PROGRAM SYLLABUS - Medscapeimg.medscape.com/...program-syllabus-9989-v2.pdf · received his medical degree from the Medical College of ... Rini was the Principal Investigator of an

P R O G R A M S Y L L A B U S

A CME-certified Oncology Exchange Activity

Challenges in Treating Renal Cell Carcinoma in the Community A Grand Rounds Series

Program #9989 A CME-certified Oncology Exchange Activity Page 2

TABLE OF CONTENTS Program Content and Format ..................................................... Page 3

Target Audience/Learning Objectives ......................................... Page 4

CME Statements ........................................................................ Page 4-5

Disclosures ................................................................................. Page 5

Steering Committee ................................................................... Pages 6-7

Program Slides ......................................................................... Page 8



PROGRAM CONTENT AND FORMAT Community oncologists who treat patients with renal cell carcinoma (RCC) are constantly challenged to stay up to date with recently approved agents, emerging data from ongoing studies of novel investigational regimens, and evolving standards of care for RCC. Challenged by the lack of consensus surrounding treatment selection for patients with RCC, community oncologists need access to new information, tools, and insights, which they can integrate into their practices to improve patient outcomes. This engaging program will educate community oncologists on emerging data from ongoing studies in RCC and provide guidance on optimal treatment selection and management of treatment-related adverse effects in patients with RCC. Visit www.OncExchange.com for more information.



TARGET AUDIENCE This activity is intended for community oncologists and other clinicians who are actively involved in the care of patients with renal cell carcinoma.

EDUCATIONAL OBJECTIVES

At the conclusion of this activity, participants should be able to demonstrate the ability to: • Compare the various treatment options available and choose the optimal treatment

based on patient characteristics and emerging data from clinical studies of patients with advanced RCC

• Discuss strategies for the management of side effects associated with the therapies for advanced RCC

• Review sequential and combination treatment strategies for patients with advanced RCC • Identify key investigational regimens for advanced RCC from ongoing clinical studies

ACCREDITATION

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Potomac Center for Medical Education and Rockpointe Oncology. The Potomac Center for Medical Education is accredited by the ACCME to provide continuing medical education for physicians.

CME CREDIT

The Potomac Center for Medical Education designates this live activity for a maximum of 1.0 AMA PRA Category I credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

For information about the accreditation of this program, please email [email protected].

SPECIAL SERVICES

Event staff will be glad to assist you with any special needs (e.g. physical, dietary, etc.).

FEE AND RECEIVING CME CREDIT

There is no fee for this educational activity. To receive CME credit the participant must: • Participate in this one-hour-long program in its entirety; • Sign in / sign out on the sheet provided by the host coordinator; • Complete and sign the registration and evaluation form; and • Return the registration and completed evaluation form to the host coordinator.



DISCLOSURE STATEMENT Potomac Center for Medical Education (PCME) adheres to the policies and guidelines, including the Standards for Commercial Support, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of a continuing medical education program sponsored by the Potomac Center for Medical Education are required to disclose any relevant financial relationships with any commercial interest to PCME as well as to learners. All conflicts are identified and resolved by PCME in accordance with the Standards for Commercial Support in advance of delivery of the activity to learners. The content of this activity was vetted by an external medical reviewer to assure objectivity and that the activity is free of commercial bias.

PROGRAM DISCLOSURES The faculty/steering committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

Steering Committee:

Robert A. Figlin, MD, FACP: Research Funding: Argos, Bristol-Myers Squibb, Immatics, Novartis; Scientific Advisory Board: Onyx, Pfizer Brian I. Rini, MD, FACP: Advisor: Aveo, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer; Primary Investigator: GlaxoSmithKline, Pfizer

Non-faculty Content Contributors:

Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to disclose

FDA DISCLOSURE

The contents of some CME/CE activities may contain discussions of non-approved or off-label uses of some agents mentioned. Please consult the prescribing information for full disclosure of approved uses.



STEERING COMMITTEE

Robert A. Figlin, MD, FACP Steven Spielberg Family Chair in Hematology/Oncology Professor of Medicine and Biomedical Sciences Director, Division of Hematology/Oncology Deputy Director, Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Los Angeles, CA

Robert A. Figlin, MD, FACP is the Steven Spielberg Family Chair in Hematology/Oncology, a Professor of Medicine and Biomedical Sciences, the Director of the Division of Hematology/Oncology, and the Deputy Director of the Samuel Oschin Comprehensive Cancer Institute, all at Cedars-Sinai Medical Center in Los Angeles, CA. Dr. Figlin received his medical degree from the Medical College of Pennsylvania, then completed his residency and chief residency in internal medicine at Cedars-Sinai Medical Center and a fellowship in hematology/oncology at the David Geffen School of Medicine at UCLA. He is an Emeritus Professor of Medicine and Urology at the David Geffen School of Medicine at UCLA. Prior to joining Cedars-Sinai, Dr. Figlin was the Arthur and Rosalie Kaplan Endowed Chair of the Department of Medical Oncology and Therapeutics Research, and the Associate Director for Clinical Research at the City of Hope Comprehensive Cancer Center. Prior to that, Dr. Figlin served as the Henry Alvin and Carrie L. Meinhardt Endowed Chair in Urologic Oncology and Professor of Medicine and Urology in the Divisions of Hematology/Oncology and Urologic Oncology at the David Geffen School of Medicine at UCLA. Dr Figlin joined the UCLA faculty as Assistant Professor of Medicine in the Division of Hematology/Oncology and was appointed Co-director of the Jonsson Comprehensive Cancer Center’s Oncology Program. He also held the post of Medical Director of the Thoracic and Genitourinary Oncology Program in the Departments of Medicine, Surgery, and Urology, and served as Program Director of Solid Tumor Developmental Therapeutics within the Cancer Center. Dr. Figlin serves as Editor for Kidney Cancer Journal, and his studies have appeared in Clinical Cancer Research, Journal of Clinical Oncology, New England Journal of Medicine, Lancet, JNCI, Lancet Oncology, and Journal of Urology, among others. He has authored more than 300 peer-reviewed articles, more than 60 book chapters, and has published multiple books in kidney cancer. He is the Editor of the recently released book, Renal Cell Carcinoma: Translational Biology, Personalized Medicine, and Novel Therapeutic Targets. A nationally recognized leader in genitourinary and thoracic oncology, Dr. Figlin’s research focuses on renal cell carcinoma and thoracic malignancies. He established and directs the Kidney Cancer Program at Cedars-Sinai Medical Center, which aims to understand the biology of kidney cancer and translate that knowledge into novel treatment approaches.



