007 provide a framework for

which patients should be screened with breast MRI. MRI

does have limitations due to its reduced specificity com-

pared with mammography and its cost. Furthermore, de-

fining risk with existing models can be challenging and is

not an exact science. As a result, controversy can exist for

women categorized as having intermediate risk, or where

existing literature suggests there are insufficient data to

recommend for or against MRI. Contemporary data re-

garding MRI screening are reviewed in this article, as are

some of the screening controversies.

Key words: breast magnetic resonance imaging, MRI

screening guidelines, risk assessment

VOL. 11, NO. 8 tHE aMERICaN JOuRNaL OF HEMatOLOgY/ONCOLOgY 27

MRI ScReenIng foR BReaSt canceR

ing MRI accounts for nearly 30% of all MRIs performed.11,12 Lit-tle controversy remains on the effectiveness of screening breast MRI, with contemporary data continuing to demonstrate an incremental cancer yield of 15 to 18 cancers per 1000 women screened found by MRI alone after negative mammography in these highest-risk populations.13

the current National Cancer Center Network (NCCN) guide-lines14 endorse the aCs recommendations and further address when screening should start and end. For BRCA mutation car-riers, screening should begin with MRI annually from ages 25 to 29 years, then annually with mammography and MRI from ages 30 to 74 years, and individualized screening strategies after age 74. Women with a lifetime risk greater than 20% by a family history–specific model should begin annual mammography and MRI at age 30. the guidelines allow for physician discretion as to whether the mammogram and MRI should be performed to-gether or at 6-month staggered intervals. Limited studies have evaluated this question of timing. the MRI-screening trials per-formed mammogram and MRI at the same time point annually and found an interval cancer rate of approximately 3%.

Le-Petross et al15 studied 73 BRCA1/2 mutation carriers, alter-nating mammogram and MRI every 6 months. With a median follow-up of 2 years, they found 12 cancers detected by MRI that were not visualized on the mammogram 6 months prior. they concluded that further prospective study is warranted, question-ing whether the already low interval cancer detection rate could be further reduced.

Risk Assessmentthe debate surrounding screening MRI focuses on resource allo-cation, on the ability to adequately quantify risk by identifying el-igible patients with and without a family history of breast cancer, and on emerging data on lifetime risks of breast cancer primarily in the group classified by aCs as having insufficient evidence to support screening MRI. Clearly, an educational opportunity exists to improve patient and clinician knowledge regarding the role of MRI in breast cancer screening. Wernli et al11 recently reviewed 5 national Breast Cancer surveillance Consortium reg-istries and documented that less than 5% of women with a life-time risk of breast cancer greater than 20% are being screened, and that among the MRI-screened population, only 29% had a lifetime risk greater than 20%.

the ability of clinicians to consistently and reliably quanti-fy an individual patient’s cancer risk remains challenging and may explain the discordance found in the Wernli study between estimated risk and use of MRI. the existing aCs and NCCN guidelines do not recommend one risk assessment model over another, but rather suggest using a model that is heavily reliant on family history, such as the BRCaPRO, tyrer-Cuzick, or Claus models. using the gail model is discouraged because it assesses only limited family history. unfortunately, because the models

rely on different input variables, and because they were derived from different populations, it is likely that the models will dis-agree on exact risk. In fact, Ozanne et al16 compared risk assess-ment values attained by the Claus, tyrer-Cuzick, and BRCaPRO models in a community-based hospital setting of 5894 women undergoing screening mammography, of whom 5.8% were eligi-ble for MRI. they found significant variation in the number of women identified by each model who met the 20% threshold, and that the models collectively agreed on patient risk greater than 20% in only 18 of 342 eligible high-risk patients. Improving and individualizing patient risk assessment remains an area of active research.

While these risk-assessment models remain the most highly discussed standardized methods to define cancer risk, the ques-tion of enhanced surveillance with MRI in addition to mam-mography remains for those women with high-risk breast lesions classified as having insufficient evidence according to aCs. specifically, are there women without a family history of breast cancer, a high-risk inherited mutation, or a history of chest-wall irradiation at sufficient risk to warrant MRI screening for whom the existing models may underestimate risk? Current data with respect to the role of screening MRI in women with high-risk breast lesions or clinical situations considered by aCs and NCCN to have insufficient evidence for routine screening MRI are reviewed next.

two studies to date have evaluated the role of screening MRI in the setting of atypical ductal hyperplasia (aDH). Port et al17 found no additional cancers detected by MRI alone in 47 screened patients, while schwartz et al18 found only 2 additional cancers in 131 women. In addition, they reported a 24% need for second-look imaging and a positive predictive value (PPV) of biopsy of 20%, highlighting the complexities of additional MRI screening. Both studies concluded that MRI is not indicated in the setting of aDH. Despite these negative studies on the addi-tive value of screening MRI in the aDH population, emerging data suggest that women with atypical ductal or lobular hyper-plasia may in fact have a much higher lifetime risk of breast can-cer than previously estimated, and therefore may benefit from screening MRI.

Hartmann and colleagues19 followed 698 women with aDH or atypical lobular hyperplasia (aLH) diagnosed by breast biopsy between 1967 and 2001. With a median follow-up of 25 years, they demonstrated a cumulative risk of breast cancer of 29%, with more than 80% of the breast cancers being invasive. Fur-ther, no difference in breast cancer risk existed between those women with aDH or aLH. these data mirror those of the Nash-ville breast cohort.19,20 Interestingly, the number of foci as 1, 2, or more than 3 further stratifies risk, with more foci of aDH conferring higher risk for future breast cancer. although these studies did not specifically evaluate MRI effectiveness in women with aDH or aLH, this unique, robust dataset argues in favor of


· SCREENING ·

screening MRI in this population based on increased lifetime risk. MRI screening for lobular carcinoma in situ (LCIs) also has

been studied. Of the 5 available studies, the collective incremen-tal cancer detection rate for MRI screening ranged from 0% to 4%17,18,21-23 (Table). the largest study by King et al23 followed 776 patients diagnosed with MRI, of whom 455 were screened with MRI at the discretion of the treating physician. With a median follow-up of 58 months and a median of 3 MRIs per patient, no difference in crude cancer detection rate was demonstrated, finding cancer in 13% of those screened with MRI and in 13% of those screened with conventional imaging. Further, the study demonstrated that patients followed with MRI were 3 times as likely to have an additional needle biopsy (P <.0001). Finally, MRI screening was not associated with finding smaller tumors or an earlier stage at diagnosis. the authors concluded that insuffi-cient evidence exists to support MRI screening in patients with a diagnosis of LCIs.23

Breast density is currently a screening challenge. With in-creasing legislation regarding breast density reporting, there is significant interest in screening modalities for these patients. However, to date, consensus opinion on the specific modality recommended or proven to be most effective is lacking. about 50% of women are categorized as having heterogeneously (D3) or extremely dense (D4) breast tissue. Magnetic resonance imag-ing screening studies thus far have screened women at high risk for breast cancer regardless of breast density. the aCRIN 6666 trial7 evaluated MRI in women at elevated risk for breast cancer after negative mammogram and ultrasound studies. the MRIs did find an additional 14.7 cancers per 1000 women screened. However, screening MRI in this population was associated with a high false-positive rate, increased biopsies, and a PPV for biopsy of only 18%.

again, because aCRIN 6666 and other MRI screening stud-ies were performed on women with elevated breast cancer risk regardless of breast density, the benefit of MRI screening in women with dense breast tissue and average breast cancer risk is unclear. Based on the high false-positive rates, cost, and need for IV contrast, the aCR appropriateness Criteria24 and aCs recommend screening MRI only in women at high risk for breast cancer. specifically, aCs reaffirms that insufficient cri-teria remain for MRI screening for patients with dense breast parenchyma without other risk

factors.8 Further, no current risk-assessment models incorporate breast density as an input variable. as a result, there is no con-sensus on whether supplemental screening should be pursued in these patients.

