Linda M. Sutton, MD Medical Director

Duke Cancer NetworkAssociate Professor of MedicineDuke University Medical Center

Durham, North Carolina

ENDURENGAGEMENT WITH OVEL THERAPIES

AND ECISION MAKING THRO GHB EAST CANCER DUCATION

Investigations and Clinical Applications of CDK4/6 Inhibitors in Breast Cancer

OVERVIEW OF CDK4/6 INHIBITORS IN BREAST CANCER

Preclinical and Clinical Trial Data

Richard Finn, MD Associate Professor of Medicine

Department of Medicine, Division of Hematology/OncologyGeffen School of Medicine

University of California, Los Angeles

Cell Cycle Proteins: Cyclins and Cyclin-Dependent Kinases (CDKs)

• CDKs– Family of protein kinase

catalytic subunits1

– “…Engines that drive the events of the eukaryotic cell cycle and the clock that times them”1

• Cyclins– Family of regulatory

protein subunits that interact with and activate CDKs1,2

– Degraded periodically at each cell division2

cdc25a=cell division cycle 25a; P=phosphate.1. Morgan DO. Annu Rev Cell Dev Biol. 1997;13:261-291; 2. Evans T et al. Cell. 1983;33:389-396.Figure modified from Biggar KK, Storey KB. Curr Genomics. 2009;10:573-584.

Cyclin

CDK

Cyclin

CDK

Cyclin

Cyclin

CDK

cdc25a

Phase transition

Pre-activation Active

Degradation

PPP

P

P

Regulation of Cyclin D:CDK4/6 Signaling in Breast Cancer

HER=human epidermal growth factor receptor; E2=estrogen; ER=estrogen receptor; PI3K=phosphoinositide 3-kinase; mTOR=mammalian target of rapamycin.1. Hamilton E, Infante JR. Cancer Treat Rev. 2016;45:129-138.Figure modified from O'Leary B et al. Nat Rev Clin Oncol. 2016;13(7):417-430; Finn RS et al. Breast Cancer Res. 2016;18(1):17.

G1 S phaseCell cycleNucleus

Cell membrane

ERE2

HER family and other receptor tyrosine kinases

Cyclin D1

CDK4/6

RbRb

Cyclin E

CDK2PP

PP

P

p53

INK family CIP/KIP family

Other promoter pathways1

• Wnt/β-catenin• JAK-STAT• NF-κB

p16

p15 p18

p19

mTOR

AKT

PI3K

RAS

RAF

MEK

ERKp21 p27

E2FE2F

Oncogenic Alterations in the Cyclin D:CDK4/6 Pathway in Breast Cancer

• Amplification of CDK4 gene (approximately 15% of breast tumors)1

– Increased CDK4 protein expression can occur with or without gene amplification

• Amplification of cyclin D1 gene (15%–20% of breast tumors)2,3,4

• Overexpression of cyclin D1 protein (approximately 50% of breast tumors)2,3,4

• Alterations in p165

– Expression is inversely related to cyclin D and ER expression

ER=estrogen receptor.1. An H-X et al. Am J Pathol. 1999;154(1):113-118; 2. Bartkova J et al. Int J Cancer. 1994;57(3):353-361; 3. Dickson C et al. Cancer Lett. 1995;90(1):43-50; 4. Buckley MF et al. Oncogene. 1993;8(8):2127-2133; 5. Cancer Genome Atlas Network. Nature. 2012;490(7418):61-70; 5. Hui R et al. Clin Cancer Res. 2000;6(7):2777-2787.

Alterations in Cyclin D, CDK4, and Rb by Intrinsic Breast Cancer Subtype

Alteration

Subtype

Luminal A Luminal B HER2-Enriched Basal-Like

Cyclin D1 amplification

29% 58% 38% NR

CDK4 gain 14% 25% 24% NR

Rb1 expression High NR NR Low

NR=not reported.Cancer Genome Atlas Network. Nature. 2012;490(7418):61-70.

Selectivity Profiles of CDK4/6 Inhibitors

IC50 (nM)

Palbociclib Abemaciclib Ribociclib

CDK1 >10,000 >1000 >100,000

CDK2 >10,000 >500 >50,000

CDK4 9–11 2 10

CDK5 >10,000 NR NR

CDK6 15 5 39

CDK7 NR 300 NR

CDK9 NR 57 NR

Half maximal inhibitory concentrations (IC50) are lowest for CDK4 and CDK6, indicating greater selectivity for those targets

Table modified from O'Leary B et al. Nat Rev Clin Oncol. 2016;13(7):417-430.