STEERING COMMITTEE

Brian I. Rini, MD, FACP Professor of Medicine, Lerner College of Medicine Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Institute Glickman Urological Institute Cleveland, OH

Brian I. Rini, MD, FACP is a Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Cleveland, OH. A staff member of the Department of Solid Tumor Oncology and Co-leader of the Genitourinary Program of the CASE Comprehensive Cancer Center, Dr. Rini’s work focuses on genitourinary malignancies. Dr. Rini earned his medical degree at the Ohio State University College of Medicine. Dr. Rini completed a residency program in internal medicine and a fellowship in hematology/oncology at University of Chicago Hospitals. Dr. Rini was an Assistant Professor at the University of California San Francisco before moving to the Cleveland Clinic. Dr. Rini’s primary research has been in renal cell carcinoma (RCC) and prostate cancer, with special focus on antiangiogenic therapy and immunotherapy. Dr. Rini has been involved in the initial and ongoing development of targeted agents for metastatic RCC, and was an integral investigator in the clinical development of several agents which are now FDA approved. Dr. Rini was the Principal Investigator of an international phase III cooperative group trial of bevacizumab plus interferon and the PI of the phase III axitinib trial in metastatic RCC that lead to FDA approval, and is currently the PI of several global phase III trials in RCC. Dr. Rini’s research has been published in numerous peer-reviewed journals, such as Journal of the National Cancer Institute, Journal of Clinical Oncology, Cancer, Lancet, and JAMA. He is a member of the editorial board of Journal of Clinical Oncology and Co-chair of the NCI RCC Task Force.

CHALLENGESINTREATINGRENALCELLCARCINOMAINTHECOMMUNITY

©2013PCME Page8

A CME-certified Oncology Exchange ActivityA CME-certified Oncology Exchange Activity

This activity is supported by educational grants fromAstellas Scientific and Medical Affairs, AVEO Oncology, and Novartis Oncology.

Jointly sponsored byPotomac Center for Medical Education and Rockpointe Oncology.

DisclosuresAll relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers, or their spouses/partners have been listed on page 5 of your program syllabus.

Off-label Discussion DisclosureThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Educational Objectives

At the conclusion of this activity, participants should be able to demonstrate the ability to:

• Compare the various treatment options available and choose the optimal treatment based on patient characteristics and emerging data from clinical studies of patients with advanced RCC data from clinical studies of patients with advanced RCC

• Discuss strategies for the management of side effects associated with the therapies for advanced RCC

• Review sequential and combination treatment strategies for patients with advanced RCC

• Identify key investigational regimens for advanced RCC from ongoing clinical studies

Renal Cell Carcinoma

FH = fumarate hydratase; LOH = loss of heterozygosity; VHL = von Hippel-Lindau

DeVita VT et al, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1142.

Signaling Pathways and Selective Inhibitors in RCC

VEGFR

VEGF

VEGFBevacizumab

EC

Growth factor receptor

Growth factor(e.g. PDGF, TGF-α, EGF)

Tumor cell

EC=endothelial cell; EGF=epidermal growth factor; MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; TGF=transforming growth factor; VEGFR=VEGF receptor.

Garcia. CA Cancer J Clin. 2007;57:112; Patel. Br J Cancer. 2006;94:614; Motzer. J Clin Oncol. 2006;24:5601; Sonpavde. Curr Oncol Rep. 2007;9:115; Hu-Lowe. Clin Cancer Res. 2008;14:7272; Kay. ASCO GU. 2009 (abstr 278); US National Institutes of Health website. http://clinicaltrials.gov/ct2/show/NCT00836927. Accessed 10/13/09.

↑ HIF1-α expression

Sorafenib Sunitinib

PazopanibAxitinib

TivozanibCediranibDovitinibVascular

permeability EC migration

TemsirolimusEverolimus

Ridaforolimus (Deforolimus)

Akt

PI3K

MAPK

Raf

MEK

Erk

P

P P

P

EC survival

EC proliferation

Sorafenib Akt

PI3K Raf

MEK

Erk

P

P P

P

mTOR

Tumor cell proliferation

CediranibDovitinibErlotinib

Patients with mRCC are Heterogeneous

Need no Predict risk of recurrence?

Previously untreated metastatic disease

Long-term responders

25%

Need no therapy

15% Primary refractory

15%Partial

responders20-40%

Toxicities15%

Choose appropriate therapy?