Personal/Family History of Breast Cancerthe aCs also has categorized a personal history of breast can-cer as insufficient evidence to support routine use of screening breast MRI after cancer treatment. Emerging data challenge this paradigm, but to date are not widely accepted. Brennan et al25 reviewed 144 women with a personal history of breast cancer without a family history of breast cancer. they reported a 7% in-cremental cancer detection rate in the ipsilateral or contralateral breast with MRI, resulting in a PPV of biopsy of 39%. schacht et al26 expanded upon these findings, evaluating 97 women with both a personal and family history of breast cancer. all women had mammogram and MRI. screening MRI detected cancer in 6 of 92 women (6.5%; ipsilateral or contralateral breast) for a relative risk of 3.04 (95% CI, 1.05-8.86), where family history of breast cancer was used as the referent value. a personal history of breast cancer alone carried a relative risk of only 1.42 (95% CI, 0.48-4.17). they concluded that women with a personal and family history of breast cancer should be screened with MRI and the highest degree of scrutiny.26 together, these data are hypoth-esis-generating, but should be interpreted with caution because they were retrospectively collected, did not further delineate lifetime risks of breast cancer in the MRI-screened population having both personal and family history of breast cancer, and likely represent a highly selected population, limiting their gen-eralizability.

Finally, in this era of personalized medicine and the rapid ex-pansion and adoption of genetic panel testing, clinicians will be

Table. MRI-Screening Studies in Women With Lobular Carcinoma in Situ

Study Patients (N)

additional Cancers Detected by MRI Only (n)

MRI Sensitivity

PPV of biopsy

Incremental Cancer Detection Rate by MRI

Port et al, 200717 135 6 75% - 4%

Sung et al, 201121 220 12 - - 4.5%

Friedlander et al, 201122 133 5 - 23.8% 3.8%

King et al, 201323 455 0 - - 0%a

Schwartz et al, 201518 48 1 - 20% 2%

aKing et al found a cancer detection rate of 13% in both the MRI-screened and MMG-only-screened cohorts.

MMG indicates mammography; MRI, magnetic resonance imaging; PPV, positive predictive value.

VOL. 11, NO. 8 tHE aMERICaN JOuRNaL OF HEMatOLOgY/ONCOLOgY 29

MRI ScReenIng foR BReaSt canceR

faced with genetic mutations and variants of lesser known or studied genes. Careful attention to a patient’s family pedigree may help determine the need for enhanced screening. as data accumulate on these new mutations, they can be reclassified. For example, it is now clear that germline mutations in PALB2 sig-nificantly increase the risk of breast cancer by age 70. Carriers without a family history of breast cancer have a 33% risk, and those with 2 or more first-degree relatives have a 58% risk of breast cancer by age 50.27 Clearly, these women meet lifetime breast cancer risk criteria for screening MRI.

Advancements in ScreeningWhile the discussions continue regarding the role of MRI in spe-cific clinical situations, clinicians must recognize that advances are being made in the technology of image acquisition and MRI access, as well. Kuhl et al28 recently published prospective, ob-servational, reader study data obtained from 443 women with mild-to-moderate breast cancer risk who had completed 606 rapid (3-minute) screening breast MRIs.28 they found compa-rable performance results between the rapid and the standard 21-minute MRI screen for breast cancer. specifically, rapid MRI found 11 cancers after negative mammogram, of which 7 were invasive and 4 were ductal carcinoma in situ (DCIs), for an additional cancer yield of 18.2 per 1000. Furthermore, this ab-breviated-protocol MRI required less than 30 seconds to read a complete exam.28 these advancements eliminate several of the barriers that currently limit MRI screening to women at high-est risk by providing an option that is quick, sensitive, and far more affordable. additional trials are needed to confirm these promising results, but confirmation could alter future screening recommendations.

In summary, the value of screening MRI is in the increased detection of breast cancer. screening MRI is recommended for women at highest risk of breast cancer. Clinicians must under-stand the limitations and value of risk-prediction models, as this may influence patient eligibility for screening MRI. some wom-en with atypia or a personal history of breast cancer may bene-fit from MRI screening, but overall, a one-size-fits-all screening model does not work. as with treatment paradigms, screening must be individualized, and models and guidelines may not accu-rately capture all women who may benefit from MRI screening. It remains difficult to assess the long-term outcomes and benefits of MRI because the MRI screening trials were not powered to evaluate survival.6 Furthermore, research is needed to assess the impact of anxiety and additional procedures resulting from the variable specificity of MRI on patient quality of life and on the biologic significance of MRI-only-detected cancers.

Affiliations: sarah a. McLaughlin, MD, is associate professor of surgery, Mayo Clinic, Jacksonville, FL.Disclosure: Dr McLaughlin reports no relevant financial con-

flicts of interest to disclose.Address correspondence to: sarah a. McLaughlin, MD, Depart-ment of surgery, Mayo Clinic, 4500 san Pablo Rd, Jacksonville, FL 32224. Fax: 904-953-7368; email: [email protected].

ReFeRenCeS1. Bleyer a, Welch Hg. Effect of three decades of screen-ing mammography on breast-cancer incidence. N Engl J Med. 2012;367(21):1998-2005.2. Rebner M. sBI statement on united states Preventive services task Force Draft Research Plan for Breast Cancer. November 25, 2013. http://www.sbi-online.org/Portals/0/Position%20statements/2013/sBI%20Response%20to%20usPstF%20Draft%20Review%20Process%20-%2011-13.pdf. accessed July 7, 2015.3. screening for breast cancer: us Preventive services task Force recommendation statement. Ann Intern Med. 2009;151(10):716-726, W-236.4. Lauby-secretan B, scoccianti C, Loomis D, et al. Breast-cancer screening--viewpoint of the IaRC Working group. N Engl J Med. 2015;372(24):2353-2358.5. Hofvind s, skaane P, Vitak B, et al. Influence of review design on percentages of missed interval breast cancers: retrospective study of interval cancers in a population-based screening pro-gram. Radiology. 2005;237(2):437-443.6. Warner E, Messersmith H, Causer P, et al. systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer. Ann Intern Med. 2008 6;148(9):671-679.7. Berg Wa, Zhang Z, Lehrer D, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screen-ing MRI to mammography in women with elevated breast cancer risk. JAMA. 2012 4;307(13):1394-1404.8. saslow D, Boetes C, Burke W, et al. american Cancer society guidelines for breast screening with MRI as an adjunct to mam-mography. Cancer. 2007;57(2):75-89.9. Claus EB, Risch N, thompson WD. autosomal dominant inheritance of early-onset breast cancer. Implications for risk pre-diction. Cancer. 1994;73(3):643-651.10. antoniou aC, Pharoah PP, smith P, Easton DF. the BOaD-ICEa model of genetic susceptibility to breast and ovarian can-cer. Br J Cancer. 2004;91(8):1580-1590.11. Wernli KJ, DeMartini WB, Ichikawa L, et al. Patterns of breast magnetic resonance imaging use in community practice. JAMA Intern Med. 2014;174(1):125-132.12. stout NK, Nekhlyudov L, Li L, et al. Rapid increase in breast magnetic resonance imaging use: trends from 2000 to 2011. JAMA Intern Med. 2014;174(1):114-121.13. Chiarelli aM, Prummel MV, Muradali D, et al. Effectiveness of screening with annual magnetic resonance imaging and mam-mography: results of the initial screen from the Ontario high risk