Effects of Selective CDK4/6 Inhibitors in Preclinical Studies

• Potent inhibition of Rb phosphorylation in a variety of tumor models1-4

• Antiproliferative activity1-5

– Primarily cytostatic effects (ie, G1 arrest) in vitro1-3

– Tumor regression has been observed in some in vivo models1,3,5

• Lack of activity against Rb-deficient cells1,2,4

• Variable degrees of efficiency penetrating the blood-brain barrier6

Rb=retinoblastoma.1. Fry DW et al. Mol Cancer Ther. 2004;3(11):1427-1437; 2. Finn RS et al. Breast Cancer Res. 2009;11:R77 3. Kim S. et al. Mol Cancer Ther. 2013;12:R02; 4. Gelbert LM et al. Invest New Drugs. 2014;32(5):825-837; 5. Patnaik A et al. Cancer Discov. 2016;6(7):740-753; 6. Raub TJ et al. Drug Metab Dispos. 2015;43:1360-1371.

Differential Sensitivity to CDK4/6 Inhibitors in Breast Cancer Cell Lines

• In vitro, sensitivity to palbociclib was greatest in ER-positive and HER2-amplified cell lines1

– Of the genes more highly expressed in the sensitive cell lines, 76% were luminal and none were nonluminal markers

– In the resistant gene set, 59% were nonluminal and none were luminal markers

– There were higher levels of Rb1 and cyclin D1, and lower levels of p16, in the sensitive group

• Ribociclib activity was demonstrated in breast cancer models with intact ER and/or activating aberrations of PIK3CA/HER22

• Abemaciclib activity was observed predominately in multiple luminal breast cancer cell lines and a small subset of triple negative cell lines that had intact Rb signaling3

– Activating mutations in PIK3CA were also associated with sensitivity

ER=estrogen receptor; HER=human epidermal growth factor receptor; Rb=retinoblastoma; E2=estrogen; PI3K=phosphoinositide 3-kinase.1. Finn RS et al. Breast Cancer Res. 2009;11:R77; 2. Kim S et al. Mol. Cancer Ther. 2013;12:R02; 3. O’Brien NA et al. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract 2828.

Clinical Implications of Preclinical Data on CDK4/6 Inhibitors

• Potential biomarkers for sensitivity

– Hormone receptor status

– HER2 amplification/expression

– Rb1

– Cyclin D

• Rationale for combination therapy

– Synergy

– Overcoming resistance

• Timing in relation to chemotherapy

Clinical Trial Data: Topic Outline

• Overview of clinical development of CDK4/6 inhibitors in breast cancer

• Clinical data and ongoing trials of single-agent CDK4/6 inhibitors in breast cancer– Advanced/metastatic

– Neo/adjuvant

• Clinical data and ongoing trials of CDK4/6 inhibitors in combination with endocrine therapies – Advanced/metastatic

– Neo/adjuvant

• Examples of other ongoing investigations

Phase 1 Phase 2 Phase 3 Approved

Clinical Development of CDK4/6 Inhibitors: Trials Including Patients with Breast Cancer

Combination with other therapies; Metastatic

Monotherapy; Metastatic*

Combination with ET;Metastatic*

Combination with ET;Neo/adjuvant

*Breakthrough therapy designation has been granted for abemaciclib as monotherapy for patients with refractory HR+/HER2- advanced breast cancer and for ribociclib in combination with letrozole as a potential frontline therapy for HR+/HER2- advanced breast cancer. http://www.onclive.com/web-exclusives/fda-grants-abemaciclib-breakthrough-status-for-refractory-breast-cancer. Accessed September 15, 2016. http://www.onclive.com/web-exclusives/fda-grants-ribociclib-breast-cancer-breakthrough-designation. Accessed September 15, 2016; Clinicaltrials.gov. Accessed September 23, 2016.ET=endocrine therapy; HR=hormone receptor; HER=human epidermal growth factor receptor.

AbemaciclibPalbociclibRibociclib

Monotherapy; Neo/adjuvant

Combination with other therapies; Neo/adjuvant

SINGLE-AGENT CDK4/6 INHIBITORS IN BREAST CANCER

Phase 1 Trials of Single-Agent CDK4/6 Inhibitors in Advanced Breast Cancer

Drug/Trial Identifier Patient Population Key Results and Takeaways

AbemaciclibNCT013940161

Advanced solid tumors (173 patients; 47 breast cancer)

• Established dosing at 200 mg twice daily, continuously • Most common (>10%) treatment-emergent adverse events

(AEs) (all grades): fatigue (DLT), diarrhea and other gastrointestinal symptoms, cytopenias, increased creatinine

• Febrile neutropenia occurred in 1 patient (breast cancer)• In HR+ breast cancers• 31% overall response rate• 61% achieved either response or stable disease ≥6 months• Clinical activity seen with or without PIK3CA mutations

PalbociclibNCT001412972

Advanced Rb+ solid tumors or lymphomas (41 patients; 5 breast cancer)

• Established dosing at 125 mg daily, 3 weeks on/1 week off • Neutropenia was the only DLT• 10 of 37 patients (27%) had stable disease for ≥4 cycles

RibociclibNCT012372363,4

Rb+ advanced solid tumors or lymphomas (132 patients; 20 breast cancer [as of April 24, 2014])

• Established dosing at 600 mg daily, 3 weeks on/1 week off • Grade 3/4 adverse events included neutropenia (27%),

lymphopenia (16%), and leukopenia (17%)• Most common DLTS: neutropenia (3 patients) and

thrombocytopenia (2 patients)• Partial response rate: 2.3%; stable disease was best response in

33% (43 patients); 8 patients had stable disease >6 months

DLT=dose-limiting toxicity; HR=hormone receptor; Rb=retinoblastoma.1. Patnaik A et al. Cancer Discov. 2016;6(7):740-753; 2. Flaherty KT et al. Clin Cancer Res. 2012;18(2):568-576; 3. Clinicaltrials.gov. Accessed September 23, 2016; 4. Infante JR et al. Clin Cancer Res. 2016; Aug 19 [Epub ahead of print].