Predict risk of recurrence?

Avoid toxicity?

Modified from: Srinivas S. Presented at: ASCO 2011 Education session.


©2013PCME Page9

Management of mRCC: Strategies for today

• How can we optimise outcomes with current therapies in the treatment of mRCC?

I d ti t

Strategies for today

M lti l t t d Eff ti th Improved patient outcomes

Multiple targetedagents

Effective therapy management

Adverse event management

Maximize treatment duration

Dose optimization

Management of mRCC Strategies for Today and Tomorrow

How can we achieve our goal of long-term survival in mRCC?

Goal

Strategies for tomorrow

Challenge Potential solutions

Sequencing and combination of agents

Appropriate treatment selection

Individualization of treatment

Resistance to current agents

Novel agents

Long-term survival

Biomarkers

Adverse-event Management

• Patient education about potential adverse events

• Assess and stabilize baseline comorbidities

Prior to treatment

During treatment

• Monitor patients frequently

• Prompt adverse event management- Standard medical intervention

- Consider dose reductions/ interruptions

Schmidinger M et al. Cancer Invest. 2010;28:856-864.

Current State of RCC Therapy in 2013

• Explosion of choices in the last 7 years• 8 FDA-approved agents• 3 classes of drugs• Slowing of disease• Prolongation of life

• Immunotherapy– IL-2– IFN-α

• mTor Inhibitors– Temsirolimus– Everolimus

* Not FDA approved

NCCN Guidelines: Kidney Cancer v1.2013. www.nccn.org.

VEGF Inhibitors- Sunitinib- Sorafenib- Pazopanib- Axitinib - Bevacizumab + IFN-α- Tivozanib*

Potential Prognostic/Predictive Markers in RCC

• Hypertension (sunitinib, bevacizumab, and axitinib therapy)

• VEGF expression (TARGET trial; sorafenib therapy)

• HIF2 (sunitinib therapy)

VHL t t (VEGF t t d th )• VHL status (VEGF-targeted therapy)

• HFS (sunitinib therapy)

• Asthenia and fatigue (sunitinib therapy)

Rini. J Natl Cancer Inst. 2011;103:763. Rixe. ASCO. 2009 (abstr 5045). Escudier. J Clin Oncol. 2009;20:3312. Patel. ASCO. 2008 (abstr 5008).Choueiri. J Urol. 2008;3:860. Hutson. ASCO. 2008 (abstr 5046).Michaelson. ASCO GU. 2011 (abstr 320). Davis. ESMO. 2011 (abstr 1139).

Biomarker in RCC

Hypoxia-inducible factors/

angiogenesis

Regulators of apoptosis/

growth

Regulators of cell cycle

Regulator of T/dendritic cell

activity

Adhesion molecules

HIF-1 alpha P53 P27 B7H1 EpCAM

CA IX Bcl-2 pTEN B7H4 EphA2

VHL alteration Survivin PD1 Vascular-Cell VHL alteration (mutation/

methylation)

Survivin PD1 Vascular-Cell Adhesion

Molecule-1

VEGF and VEGF-receptors, CAIX

Smac/DIABLO B7H3

IMP3

Choueiri TK. Prognostic factors in metastatic renal cell carcinoma. In: Rini and Campbell, 2009.

Tumor/Host Single genes/Signatures DNA/RNA/miRNA/proteins


©2013PCME Page10

Risk Factor Criteria for Advanced RCC

Parameters

Karnofsky PS <80%

Time from diagnosis to treatment <12 mos

Hemoglobin <LLN

Risk Level Number of Factors

Favorable 0

Intermediate 1-2

Heng. J Clin Oncol. 2009;27:5794.

Calcium >ULN

Neutrophil count >ULN

Platelet count >ULN

LLN = lower limit of normal; ULN = upper limit of normal

Intermediate 1 2

Poor ≥3

Therapy ManagementAdverse Event Management

Key adverse events associated with targeted agents

VEGFR-targeted therapy mTOR inhibitors

Fatigue/astheniaSkin toxicities

Gastrointestinal symptomsStomatitis

Hypertension

Metabolic abnormalities (e.g. hyperglycaemia)

Fatigue/astheniaRash

AnemiaPneumonitis (rarely)

Motzer RJ et al. N Engl J Med. 2007;356:115-124. Escudier B et al. N Engl J Med. 2007;356:125-134. Escudier B et al. Lancet. 2007;370:2103-2111. Rini B et al. J Clin Oncol. 2008;26:3743-3748. Hudes G et al. N Engl J Med. 2007;356:2271-2281. Sternberg C et al. J Clin Oncol. 2010;28:1061-1068.Motzer RJ et al. Lancet. 2008;372:449-456. Schmidinger M, Bellmunt J. Cancer Treat Rev. 2010;36:416-424.

Common Adverse Events

Adverse Event Bevacizumab Sunitinib Sorafenib Pazopanib Temsirolimus Everolimus

Fatigue ++ +++ ++ + + ++

Rash - + ++ - +++ ++

Hand-foot syndrome - + ++ - - -

Hypertension + + + + -

Diarrhea + ++ ++ ++ + +

Stomatitis - ++ + - ++ ++

Myelosuppression - ++ - + + +

Metabolic syndrome - - - ++ ++ ++

Epistaxis/bleeding + - - -

Proteinuria ++ + + + - -

Prescribing information: Avastin (2013), Sutent, Nexavar, Votrient, Torisel, Afinitor (2012).