· SCREENING ·

breast screening program. J Clin Oncol. 2014;32(21):2224-2230.14. National Comprehenisve Cancer Network. NCCN guidelines for breast cancer screening and diagnosis. www.nccn.org. accessed July 7 , 2015.15. Le-Petross Ht, Whitman gJ, atchley DP, et al. Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCa mutations at high risk of breast cancer. Cancer. 2011;117(17):3900-3907.16. Ozanne EM, Drohan B, Bosinoff P, et al. Which risk model to use? Clinical implications of the aCs MRI screening guide-lines. Cancer Epidemiol Biomarkers Prev. 2013;22(1):146-149.17. Port ER, Park a, Borgen PI, et al. Results of MRI screening for breast cancer in high-risk patients with LCIs and atypical hyperplasia. Ann Surg Oncol. 2007;14(3):1051-1057.18. schwartz t, Cyr a, Margenthaler J. screening breast magnet-ic resonance imaging in women with atypia or lobular carcinoma in situ. J Surg Res. 2015;193:519-522.19. Hartmann LC, Degnim aC, santen RJ, et al. atypical hyper-plasia of the breast--risk assessment and management options. N Engl J Med. 2015;372(1):78-89.20. Hartmann LC, Radisky DC, Frost MH, et al. understand-ing the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res. 2014;7(2):211-217.21. sung Js, Malak sF, Bajaj P, et al. screening breast MR imag-ing in women with a history of lobular carcinoma in situ. Radiol-ogy. 2011;261(2):414-420.22. Friedlander LC, Roth sO, gavenonis sC. Results of MR imaging screening for breast cancer in high-risk patients with lob-ular carcinoma in situ. Radiology. 2011;261(2):421-427.23. King ta, Muhsen s, Patil s, et al. Is there a role for routine screening MRI in women with LCIs? Breast Cancer Res Treat. 2013;142(2):445-453.24. Mainiero MB, Lourenco a, Mahoney MC, et al. aCR ap-propriateness Criteria Breast Cancer screening. J Am Coll Radiol. 2013;10(1):11-14.25. Brennan s, Liberman L, Dershaw DD, Morris E. Breast MRI screening of women with a personal history of breast cancer. AJR Am J Roentgenol. 2010;195(2):510-516.26. schacht DV, Yamaguchi K, Lai J, et al. Importance of a per-sonal history of breast cancer as a risk factor for the development of subsequent breast cancer: results from screening breast MRI. AJR Am J Roentgenol. 2014;202(2):289-292.27. antoniou aC, Casadei s, Heikkinen t, et al. Breast-can-cer risk in families with mutations in PaLB2. N Engl J Med. 2014;371(6):497-506.28. Kuhl CK, schrading s, strobel K, et al. abbreviated breast magnetic resonance imaging (MRI): first postcontrast subtracted images and maximum-intensity projection-a novel approach to breast cancer screening with MRI. J Clin Oncol. 2014;32(22):2304-2310.


· Surgery ·

Contemporary Strategies in Breast Reconstruction

Merisa L. Piper, MD, and Hani Sbitany, MD, FACS

IntroductionOver time, the surgical management of breast cancer has become less radical, as improved adjuvant therapy has allowed more women to be candidates for breast-conserving therapy (BCT). The development of “oncoplastic” surgery has accompanied this evolution. The term oncoplastic surgery broadly refers to the recon-struction of partial mastectomy defects immediately at the time of lumpectomy/partial mastectomy to provide improved aesthet-ic outcomes. Several different oncoplastic techniques have been described, including local tissue rearrangement, local-regional flap transfer, mastopexy (breast lift), and reduction mammoplas-ty. Growing evidence suggests that these techniques make breast conservation available to more women,1-3 provide better control of tumor margins,4 and result in improved aesthetic5,6 and pa-tient-reported outcomes.7-9

In patients with breast cancer who require mastectomy, sur-

geons now place greater emphasis on preserving the external nipple-areolar complex (NAC) and the entire breast skin enve-lope.10-13 At many institutions, nipple-sparing mastectomy or total skin-sparing mastectomy is now the standard of care for wom-en who require mastectomy.14 Implant-based and autologous tissue reconstructions have evolved to provide a more natural appearance and feel to the reconstructed breast. These changes have led to higher patient satisfaction and improved aesthetic re-sults.11,12,15,16 This, in turn, has led to higher rates of contralateral and bilateral prophylactic mastectomies in women who previous-ly hesitated when aesthetic results were not as successful.17

Even with the greater focus on aesthetic and patient-reported outcomes and on breast conservation, equivalent oncologic safe-ty has been maintained.14,18-20 This is partly attributed to the ex-panding use of chemotherapy and radiation therapy (RT).21 Both are critical components of breast cancer treatment, but markedly increase the complexity of reconstruction and influence the tim-ing of reconstruction.22,23

With regard to mastectomy and whole-breast reconstruction, chemotherapy will primarily affect the timing of the reconstruc-tive process. RT will have a greater effect on the specific proce-dure chosen for breast reconstruction.24 Ultimately, all of these factors combined will determine outcomes and dictate the rates of complications encountered throughout the reconstructive process. This review will highlight what interventions influence the reconstructive decision tree (Figure 1) and provide a compre-hensive overview of associated outcomes.

Partial Mastectomy (Lumpectomy) ReconstructionRepair of partial mastectomy defects is fundamentally catego-rized into 2 types: volume displacement/rearrangement and volume replacement.25 Several algorithms for reconstruction of partial mastectomy defects have been proposed, factoring in breast size and shape, tumor location, timing of radiotherapy, and patient desires.26

The most straightforward oncoplastic technique involves local tissue rearrangement.25 This is reserved for patients with ade-quate breast tissue (B or C cup), minimal ptosis, sufficient skin, and small tumors.24,27,28 This involves a redistribution and rearrangement of the remaining breast tissue following lumpecto-my, to prevent a large regional cavity. If there is insufficient adja-cent tissue, local or regional soft-tissue flaps can be used, such as

Abstract

Improvements in neoadjuvant therapy have allowed

more women to be candidates for breast-conserving

therapy (BCT). “Oncoplastic” surgery, which combines

plastic surgery techniques with oncology surgery, devel-

oped as a way to reconstruct defects that occur following

partial mastectomy. A variety of oncoplastic techniques

are available that primarily depend on breast size, tumor-

to-breast ratio, degree of ptosis, and radiation history.

Additionally, in those women who are not candidates for

BCT and require mastectomy, modifications have been

made to improve aesthetic and patient-reported out-

comes. Care is taken to preserve the entire skin envelope

and nipple areolar complex, and reconstruction focuses

on creating a soft, natural breast. This review provides

an overview of the various techniques for breast recon-

struction. It also discusses which factors influence the

reconstructive algorithm, and the outcomes of various

techniques, with a focus on the influence of chemothera-

py and radiation therapy on these outcomes.

Key words: breast reconstruction, oncoplastic surgery,

partial mastectomy, breast-conserving therapy, immedi-

ate versus delayed breast reconstruction


· Surgery ·

flaps from the subaxillary region or the latissimus dorsi flap.27,28

Mastopexy (breast lift) and oncoplastic reduction mammoplas-ty have become invaluable techniques in treating large-breasted patients with ptosis who require some additional skin resection (Figures 2 and 3).29-31 Tumor location dictates the incision pat-tern, as there are many possible options. Oncoplastic reduction mammoplasty provides the added benefit of a symmetrizing con-tralateral reduction, which improves the overall cosmetic out-come.5,32 This technique enables wide tumor resections,4,33 which extends the option for BCT1,2 without compromising oncologic safety.3,34 Additionally, in women who require RT, this technique can be used as a strategy for reducing complication rates.3

Postmastectomy ReconstructionMastectomy can be categorized into 4 types: simple, skin-sparing, nipple-sparing, and total skin-sparing. In simple mastectomy, all of the breast parenchyma, NAC, and excess breast skin are re-moved. Skin-sparing mastectomy preserves the skin envelope but removes the NAC. In nipple-sparing mastectomy, the skin and NAC are preserved. Finally, in total skin-sparing mastectomy, the entire skin envelope and NAC are preserved, and the nipple tissue beneath the NAC is completely cored out.35,36 Reconstruc-tion following mastectomy is either implant-based, autologous tissue–based, or a combination of the 2. Abdominally based flaps are the preferred autologous tissue for breast reconstruction given their reliability and tissue bulk. These flaps may be rotat-ed on a vascular pedicle, thus maintaining their original blood supply, or may be transferred as free flaps, which require a mi-crovascular anastomosis to provide new blood flow. Transverse rectus abdominus myocutaneous (TRAM) flaps may be used as pedicled flaps or as free flaps. However, these put patients at risk for developing abdominal hernias because muscle and fascia are removed from the abdomen. Muscle-sparing TRAM flaps have minimized this donor site morbidity. Going one step further,

deep inferior epigastric perforator (DIEP) flaps were developed, which leave the entire abdominal musculature and fascia intact.