Phase 2 Trials of Single-Agent CDK4/6 Inhibitors in Advanced Breast Cancer

Drug Name/Identifier Patient Population Status

Abemaciclib

MONARCH-1;NCT02102490

HR+/HER2- metastatic breast cancer and disease progression on or after endocrine therapy and chemotherapy (132 patients)

Ongoing; preliminary results reported1,2

JPBO;NCT023080203,4

Solid tumors and brain metastases (estimated 247 patients, including 120 with HR+ metastatic breast cancer)

Recruiting; early brainconcentration results reported5

Palbociclib

NCT01037790 Various malignancies (estimated 205 patients; 37 Rb+ advanced breast cancer)

Final results reported6

Ribociclib

SIGNATURE; NCT021877834,7

Advanced solid tumors or hematologic malignancies and CDK4 amplification or mutation, CDK6 amplification or mutation, Cyclin D1 (CCND1) amplification, Cyclin D3 (CCND3) amplification, or p16 (CDKN2A) mutation and progression after ≥1 prior therapy (estimated 90 patients, including those with triple negative breast cancer)

Ongoing; breast-cancer specific results not reported

HR=hormone receptor; HER=human epidermal growth factor receptor. 1. Dickler M et al. Presented at the American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL: 510; 2. Tolaney SM et al. Presented at the European Society of Medical Oncology Annual Congress; October 7–11, 2016; Copenhagen, Denmark: LBA12; 3. Anders C et al. Cancer Res. 2016;76(4 Suppl):OT1-03-04; 4. Clinicaltrials.gov. Accessed September 23, 2016; 5. Sahebjam S et al. J Clin Oncol. 2016;34(Suppl;abstr 526); 6. DeMichele A et al. Clin Cancer Res. 2015;21(5):995-1001; 7. Peguero JA et al. J Clin Oncol. 2016;34(Suppl; abstr 2528).

Phase 2 Trials of Single-Agent CDK4/6 Inhibitors in Early Breast Cancer

DrugName/Identifier

Patient Population;Setting

Primary Outcome Measure Key Findings/Status

Abemaciclib

ABC-POP; NCT02831530

HR+/any HER2 status; preoperative

Antiproliferativeresponse (Ki67 expression)

Recruiting1

Palbociclib

POP; NCT02008734

Any HR or HER2 status,grade 3 or Ki67 ≥ 20%; preoperative

Antiproliferative response (Ki67 expression; natural logarithm [ln]<1 at day 15)

•N=100 (74 palbociclib; 26 no treatment)2

• 93% HR+; 8% HER2+• Antiproliferative response: 58% vs 10% in palbociclib

vs control groups; P=0.0003)• In patients with HR+/HER2- tumors, Ki67 decreased

in 72% vs 5% of palbociclib vs control groups•No Ki67 response was observed in triple negative or

HER+ tumors • Palbociclib decreased pRb vs control (P=0.0027)• Baseline Rb, pRb, and p16 did not predict effect on

Ki67• Palbociclib effect in Ki67 correlated with changes in

pRb from baseline (P<0.0001)

HR=hormone receptor; HER=human epidermal growth factor receptor; Rb=retinoblastoma. 1. Clinicaltrials.gov. Accessed September 23, 2016; 2. Arnedos M et al. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract CT041.

Common Adverse Events with CDK4/6 Inhibitor Monotherapy

Adverse event, %

Abemaciclib(N=132)1

Palbociclib2

(N=37)Ribociclib3

(N=132)

All gradesGrade

3/4 All gradesGrade

3/4 All gradesGrade

3/4

Hematologic

Anemia 69 0 70 5 26 3

Lymphopenia NR NR 65 30 24 16

Neutropenia 88 27 95 54 46 27

Thrombocytopenia 41 2 76 19 30 8

Nonhematologic

Creatinine increase 99 <1 NR NR 11 0

Diarrhea 90 20 16 0 23 2

Fatigue 65 13 68 0 45 2

Nausea 64 5 24 0 42 2

QTc prolongation NR NR NR NR 11 2

Vomiting 35 2 5 0 26 0

NR=not reported.1. Dickler M et al. Presented at the American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL: 510; 2. DeMichele A et al. Clin Cancer Res. 2015;21(5):995-1001; 3. Infante JR et al. Clin Cancer Res. 2016; Aug 19 [Epub ahead of print]. Table modified from Barroso-Sousa R et al. Breast Care. 2016;11:167-173.