Case Discussion

• 52-year-old male, PS 0, Weight 102 kg, Height 180 cm, BP 130/78, pulse 82, resp rate 16

• Presenting symptoms: Left rib pain – 3 weeks duration, onset after playing touch football, minimal pain relief with ibuprofen

• PMH: hypertension, hyperlipidemia

• Meds: HCTZ 25 mg qd, atorvastatin 20 mg qd

• ROS: non-contributory

• CXR was obtained to rule out rib fracture and revealed lytic lesion, left fourth rib and numerous bilateral pulmonary nodules

• F/U CT scan recommended

• CT chest, abdomen, and pelvis performed– 8 cm mass, upper pole left kidney– Multiple bilateral pulmonary nodules suspicious for metastatic disease– Largest = 2.4 cm x 1.8 cm

Case Discussion

• Referred to urologist • Underwent laparoscopic nephrectomy• Pathology

– Revealed tumor extension into renal vein with invasion of left adrenal gland (T3a)of left adrenal gland (T3a)

– Lymph nodes negative (N0)– Tumor stage: T3aN0M1– Histology: clear cell– Fuhrman Grade 3

• Referred to medical oncologist for discussion of treatment options

What is the Optimal Treatment Choice for this Newly Diagnosed Patient with Metastatic Renal Cell Carcinoma? (choose all that apply)

1. Initiate radiation therapy for minimally symptomatic disease

2. Assessment of prognostic variables and comorbidities and initiate VEGF targeted therapy

3. Referral to an IRB-approved clinical trial

4. Initiate combination targeted therapy outside of a clinical trial

5. Screen for the presence of a VHL mutation


©2013PCME Page11

What Treatment Options are Reasonable in the Frontline Setting in Patients with Metastatic Disease and Intermediate Risk?

1. Bevacizumab plus interferon

2. Pazopanib

3. Temsirolimus

4. Everolimus

5. Sunitinib

6. Interleukin 2, high dose

NCCN Guidelines First-line Therapy for Clear Cell RCC

a Category 1. b Category 1 for poor-prognosis pts; category 2B for selected pts of other risk groups. c Category 2A for pts with excellent PS and normal organ function.

+Best Supportive Care


NCCN GuidelinesSystemic Therapy for Non-clear Cell Histology

a Preferred. b Category 1 for poor-prognosis pts; category 2A for other risk groups. c Category 3.

+Best Supportive Care

Axitinibc


Firstline Therapy

PFS: 11 vs 5 mo. PFS: 9.2 vs 4.2 mo.PFS: 10.2 vs 5.4 mo.

Pazopanib vs BSCBevacizumab + IFN-αSunitinib vs IFN-α

Temsirolimus vs IFN Ti o anib s Sorafenib

Motzer RJ et al. J Clin Oncol. 2007;25:3958-3964. Escudier B et al. Lancet. 2007;370:2103-2111.Sternberg C et al. J Clin Oncol. 2010;28:1061-1068. Rini BI at el. Lancet. 2009;373:1119-1132. Motzer RJ et al. J Clin Oncol. 2012;30:1371-1377.

Temsirolimus vs IFN Tivozanib vs Sorafenib

Temsirolimus1-3 Sunitinib4 Bev + IFN-α1.5,6 Pazopanib7,8 Tivozanib

Patient Population Poor risk Tx naive Tx naive Tx naive Tx naive

Comparator IFNα IFNα IFNα placebo Sorafenib

ORR, % 8.6 47 31/25.5* 32 33

Summary Firstline Therapy in mRCC

,(vs comparator) (vs 4.8) (vs 12) (vs 12/13.1) (vs 3) (vs 23)

PFS, mos

(vs comparator)

5.5(vs 3.1)

11 (vs 5)

10.2/8.4*(vs 5.4/5.2)

11.1(vs 2.8)

12.7(vs 9.1)

OS, mos(vs comparator)

10.9(vs 7.3)

26.4(vs 21.8)

23.3/18.3*(vs 21.3/17.4)

22.9(vs 23.5) NR

1. Escudier et al. J Clin Oncol. 2009;27:3312-3318.2. Nexavar® (sorafenib) Prescribing information, 2012.3. Hudes et al. N Engl J Med. 2007;356:2271-2281. 4. Motzer et al. J Clin Oncol. 2009;27:3584-3590.5. Escudier et al. J Clin Oncol. 2010;28::2144-2150. 6. Rini et al. J Clin Oncol. 2010; 28:2137-2143.

Effective Therapy Management

Dosing

Treatment Duration

Optimum Efficacy

Adverse Event Management

Ravaud A. Ann Oncol. 2009;20:i7-i12.


©2013PCME Page12

Probability of a Tumour Response Increases with Mean Daily Sunitinib Exposure

resp

onse

0 6

0.8

1.0

Mean

95% CI

P=0.023 for AUC

AUC sunitinib (ug•hr/mL)

Prob

abili

ty o

f a r

0.5 1.0 1.5 2.0

0.0

0.2

0.4

0.6

Source: Houk BE et al. Cancer Chemother Pharmacol. 2010;66:357-371.

Higher Exposure to Sunitinib Is Associated with Longer Time to Progression and OS

1.0

ivin

g 1.0

AUC >Median (n=120)AUC <Median (n=117)

AUC >Median (n=120)AUC <Median (n=117)

Time to Tumour Progression OS

Source: Houk BE et al. Cancer Chemother Pharmacol. 2010;66:357-371.