The initial decision when planning reconstruction is deter-mining when the reconstruction should be performed, either im-mediately at the time of mastectomy or in a delayed fashion fol-lowing healing from mastectomy. Delayed breast reconstruction offers suboptimal aesthetic outcomes, as it does not allow for maintenance of the shape of the original breast skin envelope. Furthermore, this technique does not allow for aesthetic preser-vation of the NAC position, due to postmastectomy skin healing and contraction on the chest wall, and is thus only compatible with skin-sparing mastectomy techniques (non–nipple-sparing).

Overall, the reported outcome rates for delayed reconstruction are highly dependent on whether the patient received postmas-tectomy RT.37-40 Quoted complication rates for delayed recon-struction range from 31% to 41%.41,42 Patients who undergo delayed reconstruction and do not require RT have lower compli-cation rates than those who undergo immediate reconstruction or those who do undergo postmastectomy RT. In patients who do require RT, many authors advocate delaying definitive recon-struction until the RT course has been completed.43-45

Immediate prosthetic breast reconstruction is the authors’ preferred technique, as it offers superior aesthetic outcomes and allows for preservation and aesthetic positioning of the NAC on the reconstructed breast mound. Most commonly, this is done as a 2-stage process, with a tissue expander placed at the time of mastectomy and only partially filled. Over the following months, the tissue expander is slowly inflated to redevelop the breast pocket. Following completion of expansion, the patient undergoes operative exchange of the expander for a permanent breast implant.

Complications specific to prosthetic reconstruction include capsular contracture, implant malposition, implant exposure, and implant deflation.42 In cases of immediate prosthetic re-

figure 1.

Reconstructive decision tree based upon whether a patient is a candidate for breast-conserving therapy (BCT) or requires mastectomy.

Breast Cancer Diagnosis

Candidatefor BCT

Autologous reconstruction

Requiresmastectomy

Expander/Impant-based reconstruction

Volumereplacement

Transpositionor rotational

flaps

Autologous fat grafting

Local tissue rearrangement

Reduction mammoplasty

Mastopexy(breast lift)

ImmediateImplant

Abdominaltissue (DIEP,

TRAM)

Two-stage expanderimplant

Latissimusdorsi flap

Gluteal tissue/ other tissue

sources

Volume displacement/ rearrangement


Breast reconstruction

construction, the reported infection rate is 7% to 13% in the nonradiated population.46 The major-ity of these cases resolve with antibiotic treatment. Cases of cellulitis generally resolve with a course of outpatient antibiotic therapy, while deeper-tis-sue infections may require intravenous (IV) anti-biotics for resolution. Ultimately, 3% of patients will require an operative washout for resolution of infection. The reported explantation rates range from 2% to 5%, and this includes explantation for all indications (ie, infection, expander/im-plant exposure, and capsular contracture).

The addition of postmastectomy RT significant-ly alters the outcomes profile of immediate breast reconstruction. This is due to the significant re-duction in microvascular skin circulation induced by external-beam radiation therapy (EBRT) and its subsequent effect on healing and antibiotic delivery to the skin envelope. In this patient cohort, rates of infection range from 22% to 26%, with cellulitis the predominant finding in the vast majority of cases. Ultimately, the explantation rate in this population varies widely. Sbitany et al46 and Spear et al47 reported overall failure rates in the population undergoing immediate prosthetic recon-struction with postmastectomy RT of 17.7% and 21.4%, respec-tively. The Italian experience reported by Nava and colleagues48 indicated a 40% failure rate in the same population.

The vastly different reported failure rates in the radiated pop-ulation are likely multifactorial, but one caveat that has been reported to significantly influence complication rates is the use of acellular dermal matrix (ADM) to cover the prosthesis at the time of placement. ADM is decellularized human or animal tis-sue that can be safely placed within the breasts over a device, and revascularizes to provide added coverage and protection over the implant. Seth et al49 reported a significant reduction in im-plant-related complications in the setting of EBRT when ADM was used to cover the implant versus when no ADM was used. Similar findings have been reported by Spear et al47 and Sbitany et al.46

The effects of chemotherapy on immediate prosthetic breast reconstruction outcomes reported in the literature are similarly wide ranging and conflicting.50,51 However, the majority of stud-ies show women who receive chemotherapy do not have higher overall complication rates.52,53 Donker et al53 analyzed the effect of neoadjuvant chemotherapy on complications in women un-dergoing skin-sparing mastectomy and immediate prosthetic reconstruction. Surprisingly, they found that the overall rate of short-term postoperative complications was significantly less among neoadjuvantly treated women (15% vs. 29%; P = .042), but this did not reduce the rate of prostheses lost (8% vs 11%; P = .566). The higher complication rate in the control group was primarily influenced by higher rates of skin necrosis. The in-

vestigators attributed this reduced incidence of complications in neoadjuvant patients to their younger age, fewer comorbidities, and lower incidence of smoking.

A systematic review performed by Oh et al50 assessed the im-pact of chemotherapy on reconstructive outcomes in immediate breast reconstruction. Several studies found that the use of ad-juvant chemotherapy after immediate reconstruction negatively impacted reconstructive outcomes, with reported reconstructive failure rates of up to 38% in the adjuvant chemotherapy group54 and overall higher complication rates.55 However, the majority of studies found no difference in complication rates or reconstruc-tive failures in those who received chemotherapy.56-58 Overall, Hu et al concluded that neoadjuvant chemotherapy did not neg-atively impact reconstructive outcomes, but may delay surgical timing.59

With regard to initiation of adjuvant chemotherapy following mastectomy and immediate breast reconstruction, the reported delays in treatment initiation vary widely in the literature.60 Al-though not commonly observed, women who have had mastec-tomy and tissue expander placement may have a slight delay in starting adjuvant chemotherapy.61,62 Yule et al61 recorded delays of more than 1 month in 2 of 23 patients requiring adjuvant chemotherapy, out of a total of 46 patients treated with mastec-tomy and immediate breast reconstruction. Conversely, numer-ous other studies compared time to onset of chemotherapy after mastectomy and immediate breast reconstruction with control groups treated by mastectomy alone (no reconstruction) and re-vealed no significant difference; chemotherapy commenced, on average, 41 to 53 days after surgery.51,52,63

It is our clinical experience that immediate breast reconstruc-tion does not delay the initiation of adjuvant chemotherapy when reconstruction is performed with placement of a tissue expander at the time of mastectomy. Great care is taken not to overfill the expander at the time of placement. This reduces the tension on the overlying skin envelope as it heals, and thus re-

figure 2.

A woman who underwent mastopexy with subpectoral implants following partial mastectomy of the right breast. Preoperative (left) and postoperative (right) photos.


· Surgery ·

duces the incidence of wound dehiscence and skin necrosis that may delay the initiation of chemotherapy.