CDK4/6 INHIBITORS IN COMBINATION WITH ENDOCRINE THERAPY (ET) IN BREAST CANCER

PALOMA Studies: Summary of Efficacy of Palbociclib Plus ET Versus Comparator

PALOMA-1 (N=165)1

PALOMA-2 (N=666)2

PALOMA-3 (N=521)3

Study designPhase 2; randomized,

open-labelPhase 3; randomized,

DBCPhase 3; randomized,

DBC

Population/settingAdvanced HR+/HER2-

breast cancer; first-lineAdvanced HR+/HER2-

breast cancer; first-line

Advanced HR+/HER2-breast cancer;

progressed on ETET/comparator Letrozole Letrozole Fulvestrant

Primary endpoint: PFS51% reduction in RR of

progression42% reduction in RR of

progression54% reduction in RR of

progression

Hazard ratio 0.49 (P=0.0004) 0.58 (P<0.000001) 0.46 (P<0.0001)

Median PFS, months 20.2 vs 10.2 24.8 vs 14.5 9.5 vs 4.6

Secondary endpoints, %

ORR

ITT 43 vs 33 (P=0.13) 42 vs 35 (P=0.0310)19 vs 9

(OR=2.47; P=0.0019)

Measurable disease 55 vs 39 (P=0.047) 55 vs 44 (P=0.0132)25 vs 11

(OR=2.69; P=0.0012)

CBR (ITT) 81 vs 58 (P=0.0009) 85 vs 70 (P<0.0001)67 vs 40

(OR=3.05; P<0.0001)DBC=double-blind, controlled; HR=hormone receptor; HER=human epidermal growth factor receptor; ET=endocrine therapy; PFS=progression-free survival; RR=relative risk; ORR=objective response rate; ITT=intent-to-treat; CBR=clinical benefit response; OR=odds ratio. 1. Finn RS et al. Lancet Oncol. 2015;16(1):25-35; 2. Finn RS et al. Presented at the American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL: 507; 3. Cristofanilli M et al. Lancet Oncol. 2016;17(4):425-439.

PALOMA-3: Key Findings from Subgroup Analyses

• Treatment effects on PFS similar across subgroups defined by the following parameters:

–Menopausal status1

–Number or type of previous endocrine therapies1

–Reported sensitivity to previously received endocrine therapy1

–Level of expression of estrogen and progesterone receptors1

–PIK3CA mutation status1

–ESR1 mutation status2

PFS=progression-free survival; ESR1=estrogen receptor-1.1. Cristofanilli M et al. Lancet Oncol. 2016;17(4):425-439; 2. Turner NC et al. J Clin Oncol. 2016;34:(Suppl;abstr 512).

PALOMA Studies: Hematologic Adverse Events

Event, %

PALOMA-11 PALOMA-22 PALOMA-33

PAL + LET (n=83)

LET(n=77)

PAL + LET(n=444)

PCB + LET(n=222)

PAL + FUL(n=345)

PCB + FUL (n=172)

Any G G 3/4 Any G G 3/4 Any G G 3/4 Any G G 3/4 Any G G 3/4 Any G G 3/4

Anemia 35 6 6 1 24 ~6 9 2 28 3 11 2

Leucopenia 43 19 2 0 39 25 2 0 50 28 4 1

Lymphopenia NR NR NR NR NR NR NR NR 2 <1 1 <1

Neutropenia 75 54 5 1 80 66 6 ~2 81 65 3 1

Thrombocytopenia 17 2 1 0 16 ~2 1 0 21 2 0 0

PAL=palbociclib; LET=letrozole; FUL=fulvestrant; PCB=placebo; NR=not reported. 1. Finn RS et al. Lancet Oncol. 2015;16(1):25-35; 2. Finn RS et al. Presented at the American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL: 507; 3. Cristofanilli M et al. Lancet Oncol. 2016;17(4):425-439.

PALOMA-11 PALOMA-22 PALOMA-33

No cases reported in either treatment group

1.6% in PAL + LET group; 0 in PCB + LET group

3 cases in PAL + FUL group;

1 case in PCB + FUL group

Incidence of febrile neutropenia

Hematologic Toxicity in the Fulvestrant Plus Palbociclib Arm of PALOMA-3

Verma S et al. The Oncologist. 2016; Jul 1 [Epub ahead of print].