P=0.014Relative risk 0.49

P=0.001Relative risk 0.52

Days

Frac

tion

of p

atie

nts

not p

rogr

esse

d

0 100 200 300 400 500

0.0

0.2

0.4

0.6

0.8

Days

Frac

tion

of p

atie

nts

surv

0 100 200 300 400 500

0.0

0.2

0.4

0.6

0.8

600

Renal EFFECT Trial: Phase II Study of Intermittent vs Continuous Sunitinib

Pts with locally recurrent clear-cell carcinoma or

mRCC, measurable disease, and Karnofsky PS

≥70%; no previous systemic

Sunitinib 50 mg/day 4 wks on, 2 wks off

(n=146)

• Stratified by MSKCC risk group

• Sunitinib continued until unacceptable toxicity, progression, or for 2 yrs

• Primary endpoint: TTP

• Secondary endpoints: ORR, OS, and safety

therapy for advanced disease

(n=292)

Sunitinib 37.5 mg/day continuously

(n=146)

Motzer. ASCO GU. 2011 (abstr LBA308).

MSKCC = Memorial Sloan-Kettering Cancer Center; PS = performance status; TTP = time to progression

EFFECT: Efficacy

OutcomeIntermittent

Sunitinib

(n=146)

Continuous Sunitinib

(n=146)

PValue

Median OS, mos 23.1 23.5 0.615

ORR, % 32.2 28.1 0.444

Median PFS, mos* 8.5 7.0 0.070

TTP

lity

of N

o Tu

mor

ro

gres

sion

1.0

0.8

0.6

0.4

Schedule 4/2 Median: 9.9 mos(95% CI: 7.0-13.4)

Intermittent sunitinib

Continuous sunitinib

• Trend toward inferior TTP with continuous sunitinib

• Safety: AEs were similar between the 2 arms

Reproduced with permission from Motzer. ASCO GU. 2011(abstr LBA308).

,

Median time to deterioration, mos

4.0 2.9 0.034

*Sensitivity analysis for TTP; AE=adverse event

Prob

abi

Pr

0.2

0.00 10 20

Mos

HR: 0.77(95% CI: 0.57-1.04)P=0.090 (unstratified log-rank test)

30

Phase III Non-inferiority Trial of Pazopanibvs Sunitinib in First-line mRCC (COMPARZ)

*Pazopanib 800 mg/dayEligibility criteria

• Locally advanced or mRCC with clear-cell histology

RANDOMI 1:1

Motzer et al. ASCO 2012.www.clinicaltrials.gov (NCT00720941).

Sunitinib50 mg/day

(Schedule 4/2)

Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL

n=876clear cell histology

• No prior systemic therapy for advanced mRCC

SATION

*Conditionally approved

Hair color changeWeight decreasedSerum ALT increased

AlopeciaUpper abdominal painSerum AST increasedFatigueRashPain in extremityConstipation

Relative Risk in Adverse EventsAE occurrence ≥10% in either arm

ConstipationTaste AlterationLDH increasedSerum creatinine increasedPeripheral edemaHand-foot syndromeDyspepsiaPyrexiaLeukopeniaHypothyroidismEpistaxisSerum TSH increasedMucositisNeutropeniaAnemiaThrombocytopenia

Favors pazopanib Favors sunitinibMotzer et al. ASCO 2012.


©2013PCME Page13

Summary of the COMPARZ trial

• This phase III trial demonstrates non-inferiority of pazopanib relative to sunitinib for progression-free survival

• Pazopanib efficacy is further supported by similar overall survival and higher response rates

• The differentiated safety profile of pazopanib includes:

– Lower incidence of hand-foot syndrome, fatigue, and mucositis

– Higher incidence of liver function test abnormalities

• Improved tolerability supported by better QoL scores for patients receiving pazopanib

Phase III Patient Preference Study of Sunitinib vs Pazopanib (PISCES)

*Pazopanib 800 mg/day

Eligibility criteria:• Locally advanced

or mRCC of any histology

• Non-measurable disease permitted if metastatic disease

Patient preference?

Sunitinib50 mg/day

(Schedule 4/2)

RANDMIZ

• Primary endpoints: Patient preference (questionnaire)

• Secondary endpoints: Reason for patient preference; fatigue; dose modifications and time to dose modification; safety/tolerability

*Conditionally approved

www.clinicaltrials.gov (NCT01064310).Escudier et al. ASCO 2012.

Sunitinib50 mg/day

(Schedule 4/2)

n=161metastatic disease confirmed

• No prior systemic therapy for advanced or mRCC

• ECOG PS 0 or 1 10-week treatment period

10-week treatment period

2-weekwashoutperiod

p

Pazopanib 800 mg/day

ZATION

Primary Endpoint: Patient Preference Primary Analysis Population

60

70

80

90

tient

s

70%

Difference (pazopanib vs sunitinib) 49.3%

90% CI for difference (37.0%, 61.5%)

P value <0.001

CI = confidence interval

Escudier et al. ASCO 2012.

0

10

20

30

40

Pazopanib Preferred Sunitinib Preferred No Preference

Perc

ent o

f Pat

22%

8%

50

Immunotherapy

• Interferon-α (IFN-α): “the control”– Median PFS: 4.7 mo – Median OS: 13 mo

• High dose Interleukin (IL-2)– Response rate: 15-20% – 5-7% durable CRs– NCI 1986-2006

Median Overall SurvivalCR: Not reachedPR: 39.1 moNo response: 15.1 mo

McDermott DF et al. J Clin Oncol. 2005;23:133-141.Klapper JA et al. Cancer. 2008;113:293-301.