A review of our institutional database was also performed to assess the effects of trastuzumab and hormonal therapy on pa-tients undergoing total skin-sparing mastectomy and immediate tissue expander placement for reconstruction. With regard to the complications assessed (nipple necrosis, skin necrosis, infec-tion, expander/implant loss or removal), no statistically signif-icant differences were found between the patients treated with trastuzumab and the patients not treated. A similar review of patients treated with hormone therapy showed statistical differ-ences only in the incidence of seroma (relative risk [RR], 3.43; P = .007) and minor skin necrosis (RR, 2.97; P = .021). The incidence of all other complications assessed in pa-tients taking hormonal therapy treatment was statistically equiva-lent to those patients not being treated.

RecommendationsBased on our clinical experience and data, we advocate specific timing regimens and algorithms for patients undergoing imme-diate prosthetic breast reconstruction at the time of mastecto-my. We have found that these timing schemes help to minimize surgical risk. For those patients undergoing neoadjuvant chemo-therapy, we recommend surgery 1 month after the final infusion is administered. Furthermore, for those patients on hormonal therapy, we recommend patients discontinue therapy 2 to 3 weeks before surgery to reduce the risk of minor skin necrosis and wound dehiscence. We advocate waiting 4 to 6 weeks prior to initiation of chemotherapy infusions for patients requiring adjuvant chemotherapy after mastectomy and prosthetic recon-struction. Additionally, we recommend that no tissue expansion

be performed during chemotherapy treatment, but rather that expansion should proceed follow-ing completion of all infusions.

For patients undergoing postmastectomy EBRT, we recommend full and complete expan-sion of the tissue expander prior to radiation de-livery. We wait to exchange the tissue expander for a silicone implant until RT has finished. We recommend waiting 6 months after completion of RT for this exchange operation, as this has been shown to reduce wound dehiscence and implant extrusion rates.64

ConclusionThe management of breast cancer has changed dramatically over the last 30 years. Improvements in neoadjuvant therapy and surgical techniques have allowed more women to be candidates for BCT. As a result, oncoplastic surgical techniques were developed and subsequently became invalu-

able to the field of reconstructive surgery, as well as to the com-prehensive treatment of breast cancer. Oncoplastic techniques minimize breast deformities following cancer resection and treatment, while maintaining equivalent oncologic outcomes. Additionally, modifications to mastectomy techniques have sig-nificantly improved aesthetic results and patient satisfaction, and as a result, there has been a rise in prophylactic and bilateral mas-tectomies. Surgeons routinely preserve the entire breast envelope and NAC. The primary focus in implant and autologous-based reconstruction is recreating a breast that appears and feels natu-ral. Outcomes research has enabled us to identify the risk-induc-ing effects of chemotherapy and RT on breast reconstruction. Based on these outcomes studies, we have identified various timing and technique algorithms to help minimize the risk in postmastectomy breast reconstruction.

Acknowledgments: The authors thank Pamela Derish for her review of the manuscript.Affiliations: Merisa L. Piper, MD, and Hani Sbitany, MD, FACS, are from the Division of Plastic and Reconstructive Surgery, De-partment of Surgery, University of California, San Francisco, San Francisco, CA.Disclosures: Dr Piper has no relevant financial conflicts of inter-est to disclose. Dr Sbitany is a member of the Speakers’ Bureau for LifeCell, Inc.Address correspondence to: Hani Sbitany, MD, FACS, Division of Plastic Surgery, University of California, San Francisco, 505 Parnassus Ave, Suite M593, San Francisco, CA 94143. Phone: (415) 353-4285; fax: (415) 353-4320; email: [email protected].

figure 3.

A woman who underwent mastopexy with subpectoral implants following partial mastectomy of the right breast. Preoperative (left) and postoperative (right) photos.



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· Surgery ·

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plant-based breast reconstruction following total skin-sparing mastectomy: defining the risk of preoperative and postopera-tive radiation therapy for surgical outcomes. Plast Reconstr Surg. 2014;134(3):396-404.47. Spear SL, Seruya M, Rao SS, et al. Two-stage prosthetic breast reconstruction using AlloDerm including outcomes of different timings of radiotherapy. Plast Reconstr Surg. 2012;130(1):1-9.48. Nava MB, Pennati AE, Lozza L, et al. Outcome of different timings of radiotherapy in implant-based breast reconstructions. Plast Reconstr Surg. 2011;128(2):353-359.49. Seth AK, Hirsch EM, Fine NA, Kim JY. Utility of acellular dermis-assisted breast reconstruction in the setting of radiation: a comparative analysis. Plast Reconstr Surg. 2012;130(4):750-758.50. Oh E, Chim H, Soltanian HT. The effects of neoadjuvant and adjuvant chemotherapy on the surgical outcomes of breast recon-struction. J Plast Reconstr Aesthet Surg. 2012;65(10):e267-e280.51. Allweis TM, Boisvert ME, Otero SE, et al. Immediate re-construction after mastectomy for breast cancer does not pro-long the time to starting adjuvant chemotherapy. Am J Surg. 2002;183(3):218-221.52. Caffo O, Cazzolli D, Scalet A, et al. Concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expanders after mastectomy for breast cancer. Breast Cancer Res Treat. 2000;60(3):267-275.53. Donker M, Hage JJ, Woerdeman LA, et al. Surgical compli-cations of skin sparing mastectomy and immediate prosthetic re-construction after neoadjuvant chemotherapy for invasive breast cancer. Eur J Surg Oncol. 2012;38(1):25-30.54. Mitchem J, Herrmann D, Margenthaler JA, Aft RL. Impact of neoadjuvant chemotherapy on rate of tissue expander/im-plant loss and progression to successful breast reconstruction following mastectomy. Am J Surg. 2008;196(4):519-522.55. Mehrara BJ, Santoro TD, Arcilla E, et al. Complications after microvascular breast reconstruction: experience with 1195 flaps. Plast Reconstr Surg. 2006;118(5):1100-1109.56. Zweifel-Schlatter M, Darhouse N, Roblin P, et al. Immedi-ate microvascular breast reconstruction after neoadjuvant che-motherapy: complication rates and effect on start of adjuvant treatment. Ann Surg Oncol. 2010;17(11):2945-2950.57. McCarthy CM, Mehrara BJ, Riedel E, et al. Predicting com-plications following expander/implant breast reconstruction: an outcomes analysis based on preoperative clinical risk. Plast Recon-str Surg. 2008;121(6):1886-1892.58. Azzawi K, Ismail A, Earl H, et al. Influence of neoadjuvant chemotherapy on outcomes of immediate breast reconstruction. Plast Reconstr Surg. 2010;126(1):1-11.59. Hu Y-, Weeks CM, In H, et al. Impact of neoadjuvant che-motherapy on breast reconstruction. Cancer. 2011;117(13):2833-2841.60. Taylor CW, Horgan K, Dodwell D. Oncological aspects of breast reconstruction. Breast. 2005;14(2):118-130.



61. Yule GJ, Concannon MJ, Croll G, Puckett CL. Is there liabil-ity with chemotherapy following immediate breast construction? Plast Reconstr Surg. 1996;97(5):969-973.62. Hoffman JP, Kusiak J, Boraas M, et al. Risk factors for im-mediate prosthetic postmastectomy reconstruction. Am Surg. 1991;57(8):514-521; discussion 522.63. Taylor CW, Kumar S. The effect of immediate breast recon-struction on adjuvant chemotherapy. Breast. 2005;14(1):18-21.64. Peled AW, Foster RD, Esserman LJ, et al. Increasing the time to expander-implant exchange after postmastectomy radiation therapy reduces expander-implant failure. Plast Reconstr Surg. 2012;130(3):503-509.