Consistent with the drug’s proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy

Time to Onset Duration

Thrombocytopenia

16.0 (13–293)

0

Anemia

Neutropenia

10 20 30 40 50 60

Thrombocytopenia

Anemia

Neutropenia

0

17.0 (13–147)

39.5 (15–225)

0.0 (0–0)

26.5 (15–92)

15.0 (15–24)

Median (range) time to onset fromFirst dose of palbociclib to first episode, days

Median (range) duration of each episode, days

0.0 (0–0)

7.0 (1–98)

8.0 (1–15)

7.0 (1–141)

7.0 (1–27)

7.0 (1–8)

Grade ≥3 Grade 4

1 2 3 4 5 6 7 8 9 10

PALOMA Studies: Nonhematologic Adverse Events (All-Cause)

PALOMA-11 PALOMA-22 PALOMA-33

Event, (%)PAL + LET

(n=83) LET (n=77) Event, (%)PAL + LET (n=444)

PCB + LET (n=222) Event, (%)

PAL + FUL (n=345)

PCB + FUL (n=172)

Fatigue 41 23 Fatigue 37 28 Infections 42 30

Nausea 25 13 Nausea 35 26 Fatigue 39 28

Arthralgia 23 16 Arthralgia 33 34 Nausea 32 27

Alopecia 22 3 Alopecia 33 16 Headache 23 19

Diarrhea 20 10 Diarrhea 26 19 Diarrhea 21 19

*6 of these 11 patients discontinued due to treatment-related adverse events (7% of the PAL + LET group).ET=endocrine therapy; PAL=palbociclib; LET=letrozole; FUL=fulvestrant; PCB=placebo.1. Finn RS et al. Lancet Oncol. 2015;16(1):25-35; 2. Finn RS et al. J Clin Oncol. 2016;34:(Suppl;abstr 507); 3. Cristofanilli M et al. Lancet Oncol. 2016;17(4):425-439.

Top 5 Most Common Events in Palbociclib + ET Groups

Treatment Discontinuation Associated with Adverse Events (%)PALOMA-11 PALOMA-22 PALOMA-33

PAL + LET LET PAL + LET PCB + LET PAL + FUL PCB + FUL

13* 2 9.7 5.9 4 2

CDK4/6 Inhibitors in Combination with ET in Advanced Breast Cancer

DrugStudy Phase;Design

Trial Name and/or Identifier

Patient Population;Setting

Combination Therapy Status

Abemaciclib

Phase 3; randomized, DBC

MONARCH-2; NCT02107703

HR+/HER2-, progressed on ET

Fulvestrant Ongoing*

Phase 3;randomized, DBC

MONARCH-3; NCT02246621

HR+/HER2-,first-line

NSAI Ongoing

Phase 2; randomized, open label

nextMONARCH 1; NCT02747004

HR+/HER2-, progressed on ET

Tamoxifen (vs. abemaciclibmonotherapy)

Not yet recruiting

Palbociclib

Phase 3; randomized, open label

PEARL; NCT02028507

HR+/HER2-; resistantto NSAI

Exemestane or fulvestrant

Recruiting

Phase 2; single arm, open label

NCT02668666 HR+/HER2-; first-line Tamoxifen Recruiting

Phase 1/2; single arm, open label

NCT02448771 HR+/HER2-; resistantto ET

Bazedoxifene Recruiting

DBC=double-blind, controlled; HR=hormone receptor; HER=human epidermal growth factor receptor; ET=endocrine therapy; NSAI=non-steroidal aromatase inhibitors.*Interim efficacy criteria not met as of August 10, 2016; an independent Data Monitoring Committee recommended continuing the study without modification. http://www.prnewswire.com/news-releases/lilly-provides-update-on-monarch-2-phase-3-trial-of-abemaciclib-300311632.html. Accessed September 23, 2016. Clinicaltrials.gov. Accessed September 23, 2016.

Examples of Other Ongoing or Planned Clinical Trials

CDK4/6 Inhibitors in Combination with ET in Advanced Breast Cancer

DrugStudy Phase/Design

Trial Name and/or Identifier

Patient Population;Setting

Combination Therapy Status

Ribociclib

Phase 3; randomized, DBC

MONALEESA-2; NCT01958021

HR+/HER2-, first-line Letrozole Ongoing;interim analysis reported1

Phase 3; randomized, DBC

MONALEESA-3; NCT02422615

HR+/HER2-, ≤1 prior ET Fulvestrant Recruiting2

Phase 3; randomized, DBC

MONALEESA-7; NCT02278120

HR+/HER2-, first-line, premenopausal

NSAI/tamoxifen + goserelin

Ongoing2

DBC=double-blind, controlled; HR=hormone receptor; HER=human epidermal growth factor receptor; ET=endocrine therapy; NSAI=nonsteroidal aromatase inhibitor.1. Hortobagyi G et al. N Engl J Med. 2016; Oct 7 [Epub ahead of print]; 2. Clinicaltrials.gov. Accessed September 23, 2016.

Examples of Other Ongoing or Planned Clinical Trials, cont

Neoadjuvant Palbociclib Plus Anastrozole: Phase 2 Study

• Complete cell cycle arrest (CCCA; Ki67≤2.7%) at day 15 of combination therapy occurred in 39 of 45 (87%) of patients

CID15=cycle 1 day 15. Ma C et al. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res. 2016;76(4 Suppl):Abstract S6-05.