High dose IL-2 NCI Experience 1986-2006

IMA901 Renal Cell Cancer Phase III Trial Study Design

n=330-350• 1st line metastatic and/or locally advanced RCC• HLA-A*02-positive• Documented tumor lesions• Favorable or intermediate risk (Heng et al. 2009)

Chief Investigator US: Brian Rini, ClevelandChief Investigator EU: Tim Eisen, London

Primary: OSSecondary: OS in biomarker subgroup, PFS

safety, immune responses, novel biomarkers

Stratification based upon number ofbaseline Heng risk factors (1, 2, 3, or 4)

Pivotal Phase III ADAPT Trial Initiating 2H’12

Diagnosis, Nephrectomy,Screening

↓Registration;

Leukapheresis (A A l )

Arm A: AGS-003 (8 doses) plusStandard treatment* for 48 weeks (n = 300)

Arm B: Standard treatment*

AGS-003 quarterly + Standard treatment*

until PD

Standard treatment*

≥ SD

Pre-treatment Induction Booster

• Open-label design, no placebo-control, single leukapheresis (Arm A only)

• Primary endpoint: Overall Survival (80% power; HR: 0.708)

• Initiating under Special Protocol Assessment (SPA) with FDA

• Global Study PIs: Robert Figlin, MD (Cedars-Sinai); Christopher Wood, MD (MDACC)

• Collaboration with SUO-CTC in North America to support multidisciplinary efforts

• Status: US sites are activating; Qualifying sites in EU, Canada and other select countries with enrollment commencing late 2012

(Arm A only) ≥ SDfor 48 weeks(n = 150)

Standard treatment* until PD

* Standard treatment initiates with 6-week sunitinib cycles (50mg daily, 4 weeks on, 2 weeks rest.)Other compatible agents may be substituted for intolerance and/or early PD prior to week 48.


©2013PCME Page14

Case 2

• Patient: Male, 64-year-old man

• Past History: hypertension and hypercholesterolemia

• Current Medications: amlodipine 5mg QD and atorvastatin 20mg QD

• Social History: married; father of 2 children; works as a consultant

• Family History: coronary artery disease and lung cancer

Case 2: History of Present Illness

• Presenting Symptoms: Hematuria

• Initial Treatment: Right radical nephrectomy (2008)

• Tumor Histology: Clear cell RCC, grade 3

• Tumor Stage: T2, NX

B i / h M N• Brain/other Metastases: None

• ECOG Performance Status: 0

• Recurrence: Multiple lung nodules and medistinal lymph nodes; biopsy-proven recurrent clear cell RCC (2010)

• Initial Systemic Treatment: Sunitinib 50 mg 4/2

• Response: Confirmed partial response after 4 cycles, continued (eventually dose-reduced to 37.5 mg 4/2 due to fatigue) for a total of 18 months before RECIST-defined PD

Best response on sunitinib PD on sunitinib

Sunitinib The next step is . . .

• Continue sunitinib, as patient is tolerating well with “clinical benefit” with no symptoms from progressive disease

• Change to axitinib at a starting dose of 5mg BID

• Change to everolimus 10mg QD• Change to everolimus 10mg QD

Resistance Appears Mediated by “Angiogenic Escape” – ASL MRI: Rodent Model

ASL MRI

Day 22Day 9Day 3Baseline

H & E

CD34

Schor-Bardach R et al. Radiology. 2009;251:731-742.

Eligibility criteria:• Histologically confirmed mRCC

with clear-cell component

• Failure of one prior first-line regimen containing ≥1 of: - Sunitinib

Phase III Study of Axitinib vs Sorafenib as Second-line Therapy for mRCC (AXIS)

Axitinib 5 mg BID

RANDOMI

Sorafenib 400 mg BID

Sunitinib- Bevacizumab + IFN-α- Temsirolimus- Cytokine(s)

Stratification• Prior regimen• ECOG PS 0 vs 1

n=723

Primary endpoint: PFS

Secondary endpoints: OS, ORR, duration of response, safety, QoL

IZATION

www.clinicaltrials.gov (NCT00920816).


©2013PCME Page15

Progression-free Survival (IRC Assessment)

1.0

0.9

0.8

0.7

0.6

0.5

P<0.0001 (log-rank)Stratified HR 0.665

AxitinibSorafenib

mPFS, mo 95% CI

6.74.7

6.3–8.64.6–5.6

n-fr

ee S

urvi

val

babi

lity)

IRC = Independent Review Committee

361 256 202 145 96 64 38 20 10 1 0362 224 157 100 51 28 12 6 3 1 0

Subjects at risk, nAxitinibSorafenib

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10

Time (months)

12 14 16 18 20

(95% CI 0.544–0.812)

Prog

ress

ion

(pro

b

PFS by Prior Regimen

Prior Treatment RegimenAxitinib(n=361)

Sorafenib (n=362) HR P value*

Cytokines (n=251)IRCInvestigator

12.112.0

6.58.3

0.464 0.636

<0.00010.005

Sunitinib (n=389)4 8 3 4 0 741 0 011

( )IRCInvestigator

4.8 6.5

3.44.5

0.7410.636

0.0110.0002

Temsirolimus (n=24)IRCInvestigator

10.12.6

5.35.7

0.5111.210

0.1420.634

Bevacizumab (n=59)IRCInvestigator

4.26.5

4.74.5

1.1470.753

0.6370.213

*One-sided log-rank test stratified by ECOG PS

Best Response by RECIST(IRC Assessment)