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40 www.ajho.com AUGUsT 2015

Data on these current and emerging myeloma treatments were recently pre-sented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. Ola Landgren, MD, PhD, chief of the Myeloma Service at Memo-rial Sloan Kettering Cancer Center (MSKCC) in New York City, shares his thoughts here on the key myeloma-related data, along with his perspective regarding where myeloma treatment might be headed in the near future.

Moderator: Dr Landgren, how do you think the phase III ELO-QUENT-2 trial results fit within the context of unmet clinical needs in the relapsed/refractory setting of multiple myeloma?Dr Landgren: The ELOQUENT-2 study presented at the AsCO meeting is the first phase III trial in myeloma using the mAb elo-tuzumab that targets the antigen signaling lymphocytic activation molecule F7, or sLAMF7. This antigen is expressed on the surface of myeloma and other cells. ELOQUENT-2 showed that patients treated with this drug in combination with lenalidomide plus dexa-methasone had significantly improved progression-free survival (PFs) compared with patients who were treated with only lenalidomide plus dexamethasone.

Looking in more detail at this trial, the median follow-up was 24 months, and, when you review the difference in the median PFs be-

tween the 2 arms—19.4 months (95% CI, 16.6-22.2 months) for the elotuzumab/lenalidomide/dexamethasone arm compared with 14.9 months (95% CI, 12.1-17.2 months) for the lenalidomide/dexameth-asone arm (hazard ratio [HR], 0.70; 95% CI, 0.57-0.85; P = .0004)—you see that the difference was not only statistically significant, but clinically meaningful, as well. What this means is that patients who are treated with this drug combination would, on average, have a 4 and one-half month longer disease-free benefit compared with the control arm, which I think is very important to patients. There was also a difference in terms of the confidence intervals: in the elotu-zumab arm, the 95% CI was between 16.6 and 22.2 months, whereas the interval in the comparator arm went all the way down to 12.1 and up to 17.2 months. In addition, the hazard ratio was 0.70, which means that patients have a 30% lower risk of progressing with the elotuzumab-containing regimen.

With several new treatment options coming into the field of my-eloma, it is getting a little bit more crowded. When that happens, aspects beyond efficacy start coming into play, including safety and quality of life. Based on this trial and also on my own experience, I think elotuzumab is a very tolerable drug, both from the short-term and the long-term perspectives. It is an infusional therapy that is giv-

Although multiple myeloma remains a largely incurable malignancy to date, advances in treatment options have succeeded in prolonging patients’ survival times. A little more than 15 years ago, the average patient with newly diagnosed myeloma was about one-third as likely as someone without the disease to live another 5 years. By 2009, that number had risen from one-third to about 45%.1 In the 1990s, growing use of stem cell transplantation was the cause of some of the improvements in survival rates, which was followed by continued improvements in the 2000s with the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor (PI) bortezomib.1,2

When the disease almost inevitably relapses after treatment, it returns in a form that is typically refractory to the currently available treat-ment options.3 There is obviously still room for improvement, whether that means prolonging survival, decreasing toxicities, overcoming mechanisms of resistance, or simply providing a more convenient administration method for patients. One of the novel strategies under investigation involves the use of monoclonal antibodies (mAbs), which have been used successfully in many other cancers in the past few years, but until now have had limited success in treating multiple myeloma.4 Two of the mAbs being studied in this field are elotuzumab and daratumumab, both of which have received breakthrough therapy designation from the Us Food and Drug Administration (FDA),5 and both of which have demonstrated efficacy in clinical trials in multiple myeloma—elotuzumab in combination with lenalidomide and dexametha-sone,6 and daratumumab as a single agent.7

While the approval of the PI bortezomib undoubtedly represented a major breakthrough in the treatment of multiple myeloma, many mechanisms for inherent or acquired resistance to this treatment exist, limiting its long-term usefulness.8 One novel strategy for overcoming some of the resistance to proteasome inhibition involves combining it with a histone deacetylase (HDAC) inhibitor, such as the recently ap-proved panobinostat, which targets one of the possible resistance pathways.9

Newer PIs also are entering the therapeutic arena within the myeloma field, including carfilzomib, which was approved in 2012,10 and ixaz-omib, which is still under investigation. Approved as a single-agent therapy that demonstrated durable antimyeloma activity with manageable toxicities,11 carfilzomib is going through further investigation regarding combination regimens and earlier lines of therapy.12,13 Meanwhile, ixazomib is still in phase III trials, but its pending approval as the first PI utilizing the oral route of administration is eagerly awaited.14

Perhaps the most revolutionary therapy being investigated is chimeric antigen receptor T-cell (CAR-T) therapy. In this approach, immune cells from a patient are extracted and re-engineered to express recombinant proteins (in this case, antigen-specific CARs), and then the re-engineered cells are reinfused into the patient. Complete remission (CR) rates of around 90% have been elicited using CAR-T therapy in relapsed/refractory pediatric acute lymphoblastic leukemia,15 and researchers hope to replicate these results in the multiple myeloma setting.

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en on days 1, 8, 15, and 22 of a 4-week schedule for the first 2 cycles, and then it is given on days 1 and 15 of the subsequent cycles. Week-ly infusions for 2 months, of course, are a little bit inconvenient. But once the dosing has moved beyond those initial 2 cycles, it can be dosed every other week. Combined with 4 and one-half months’ benefit, in my opinion, it marks quite an important contribution to myeloma therapy.

Moderator: What are the next steps for elotuzumab in terms of ongo-ing studies in frontline combinations with other available therapies, as well as in other settings in multiple myeloma?Dr Landgren: I think it’s a little bit too early to draw conclusions from ongoing studies of elotuzumab in other settings. We always have to wait for the data to come out, but from what it looks like, I think the results seem to be quite consistent. The drug seems to continue to deliver, and the data have shown that it is not a very toxic drug. It’s quite tolerable. so I think it’s an important drug. Given the fact that there is no established curative therapy for multiple myeloma, we need a lot of options, and this is a good one.

Moderator: Can you tell us about the phase II trial data released at the AsCO meeting about the anti-CD38 mAb daratumumab and the potential clinical implications?Dr Landgren: Daratumumab is 1 of 3 CD38 mAbs, along with sAR650984 and MOR202. These 3 drugs all target the CD38 an-tigen, which is highly expressed on the surface of plasma cells. As with elotuzumab, daratumumab seems to be efficacious and safe, and quality of life is good.

One thing that differs between the CD38 antibodies and elotu-zumab is that the CD38 antibodies have demonstrated efficacy as single drugs. Elotuzumab was also explored as a single drug, but it did not deliver; however, it showed an additive effect, as just discussed, when used in combination with lenalidomide and dexamethasone. Both daratumumab and sAR650984 have already been found to de-liver as single agents (in terms of durable responses).

Ongoing trials are exploring these molecules in combination with a range of different drugs. The data are not fully mature, so it is too early to know definitively how they will fare, but what we have seen so far is that they seem to be very tolerable. In 6 to 12 months, we will have a lot of exciting data to review, and we will see which are the preferred combinations. They are currently being tested in combination with PIs, IMiDs, and steroids. some studies also use a CD38 antibody instead of steroids. so I think the upcoming 6 to 12 months are going to be extremely interesting when it comes to mAb data in myeloma.

If I were to speculate based on the existing data, I think it is very likely that we are going to end up with a combination regimen of up to 4 drugs for the treatment of myeloma. such a combination could include a PI, an IMiD, low-dose steroids—maybe lower than we cur-rently use—and mAbs. Because many of these drugs are individually new and expensive, combining them will create a huge problem in terms of their extreme cost. The cost effectiveness has to be consid-

ered as well, though. If 4 drugs are given simultaneously—let’s say carfilzomib, daratumumab, lenalidomide, and dexamethasone, as an example—for 10 cycles that potentially cured patients’ myeloma, al-though the combination would be expensive, it would still be a more attractive option than using a 3-drug combination over and over again. We are not yet sure whether less-aggressive therapy can result in a greater expense in the long run. This issue will need to be worked out. But, from an efficacy perspective and also from a quality-of-life perspective, I think this potential combination is very attractive, both for newly diagnosed myeloma as well as in the relapsed setting.