Persistent non-CCCA on both anastrozole and palbociclibn=6 (14%)

Ki67 Response in Individual Patients

Anastrozole alone induced CCCA n=11 (26%)

Adding palbociclib to anastrozoleconverted non-CCCA to CCCAn=26 (60%)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

C1D15 > 10%Off study

C1D15 > 2.7%

C0D1 C1D1 C1D152.7%

N=43

Neoadjvant Palbociclib Plus Anastrozole: Adverse Events

*All AEs with >10% incidence or ≥grade 3. ALT=alanine transaminase; AST=aspartate transaminase.Ma C et al. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res. 2016;76(4 Suppl):Abstract S6-05.

Adverse Event,* % Any Grade Grade 1 Grade 2 Grade 3 Grade 4

Neutropenia 56 8 22 22 4

Leukopenia 46 24 22 0 0

Fatigue 40 26 14 0 0

Hot flashes 28 24 4 0 0

Mucositis, oral 22 20 2 0 0

Nausea 22 22 0 0 0

Myalgia 20 20 0 0 0

Thrombocytopenia 18 18 0 0 0

Arthralgia 18 18 0 0 0

Headache 14 12 2 0 0

Insomnia 14 10 4 0 0

Diarrhea 12 12 0 0 0

ALT elevation 8 2 2 4 0

AST elevation 6 4 0 2 0

Hypertension 4 0 2 2 0

Cholecystitis 2 0 0 2 0

Neoadjuvant Ribociclib Plus Letrozole: MONALEESA-1

Curigliano G et al. Breast. 2016;28:191-198.

Ki67 levels were decreased following study treatment in all 11 evaluable patients with matched baseline and posttreatment tumor samples

Mean decrease of 92% (range 75%–100%; n=3)

Mean decrease of 96% (range 78%–100%; n=6)

Mean decrease of 69% (range: 38%–100%; n=2)

Pe

rcen

tage

of

Ki6

7-p

osi

tive

cel

ls (

%)

Screening Day 15 Screening Day 15 Screening Day 150

10

20

30

40

50

60

70

80

Arm 1: letrozole 2.5 mg/day Arm 2: ribociclib 400 mg/day+ letrozole 2.5 mg/day

Arm 3: ribociclib 600 mg/day+letrozole 2.5 mg/day

MONALEESA-1: Adverse Events

Adverse Event,* n (%) Letrozole (n=4)

Ribociclib 400 mg/day + Letrozole (n=6)

Ribociclib 600 mg/day + Letrozole (n=4)

Total 1 (25) 3 (50) 4 (100)

Abdominal pain 0 0 1 (25)

Diarrhea 0 0 1 (25)

Nausea 1 (25) 0 2 (50)

Stomatitis 0 1 (17) 0

Vomiting 0 0 1 (25)

Asthenia 0 1 (17) 1 (25)

Fatigue 0 0 1 (25)

QTcF prolongation 0 0 2 (50)

Decreased appetite 0 0 2 (50)

Hypomagnesemia 1 (25) 0 0

Dyspnea 0 1 (17) 0

Hot flush 0 0 1 (25)

*All-grade events suspected to be related to study treatment (≥15% in any treatment arm).Curigliano G et al. Breast. 2016;28:191-198.

CDK4/6 Inhibitors in Combination with ET in Early Breast Cancer

DrugStudy Phase;Design

Study Name and/or Identifier

Patient Population;Setting

Combination Therapy Status

Abemaciclib

Phase 2;randomized, open label

neoMONARCH; NCT02441946

HR+/HER2-;neoadjuvant

Anastrozole Ongoing; interim results reported2

Palbociclib

Phase 3; randomized, DBC

PENELOPE-B; NCT01864746

High-risk HR+/HER2-with residual disease after neoadjuvant chemotherapy

Standardendocrine therapy

Recruiting

Phase 3;randomized, open label

PALLAS;NCT02513394

HR+/HER2-; adjuvant Standard endocrine therapy

Recruiting

Ribociclib

Phase 2; randomized, DBC

FELINE; NCT02712723*

ER+/HER2-; neoadjuvant

Letrozole Recruiting

*Includes one arm with continuous and another with intermittent dosing of ribociclib.HR=hormone receptor; HER=human epidermal growth factor receptor; DBC=double-blind, controlled.

1. Clinicaltrials.gov. Accessed September 23, 2016; 2. Hurvitz S et al. Presented at the European Society of Medical Oncology Annual Congress; October 7–11, 2016; Copenhagen, Denmark: LBA13.

Examples of Other Ongoing or Planned Clinical Trials1

Additional Ongoing Investigations of CDK4/6 Inhibitors in Breast Cancer

• HER2-targeted therapies in HER2+ disease (eg, trastuzumab, ado-trastuzumab emtansine)

• mTOR inhibitors (eg, everolimus)

• PI3K inhibitors (eg, alpelisib)

• Cytotoxic chemotherapy (eg, paclitaxel, capecitabine)

• Triple-negative, androgen-receptor positive

• Luminal subtypes

• Older patients with early HR+ breast cancer who are unable or unwilling to have surgery

• Racial/ethnic subpopulations (eg, Asian, African American)

Combination Therapies Patient Populations

HER2=human epidermal growth factor receptor-2; mTOR=mammalian target of rapamycin; HR=hormone receptor.Clinicaltrials.gov. Accessed September 23, 2016.