Best Overall Response, % Axitinib Sorafenib

Partial response*

Stable disease

19.4

49 9

9.4

54 4Stable disease

Progressive disease

Indeterminate

49.9

21.6

6.1

54.4

21.0

11.6

Risk ratio (95% CI) 2.1 (1.4–3.0)

*Axitinib vs Sorafenib: P = 0.0001

Everolimus Phase III Study (RECORD-1)Design and Prior Therapy

Everolimus + BSC

Prior Treatment

Everolimus (n = 277)

%

Placebo (n = 139)

%

VEGFR-TKI therapy

RAND

Placebo + BSC(n = 139)

(n = 277)Patients progressed on/within 6 mo of sunitinib and/or sorafenib

Prior cytokines and/or bevacizumab also permitted

Sunitinib 45 43

Sorafenib 29 31

Both 26 26

Other systemic therapy

Immunotx 65 67

Chemotx 13 1679% of patients received 2 or more prior therapies

Motzer RJ et al. Cancer. 2010;116:4256-4265.

DOMIZATION

2:1

Everolimus Phase III StudyPFS

100

bilit

y, %

80

60 Log rank P value <0.001

Everolimus (n=277)

Hazard ratio = 0.3395% Confidence Interval (CI) [0.25, 0.43]

Median PFSEverolimus: 4.90 moPlacebo: 1.87 mo

100

bilit

y, %

80

60Log rank P value <0.001

Everolimus (n=277)

Hazard ratio = 0.3295% CI [0.25, 0.41]

Median PFSEverolimus: 5.49 moPlacebo: 1.87 mo

Central Radiology Review Investigator Assessment

Months

0 142 4 6 8 10 12

0

Prob

ab

40

20

139 47 15 6 2 0 0 0277 192 115 51 26 10 1 0

Everolimus (n=277)

Placebo (n=139)

Months

0 142 4 6 8 10 12

0

Prob

ab

40

20

Number of patients at risk

EverolimusPlacebo 139 62 25 8 5 0 0 0

277 210 149 76 33 11 2 0

( )

Placebo (n=139)

1Escudier et al. Ann Oncol. 2008;19:viii45. Abstract 72O. 2Motzer et al. ASCO-GU 2009. Abstract 278.

Clinical outcome to 2nd-line VEGF-targeted therapy based on 1st-line VEGF-targeted therapy response

OR to 1st-line VEGF-targeted therapy

OR to 2nd-line VEGF-targeted therapy

CR/PR SD PD

CR/PR (n=72) 14% 36% 50%

SD (n=175) 10% 50% 40%

PD (n=76) 11% 34% 55%

Al-Marrawi MY et al. Target Oncol. 2013 Jan 9. [Epub ahead of print].


©2013PCME Page16

Correlation of First-line PFS and Second-line PFS

Pearson correlation coefficient 0.025; P=0.59

Al-Marrawi MY et al. Presented at: ASCO 2011.

Summary of PFS by Duration of Prior Sunitinib

PFS, months (95% CI), [n]<3 mo vs ≥3 mo <6 mo vs ≥6 mo <9 mo vs ≥9 mo

Axitinib4.5

(2.7, NR)[22]

4.8(4.5, 6.5)

[170]

4.6 (2.8, 8.3)

[48]

4.8(3.6, 6.5)

[144]

4.5(2.8, 6.4)

[90]

6.3(4.6, 6.7)

[102]

Sorafenib2.8

(1.4, 15.7)[21]

3.7(2.8, 4.7)

[173]

2.8 (1.6, 3.7)

[62]

4.6(2.9, 4.9)

[132]

2.9(2.8, 4.6)

[87]

4.6(2.9, 4.9)

[107]

Rini BI et al. Presented at: ASCO 2012, Abstract 354^.

PFS by Prior Response to SunitinibAxitinib vs Sorafenib

FS

Axitinib Sorafenib

1.00

0.80

1.00

0.80

Non-respondersResponders

n 95% CI

4.84.6

4.2-6.72.8-6.3

mPFSmo

14547

Non-respondersResponders

n 95% CI

3.04.7

2.8-4.62.9-6.6

mPFSmo

14352

Time (months)

Prob

abili

ty o

f PF

Time (months)

0.60

0.40

0.20

0

0.60

0.40

0.20

0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

0

Rini BI et al. Presented at: ASCO 2012, Abstract 354^.

5

6

7

8

(mon

ths)

Sunitinib-Refractory RCC

Median PFS in ...

Treatment-Refractory RCC

4.8

3 93

4

5

6

6.7

4 9 4

0

1

2

3

4

Med

ian

PFS

Axitinib: Pivotal study A4061032 ; Everolimus: Afinitor Prescribing Information, 2009; Sorafenib: Nexavar Prescribing Information, 2010; Placebo: Afinitor Prescribing Information, 2009.

3.93.4

1.8

0

1

2

4.9 4.7

1.9

Objective Response Rates in Treatment-refractory RCC

19%

9%

2% 0%

Axitinib: Pivotal study A4061032 ; Everolimus: Afinitor Prescribing Information, 2009; Sorafenib: Nexavar Prescribing Information, 2010; Placebo: Afinitor Prescribing Information, 2009.