Moderator: Are there any studies currently under way of daratu-mumab in the setting of smoldering myeloma?Dr Landgren: Yes. There is a newly opened, multicenter study that my institution is participating in to investigate dosing schedules of daratumumab in patients with smoldering myeloma. It makes sense to use mAbs in patients who are not immunocompromised because you are taking advantage of the patient’s own immune system. We know that multiple myeloma itself is usually associated with immuno-suppression. Many of the myeloma drugs studied to date cause a lot of immunosuppressive complications. so, using mAbs for patients with early disease is a very logical approach, and studies of this ap-proach are ongoing.

Moderator: Can you tell us about what was learned at the AsCO meeting about carfilzomib from the ENDEAVOR trial that evalu-ated carfilzomib/dexamethasone versus bortezomib/dexamethasone in patients with relapsed multiple myeloma?Dr Landgren: It is a very interesting era we are in right now in terms of myeloma research. There are the new drugs we just talked about, the CD38 and sLAMF7 antibodies. Also, there are drugs that I still consider to be new, despite gaining FDA approval about 2 years ago, such as carfilzomib, which we are learning more about now. Inter-im results of the ENDEAVOR study showed that depth of response, duration of response, and PFs were improved in the carfilzomib/dexamethasone group compared with the control group, which was treated with bortezomib/dexamethasone. so, carfilzomib helped to achieve deeper, longer responses.

Multiple studies in the past 6 months support the favorable find-ings from ENDEAVOR. A study published in The New England Journal of Medicine, called AsPIRE, investigated the combination of carfilzomib/lenalidomide/dexamethasone versus lenalidomide/dexamethasone in relapsed multiple myeloma. In the AsPIRE trial, PFs was 26.3 months in the carfilzomib group versus 17.6 months in the control group, which is essentially a 9-month difference in benefit. That is a pretty long time. Also, to put these results in con-text, 26.3 months was in patients with relapsed disease; this is longer than the median PFs achieved by many agents in patients with newly diagnosed disease.

Also, very recently, a National Institutes of Health (NIH) study was published. It investigated carfilzomib/lenalidomide/dexameth-asone for both newly diagnosed and high-risk smoldering myeloma,

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showing that all 12 of the patients with smoldering myeloma and 28 (62.2%) of the 45 patients with newly diagnosed myeloma achieved at least a near CR. None of those patients had received a transplant, and nearly all of them reached the point of minimal residual disease (MRD) negativity. so, here we have seen multiple studies showing that carfilzomib really delivers.

I think a key aspect with carfilzomib that is also being determined now will be the optimization of the dosing to make it a bit more convenient. Ongoing studies right now are exploring whether it can be given once a week instead of twice a week by increasing the dos-age. Hopefully, those results will be available in the next few months. That will make that drug even more accessible for patients.

Moderator: Are there any signals that increasing the dosage of carfil-zomib could increase the risk of neuropathy?Dr Landgren: That’s a very good question. None of the trials we have been discussing—ENDEAVOR, AsPIRE, the NIH studies—have found any grade 3 or higher peripheral neuropathy. They also have not encountered any worsening of peripheral neuropathy. If any-thing, there has been discussion of a possible cardiovascular signal. However, the largest study of them all, with 792 patients, was the AsPIRE trial, and that study found no significant difference in terms of cardiovascular outcomes between the 2 treatment arms. For now, that is the strongest evidence we have. What you could argue against is that the dosing for carfilzomib in AsPIRE was 27 mg/m2 twice a week, and some of these new trials are now considering using higher dosages. The full story is still unfolding, so we will have to wait for the ongoing work to fill in the blanks.

Moderator: Can you elaborate on the issue of eliminating MRD in the context of some of the more potentially potent combinations that are currently being evaluated in clinical trials?Dr Landgren: Across the board, a lot of studies are currently looking into the role of MRD testing in multiple myeloma. I recently searched on clinicaltrials.gov and found 34 myeloma trials that include MRD testing. I also did the same search on PubMed and found 424 pub-lications in myeloma. This is an exploding field. Also, I worked on a recently published review paper in Nature Reviews Clinical Oncology with sham Mailankody as the first author, which comprehensively reviews the role of MRD around the world. What we found is that no matter how MRD has been defined or measured—by flow cytometry, molecular sequencing, etc—MRD negativity is always associated with significantly more PFs and overall survival (Os) than MRD positivi-ty. That is consistent.

The last thing I want to say along those lines is that there are now emerging data showing that the depth of MRD is associated with clinical outcome, both PFs and Os. so, if you are MRD-negative with a tool that is sensitive to 10-3 versus 10-3 to 10-5 or 10-5, there is a difference. A very recent paper published in Blood by the British in-vestigators Rawstron et al from Leeds, England, suggests that for each log increase in MRD negativity—meaning, for every 10-fold improve-

ment—you gain 1 year of Os. so, if you can increase MRD negativity from 1% to 0.1% or from 0.1% to 0.01%, you gain another year.

Different drugs deliver different depths of response and MRD negativity. This concept is being explored in several different drug combinations. Even trials with drugs that have been around for a long time are looking more carefully now at patients who are in CR. some of these trials show a difference between some patients in CR in terms of their MRD status. And there is a difference in PFs and Os between these groups. I think the field is now using many new and effective drugs that are not very intense. And I expect that with the new MRD tools, we will be able to see deeper and deeper MRD negativity, which does translate into better outcomes.

The very last piece along these lines is that we held an interna-tional workshop on MRD testing in myeloma here at MsKCC on July 10, 2015. To me, it was striking to hear that, of the 70 experts in the room, everyone, even the flow cytometry experts, agreed that the molecular MRD tools are going to be the future because they are more sensitive, deliver better results, and soon are going to be more easily available. so that was very interesting.

Moderator: What are the recent data concerning some other novel mechanistic approaches in earlier stages of development [eg, CAR-T therapy]?Dr Landgren: CAR-T therapy is a relatively new concept in hema-tology. It has been studied in acute leukemia and lymphomas for a few years now. A few studies recently have been initiated for this therapeutic strategy in multiple myeloma. The first clinical trial that opened for myeloma was at the NIH with Jim Kochenderfer’s group. He had performed preclinical work targeting B-cell maturation an-tigen (BCMA), which led him to extract T-cells out of the patient, re-engineer the cells genetically, and return the re-engineered T-cells to the patient’s body. They look for BCMA that is expressed on the tumor cells; if they are there, the procedure can be performed. so far, this technology is in phase I, so no efficacy information is currently available. The dosage is being defined, and safety is being explored.

The second study of CAR-T therapy for myeloma was developed by Carl June at the University of Pennsylvania. His group developed CAR-T therapy a few years ago for lymphoma. Lymphomas express CD19, a B-cell marker. so, Carl June hypothesized that maybe B cells are more important in myeloma than previously thought. Although myeloma is considered to be a plasma cell disease, there is some ev-idence that other cells could play a key role. As recently presented, they gave CD19 CAR-modified T-cells to 6 patients with myeloma. The best result was achieved by a patient who had previously been treated with an autologous stem cell transplant (AsCT), and later received a second AsCT with CAR-modified T-cells. The duration of the effect was longer this time than it was the previous time, which was considered to be a striking finding, because typically, each suc-cessive AsCT lasts a shorter amount of time than the previous trans-plant. On the other hand, another patient in this trial received a transplant and the T-cells, but this patient’s disease progressed. It is

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too early to make final conclusions based on the short follow-up and the small numbers involved in this study, with 1 patient who seemed to have a good effect and other patients whose disease progressed.