PATIENT COMMUNICATION AND SHARED DECISION MAKING

P. Kelly Marcom, MD Associate Professor of Medicine

Director, Duke Cancer Institute (DCI) Breast Cancer Program DCI Associate Director of Breast Cancer Clinical Research

Duke University Medical CenterDurham, North Carolina

Case Study: Initial Presentation

• A 43-year-old woman with metastatic breast cancer– Treated for stage IIIC [T1N3(13)M0] IDC 12 years ago

• Grade 2; ER+/PR+/HER2-

• After surgery, received dose-dense ACweekly T followed by 4 years of tamoxifen and 5 years of letrozole following oophorectomy

– Presents with fatigue, anemia, thrombocytopenia, and diffuse bone metastases; no visceral involvement

– CA27-29: 624; circulating tumor cells: 200

– Bone marrow with metastatic breast cancer: • ER 100%/PR 2%/HER2 negative

– No other medical problems

IDC=invasive ductal carcinoma; ER=estrogen receptor; PR=progesterone receptor; HER2=human epidermal growth factor receptor 2; CA=cancer antigen.

Factors to Consider in Risk Assessment and Treatment Decisions for Metastatic Breast Cancer

• Disease-free interval• Previous therapies and

response• Biological factors

(receptor status)• Tumor burden (number

and site of metastases)• Need for rapid

disease/symptom control

• Patient preferences• Age• Menopausal status• Comorbidities and

performance status• Socioeconomic and

psychological factors• Cost, payer, insurance

coverage

Disease-Related Factors Patient-Related Factors

Cardoso F et al. Ann Oncol. 2012;23(Suppl 7):vii11-vii19.

Discussing Treatment Options with Patients

Efficacy

Side effects

Goal of treatment decision= maximize benefit while minimizing risk

Lux MP et al. Breast Cancer Res Treat. 2013;139(2):429-440.

Addressing New Therapies with Patients

• How is this treatment different from others the patient has received?

• How is it administered? (eg, route; dosing frequency and schedule)

• What are realistic goals?

• What are the risks?

• What side effects might the patient experience and how can they be managed?

Treatment Preferences of Women with Metastatic Breast Cancer

0.14

0.43

0.48

1.08

6.18

6.36

7.69

10.37

12.46

21.32

33.49

0 5 10 15 20 25 30 35 40

Dosing regimen

Mucositis/stomatitis

Myalgia/arthralgia

Diarrhea

Nausea/vomiting

Motor neuropathy

Quality of life

Neutropenia

Fatigue

Alopecia

Effectiveness

Relative Importance (%)

daCosta DiBonaventura M et al. Am Health Drug Benefits. 2014;7(7):386-396.

Patient-Ranked Relative Importance of Treatment Attributes

• Cross-sectional, internet-based survey of 181 women with metastatic breast cancer

Adherence to Anticancer Therapy for Metastatic Breast Cancer

Reason stated for nonadherenceNumber (%) of patients who discontinued/were nonadherent (n=63)

Forgot to take medicines and/or keep treatment appointment 26 (41.3)

Could not tolerate side effects 23 (36.5)

Other* 19 (30.2)

Had family obligations/an event to attend 10 (15.9)

Side effects impacted ability to perform daily activities 8 (12.7)

Unable to enjoy everyday experiences 5 (7.9)

Could no longer afford the treatment 4 (6.4)

Treatment schedule was difficult to follow 3 (4.8)

Did not trust the medicine as it was still in clinical trials 1 (1.6)

Had to travel too far to get treatment 0

Lack of support from family members/friends 0

Did not have someone to drive me to my treatment 0

*Additional information not available.daCosta DiBonaventura M et al. Am Health Drug Benefits. 2014;7(7):386-396.

• A total of 63 patients (34.8%) either discontinued or were nonadherent

• Treatment nonadherence was associated with impairment of quality of life among patients who had ever or were currently receiving oral therapy

Expectations for Treatment Benefit in the Metastatic Setting

68.9

52.4 54.6 52.4

61.6

23.9

8.113.3

9.3 6.8

0

10

20

30

40

50

60

70

80

Chemotherapy EndocrineTherapy

AntibodyTherapy

Radiotherapy Bisphosphonates

Patients Physicians

Re

spo

nd

ents

Exp

ect

ing

Tre

atm

ent

Be

ne

fit

>12

Mo

nth

s (%

)

• Survey of >2,000 breast cancer patients and >500 treating physicians

• Hypothetical scenario: assumed overall survival of 6 months without therapy

Lux MP et al. Breast Cancer Res Treat. 2013;139(2):429-440.