Case (continued)

• Patient is started on axitinib 5 mg BID

• Response to axitinib:

Best response on axitinibPD on sunitinib


©2013PCME Page17

Patients with mRCC and PD on 1st-line sunitinib(n=512)

Stratification factors:•Duration of sunitinib

Primary end point: PFS (per IRC)

INTORSECT* Study Design

RANDOMIZA

Temsirolimus25 mg IV weekly†

(n=259)

therapy (≤ or >6 mo)•MSKCC risk group•Histology (clear cell or non-clear cell)•Nephrectomy status

(per IRC)

BID = twice daily; IRC = independent review committee; IV = intravenous; mRCC = metastatic renal cell carcinoma; MSKCC = Memorial Sloan-Kettering Cancer Center; PD = progressive disease; PFS = progression-free survival

*ClinicalTrials.gov Identifier: NCT00474786.†Dose reductions were allowed: temsirolimus (to 20 mg then 15 mg), sorafenib (to 400 mg/day then every other day).

Treat until PD, unacceptable toxicity, or discontinuation for any other reason

ATION

1:1

Sorafenib400 mg oral BID†

(n=253)

1.0

0.9

0.8

0.7

0.6

0.5

Progression-free Survival Overall Survival

P=0.1933 (log-rank)Stratified HR: 0.87

(95% CI: 0.71, 1.07)

Median PFS,months 95% CI

4.283.91

4.01, 5.432.80, 4.21

roba

bilit

y)

1.0

0.9

0.8

0.7

0.6

0.5 val (

prob

abili

ty)

P=0.014 (log-rank)Stratified HR: 1.31

(95% CI: 1.05, 1.63)

12.2716.64

10.13, 14.8013.55, 18.72

Median OS,months 95% CI

0.4

0.3

0.2

0.1

0.0

CI = confidence interval; HR = hazard ratio; IRC = Independent Review Committee; PFS = progression-free survival

TemsirolimusSorafenib

252 72 22 11 6 0259 96 28 9 5 0

SorafenibTemsirolimus

Patients at risk, n

PFS

(pr

Time (months)0 5 10 15 20 25

0.4

0.3

0.2

0.1

0.0

Ove

rall

Surv

iv

0 10 20 30 40 50

TemsirolimusSorafenib

Time (months)

253 158 74 34 13 0259 132 54 22 8 0

Time to Treatment Failure From Second-line Drug Initiation (n=216)

Vickers MM et al. Urology. 2010;76:430-434.

The Benefit of Everolimus Does Not Differ Based on Number of Previous VEGFr-TKIs or MSKCC Risk

Everolimus + BSC n = 277

Placebo + BSC n = 139

Treatment Effect

n (%)Median PFS, mo

n (%)Median PFS, mo

HR (95% CI)

P

Number of previous VEGFr-TKIs

1 205 (74) 5.4 103 (74) 1.90.32

(0.24-0.43)<0.001

( )

2 72 (26) 4.0 36 (26) 1.80.32

(0.19-0.54)<0.001

MSKCC risk category

Favorable 81 (29) 5.8 39 (28) 1.90.31

(0.19-0.50)< 0.001

Intermediate 156 (56) 4.5 79 (57) 1.80.32

(0.22-0.44)< 0.001

Poor 40 (14) 3.6 21 (15) 1.80.44

(0.22-0.85)0.007

Calvo E et al. Eur J Cancer. 2012;48:333-339.

BSC = best supportive care; CI = confidence interval; HR = hazard ratio; PFS = progression-free survival; MSKCC = Memorial Sloan-Kettering Cancer Center; VEGFr-TKI = vascular endothelial growth factor receptor-tyrosine kinase inhibitor

RANDOMIZ

SWITCH: Phase III Sequential Study of Sorafenib and Sunitinib

Sunitinib 50 mg/day (Schedule 4/2)

Eligibility• mRCC with all

histologies

Stratification• ECOG PS 0 or 1 n=346

Sorafenib400 mg BID

ZATION

• Primary endpoints: overall PFS

• Secondary endpoints: total time to progression, OS, disease control rate and cardiotoxicity

Sorafenib400 mg BID

Discontinuation (due to progressive disease/toxicity)

ECOG PS 0 or 1• No prior systemic

therapy for advanced or mRCC

PI: Goebell P. www.clinicaltrials.gov. (NCT00732914).

n=346Sunitinib50 mg/day (Schedule 4/2)

RANDOMIZ

SWITCH: Phase III Sequential Study of Sorafenib and Everolimus

Sunitinib50 mg/day (Schedule 4/2)

Eligibility• Patients with

advanced RCC

Stratification• Karnofsky

performance status n=390

Everolimus10 mg/day

ZATION

• Primary endpoints: first PFS

• Secondary endpoints: second PFS, ORR, duration of response, patient-reported outcomes, OS

Everolimus

10 mg/day

Discontinuation (due to progressive disease/toxicity)

performance status ≥70%

• No prior systemic therapy for advanced or mRCC

www.clinicaltrials.gov. (NCT00903175).

n=390Sunitinib50 mg/day (Schedule 4/2)


©2013PCME Page18

Conclusions

• Deciding when to stop one therapy and change to another can be difficult in patients who have experienced significant clinical benefit to their first agent and are tolerating well.

• Axitinib has level one evidence of clinical benefit in the second line settingsecond-line setting.

• Everolimus has level one evidence of clinical benefit in the refractory setting.

• There is no reliable way to predict second-line therapy benefit based on patient, tumor, or response characteristics.

Documents

PROGRAM SYLLABUS - Medscapeimg.medscape.com/...program-syllabus-9989-v2.pdf · received his medical degree from the Medical College of ... Rini was the Principal Investigator of an