B-cell maturation antigen is a myeloma target, whereas the Uni-versity of Pennsylvania uses a CD19 target. We do not yet fully un-derstand the implications of these 2 targets. Other groups, such as those here at MsKCC, are also working to develop CAR-modified T-cells. Although you use the cells, what this strategy is attempting to do is to target antigens on the surface of either tumor cells or other cells, which is the same strategy as that of the mAbs and other treatments. There are so many different ways to try to manipulate the immune system, such as with vaccines, viral therapy, or even some small molecules. so, although we think of these as very unique strat-egies, they are simply different tools to try to kind of take advantage of these mechanisms. However, these mechanisms can sometimes be approached by other strategies.

Moderator: Can you tell us a few things that have happened recently with panobinostat and the oral PI ixazomib?Dr Landgren: The HDAC inhibitor panobinostat was approved ear-lier this year. The reason this class of medication was explored in the context of multiple myeloma in the first place was because, mecha-nistically, discovery work had shown that if you block a proteasome, you have to cross all cells in the body. Myeloma cells, in particular, are very, very susceptible and will die with this strategy. Blocking the activity of proteasomes, which degrade misfolded proteins, causes accumulation of misfolded proteins in the cell, which becomes cy-totoxic. That is the mechanism that is believed to kill myeloma cells. Myeloma cells are smart, though, and, over time, they find a way to get around the problem we caused for them by blocking the protea-some. Ubiquinated proteins work together with HDAC6, which is a specific subclass of HDAC, causing the proteins to form aggresomes, which are proteins that have been assembled in a specific way. They are then sent to lysosomes, which take the proteins apart. so, if the proteasome is blocked, cells can still use other mechanisms to by-pass the problem, such as by using lysosomes to do the job instead. In this way, the cell avoids the proteasome killing effect. And, since HDAC6 is responsible for the escape mechanism, there seemed to be a rationale to attempt to inhibit both HDAC6 and a proteasome simultaneously.

Vorinostat, which is a pan-HDAC inhibitor, was the initial drug developed in this class. While the benefit it produced was statisti-cally significant, it was a difference of only a few weeks. Therefore, it was not approved. Panobinostat was then developed for myeloma, and did gain approval earlier in the year based on its significant 4.8-month benefit, which was deemed to be clinically meaningful. Panobinostat was given in combination with bortezomib plus dexa-methasone versus bortezomib plus dexamethasone on the control arm. Although the combination of the HDAC inhibitor and the PI produced a significant and clinically meaningful difference, many patients experienced grade 3 diarrhea. There were also other safety

signals, such as bone marrow toxicity. After the drug was approved, we have learned over the past few

months that maybe panobinostat can be combined with other drugs, for example, carfilzomib. Although the rationale for using it with a PI was there, as I just explained, data also exist to suggest that an IMiD may be an option due to the redundancy in the mechanism of action between the PIs and IMiDs. We do not fully understand how these drugs work. The recently presented data suggest a much better toxicity profile, with far less diarrhea, even with increasing dosages of panobinostat. Using a low dosage in combination with these other drugs may be the way to go. This is another example of a drug that is already approved, and yet we are still learning the best ways to use it. Panobinostat will probably be a drug that is used mostly for patients who have already tried many other options that did not work, until further data can answer these questions to allow it to be used in a broader context.

The oral PI ixazomib also is currently being investigated in clini-cal trials. Ongoing phase III trials are comparing ixazomib/lenalid-omide/dexamethasone with lenalidomide/dexamethasone in the control group. Earlier this year, the manufacturer of ixazomib issued a press release to indicate that at the study’s first prespecified interim analysis, the drug was found to add significant benefit in terms of PFs compared with the control arm. No detailed information was communicated at any of the recent conferences, but perhaps we will hear more about it at the upcoming 2015 American society of He-matology (AsH) Annual Meeting. At a prior AsH annual meeting, phase II trial data were presented showing that maintenance treat-ment with single-agent ixazomib deepened the responses achieved by lenalidomide/dexamethasone induction therapy, and that it is toler-able. This represents an opportunity to use an established target, the 20s proteasome, in an oral fashion with once-weekly dosing, which would be a very attractive option.

My take on all of this is that the deepest responses seem to come from the intravenous PI carfilzomib. Data from the ENDEAVOR and NIH trials seem to indicate that it can be a very attractive option for younger patients as combination therapy, producing very deep, durable, MRD-negative responses. We do not yet have head-to-head comparison data for the ixazomib/lenalidomide/dexamethasone combination regimen, but it does seem to be a very powerful com-bination that could be extremely attractive for older people or for younger patients for whom convenience or preference side against intravenous administration. I think the new baseline therapy will include 3 drugs, and, unless there is a reason not to use a triplet combination, I think most patients in the next 6 to 12 months could receive such a regimen, which could include a PI, an IMiD, and a steroid. We have even touched upon adding a mAb to that for some patients. The field has left 2-drug regimens behind now in favor of upcoming 3-drug options, which could turn into 4, which will create issues to resolve regarding cost.

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REFEREnCES1. Pulte D, Redaniel MT, Brenner H, et al. Recent improvement in survival of patients with multiple myeloma: variation by ethnicity. Leuk Lymphoma. 2014;55(5):1083-1089.2. Ria R, Reale A, Vacca A. Novel agents and new therapeutic ap-proaches for treatment of multiple myeloma. World J Methodol. 2014;4(2):73-90. 3. Kumar sK, Rajkumar sV, Dispenzieri A, et al. Improved surviv-al in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520.4. Khagi Y, Mark TM. Potential role of daratumumab in the treat-ment of multiple myeloma. Onco Targets Ther. 2014;7:1095-1100.5. Caffrey MK. Promising results for elotuzumab presented in session on multiple myeloma. http://www.ajmc.com/journals/evidence-based-on-cology/2015/the-american-society-of-hematology-annual-meeting-2014/promising-results-for-elotuzumab-presented-in-session-on-multiple-myelo-ma#sthash.Ce08KDp6.dpuf. Accessed July 23, 2015. 6. Lonial s, Dimopoulos M, Palumbo A, et al; ELOQUENT-2 In-vestigators. Elotuzumab therapy for relapsed or refractory multiple myeloma [published online June 2, 2015]. N Engl J Med. doi:10.1056/NEJMoa1505654.7. Lonial s, Weiss BM, Usmani sZ, et al. Phase II study of daratumum-ab (DARA) monotherapy in patients with ≥3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (sirius). J Clin Oncol. 2015;33(suppl; abstr LBA8512).8. Murray MY, Auger MJ, Bowles KM. Overcoming bortezomib resis-tance in multiple myeloma. Biochem Soc Trans. 2014;42(4):804-808. 9. Hideshima T, Richardson PG, Anderson KC. Mechanism of ac-tion of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10(11):2034-2042.10. Us Food and Drug Administration. FDA News Release. FDA approves Kyprolis for some patients with multiple myeloma. July 20, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnounce-ments/ucm312920.htm. Accessed July 23, 2015. 11. stewart AK. Carfilzomib for the treatment of patients with re-lapsed and/or refractory multiple myeloma [published online June 30, 2015]. Future Oncol. 12. stewart AK, Rajkumar sV, Dimopoulos MA, et al; for the As-PIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152.13. Korde N, Roschewski M, Zingone A, et al. Treatment with car-filzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma [published online July 2, 2015]. JAMA Oncol. doi:10.1001/jamaon-col.2015.2010. 14. Moreau P. Oral therapy for multiple myeloma: ixazomib arriving soon. Blood. 2014;124(7):986-987.15. Tontonoz M. AACR 2015: report from day 4. April 21, 2015. http://www.cancerresearch.org/news-publications/our-blog/april-2015/aacr-2015-report-from-day-4. Accessed July 23, 2015.

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