Shared Decision Making

• Collaboration between patients and their clinicians to reach agreement about a health decision involving multiple medically appropriate treatment options

Definition1

• Translate evidence into clinical practice • Involve patients in health decisions• Ensure patients are fully informed of treatment options and trade-offs between risks

and benefits• Ensure patient values and preferences are incorporated into treatment decisions

Goals2

• Treatment recommendations are based on increasingly complicated information• Multiple clinicians/specialists• Potential for mismatch between information needed and information received • Suboptimal use of face-to-face time if patients “freeze up” or “tune out”

Challenges1,2

• Patient-managed decision tools (ie, decision aids)

• Use of informal or formal coaches Strategies2

1. Politi MC et al. The Oncologist. 2012;17(1):91-100; 2. Katz SJ et al. J Oncol Pract. 2014;10(3):206-208.

Five Steps in Shared Decision Making in Oncology Practice

1. Determine the situations in which shared decision making is critical

2. Acknowledge the decision to the patient

3. Describe options, including risks, benefits, and uncertainty associated with options

4. Elicit patient preferences and values

5. Agree on a plan for the next steps in the decision-making process

Politi MC et al. The Oncologist. 2012;17(1):91-100.

Communication in Breast Cancer Care: Reminders for the Clinician

• Patients usually recall facts provided at the start of a consultation more readily than those given later

• Topics deemed most relevant and important to the patient are recalled most accurately

• The greater the number of statements made by a clinician, the smaller the mean percentage of information recalled by the patient

• Items that patients do manage to recall do not decay over time as do other memories; in fact, many patients have verbatim recall of what they believe the clinician said

Parker PA et al. Breast J. 2009;15(1):69-75.

Case Study: Treatment Decision

• Treatment was initiated with palbociclib 125 mg daily, 3 weeks on/1 week off, and fulvestrant 500 mg IM, to be administered on days 1, 15, and 29 and once monthly thereafter

• Factors contributing to decision– Patient history of bone and joint discomfort during adjuvant

aromatase inhibitor therapy

– Use of injectable endocrine therapy ensures dose delivery

– Addition of CDK4/6 inhibitor increases likelihood of response to first-line therapy

IM=intramuscular

Case Study: Initial Treatment Course

• Patient returns at end of first cycle– Improved fatigue

– Afebrile; BP: 128/76; HR: 80; RR: 16

– Hgb/Hct: 9.9/31

– Lymphocytes 1900/mm3

– Platelets 247K

– ANC 400/mm3

• Palbociclib was held for two weeks until recovery of ANC over 1000/mm3

BP=blood pressure; HR=heart rate; RR=respiration rate; Hgb=hemoglobin; Hct=hematocrit; ANC=absolute neutrophil count

Side Effects of Endocrine Therapies Used in Combination with CDK4/6 Inhibitors May Affect Tolerability of Treatment Regimen

Common side effects of aromatase inhibitors and selective estrogen receptor degraders

• Hot flashes and other menopausal symptoms

• GI symptoms (eg, nausea, diarrhea)

• Musculoskeletal symptoms (eg, myalgias, arthralgias, pain)

• Fatigue

• Asthenia

• Headache

Chia S et al. J Clin Oncol. 2008;26(10):1664-1670; Litsas G. Clin J Oncol Nurs. 2011;15(6):674-681.

Impact of the Addition of Palbociclib to Letrozole on Pain in PALOMA-1

1.431.531.5 1.45

0.0

0.5

1.0

1.5

2.0

All Patients Patients with Any BoneDisease at Baseline

Palbociclib plus letrozole Letrozole

Note: higher scores indicated greater pain severity or interference.Bell T et al. Curr Med Res Opin. 2016;32(5):959-965.

• No statistically significant differences in Pain Severity or Pain Interference scores of the Brief Pain Inventory (BPI) between treatment groups for the overall population or among those with any bone disease at baseline

1.631.7

1.58 1.53

0.0

0.5

1.0

1.5

2.0

All Patients Patients with Any BoneDisease at Baseline

Palbociclib plus letrozole Letrozole

Pain Severity Scores Pain Interference Scores

Pai

n S

eve

rity

Sco

re

Pai

n In

terf

ere

nce

Sco

re

Reversible Cytopenias Associated with CDK4/6 Inhibition

• In a phase 1 dose-finding study, cytopenias associated with a dosing schedule of 3 weeks on/1 week off were manageable, reversible, and not cumulative in most patients

Change in Absolute Neutrophil Count Change in Platelet Count

Flaherty KT et al. Clin Cancer Res. 2012;18(2):568-576.

AN

C: C

han

ge f

rom

Bas

elin

e (%

)

Pla

tele

ts: C

han

ge f

rom

Bas

elin

e (%

)MeanBaselineOff drug

150

100

50

0

-50

-1000 10 20 30 40 50 60

Days

150

100

50

0

-50

-1000 10 20 30 40 50 60

Days

Case Study: 2-Month Follow Up

• Patient returns for 2-month follow-up visit

– Continues on palbociclib 100 mg daily, 3 weeks on/1 week off, plus monthly fulvestrant 500 mg

– CA 27-29: decreased to 50; circulating tumor cells: decreased to 15

CA=cancer antigen