Management of Hormone Receptor Positive Metastatic Breast Cancer

Transcription

1 Management of Hormone Receptor Positive Metastatic Breast Cancer Adam Brufsky, MD, PhD Professor of Medicine University of Pittsburgh Improving Outcomes for Metastatic Breast Cancer Giordano SH 24 Chia SK Cancer 27 1

2 Chemotherapy 15% ER,PR, HER2 25% HER2+ 6% ER+ Trastuzumab Anti-estrogens Sörlie T, et al. PAS. 21;98: Metastatic Breast Cancer Outcome and Subtype Lobbezoo et al 213 Breast can res Treat 2

3 HR+ Metastatic Breast Cancer The most common subset of breast cancer HR+ disease comprises 65-7% of patients with metastatic breast cancer Prognosis highly variable and dependent on hormone responsiveness Median survival ranges from 3 4 years (likely longer) Guidelines for treatment In patients with hormone receptor positive advanced breast cancer, hormone therapy should be the treatment of choice in the first-line setting except in the setting of rapidly progressive visceral disease Treatment choices are dependent on disease free interval, duration of response to adjuvant therapy, extent of disease, prior treatment, and menopausal status uances of HR+ MBC Discordance of HR status between primary and metastatic site is significant (15%) supporting biopsy of the initial metastatic site Bone metastasis are more common in HR+ disease (68%) which can be osteoblastic or osteolytic Bisphosphonates (pamidronate, zolendronic acid) reduce the incidence of skeletal related events (SRE), prolongs the time to development of SRE, and reduce pain Denosumab (humanized monoclonal antibody to RAKL) is superior to zolendronic acid by delaying SRE by 18% Both drugs are associated with a risk of osteonecrosis of the jaw (2%) Zolendronic acid can be given every 3 months, whereas denosumab is given monthly Amir E, et al. J Clin Oncol 212;3(6):587. Van Poznak CH, et al. J Clin Oncol. 211;29:1221. Stopeck AT, et al. J Clin Oncol. 21;28:5132. Hortobagyi G, et al. ASCO Meeting Abstracts

4 Treatment Guidelines 1 ER and/or PR +; HER2 +/- o prior endocrine therapy within 1 year Prior endocrine therapy within 1 year Visceral crisis Postmenopausal Premenopausal Visceral crisis Postmenopausal Premenopausal Consider initial chemotherapy Aromatase inhibitor or Selective ER modulators or Selective ER down-regulator Ovarian ablation or suppression + endocrine therapy as for postmenopausal women or Selective ER modulators Consider initial chemotherapy Ovarian ablation or suppression + endocrine therapy as for postmenopausal women Continue endocrine therapy until progression or unacceptable toxicity Trial of new endocrine therapy o Progression o clinical benefit after 3 consecutive endocrine therapy regimens or symptomatic visceral disease Yes Chemotherapy HER2= human epidermal growth factor receptor 2; ER=estrogen receptor; PR=progesterone receptor. 1. CC Clinical Practice Guidelines in Oncology (CC Guidelines ) for Breast Cancer V ational Comprehensive Cancer etwork, Inc

5 SERD - Fulvestrant Analog of 17-beta estradiol Causes disruption and degradation after binding to ER, inhibiting estrogen signaling and cellular growth Ciruelos E, et al. The Breast 214;23:21 De Leo A, et al. J Clin Oncol. 21;28:4594 5

6 Selective Estrogen Receptor Downregulators (SERDs) HR+ breast cancer continues to rely on ER in the endocrine resistant state Targeting ERα in the endocrine resistance state requires a dual MOA Block ER activity: bind to ER to antagonize transcriptional activity Reduce ER protein level: induce conformational changes -> degradation of ER -> reduces ligand-independent ER activities ER can be targeted by SERDS Estrogen receptor alpha mutations: Develop in setting of endocrine resistance May induce ligand independent signaling May be an actionable target for SERDs McDonnell, DP et al. J Med Chem 215;58(12):4888. Fulvestrant versus anastrozole trials 6

7 Comparison of First Line AI ± Fulvestrant Trials FACT 1 SWOG o. Patients De ovo Metastatic Disease 13% 39% Prior Adjuvant Chemotherapy 45% 33% Prior Adjuvant Endocrine Therapy (TAM) 68% 4% Prior Adjuvant AI 1.5% excluded Median TTP/PFS Range (mo) PFS Benefit o Yes Median OS Benefit, (mo) o, 37.8 vs mos Yes, 41.3 vs 47.7 mos 1. Bergh J, et al. J Clin Oncol. 212;3: Mehta RS, et al. Engl J Med. 212;367: Fulvestrant 5 mg IM on Day followed by 25 mg IM Day 14 and 28 then 25 mg every 28 days FIRST Study Update Robertson JF et al Breast Can Res Treat

8 FIRST Study TTP 23.4 mo versus 13.1 mo mos 54.1 mo vs 48.4 mo Robertson JF et al Breast Can Res Treat 212, Ellis JCO FALCO: (Fulvestrant and AnastrozoLe COmpared in hormonal therapy aïve advanced breast cancer) Postmenopausal women Locally advanced or metastatic breast cancer ER+ and / or PgR+ HER2- Endocrine therapy-naïve Fulvestrant 5 mg (5 mg IM on Days, 14 and 28, then every 28 days) + placebo to anastrozole 1:1 OS b Anastrozole 1 mg (daily PO) + placebo to fulvestrant Primary endpoint: PFS a ORR CBR DoR, EDoR DoCB, EDoCB Secondary endpoints HRQoL (FACT-B total and TOI) Safety Randomised, double-blind, parallel-group, international, multicentre study Follow-up for disease progression and survival Randomisation of 45 patients was planned to achieve 36 progression events; if the true PFS HR was.69 this would provide 9% power for statistical significance at the 5% two-sided level (log-rank test) Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic disease Subgroup analysis of PFS for pre-defined baseline covariates a Assessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; b Interim analysis at the time of PFS analysis EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy Breast; TOI, Trial Outcome Index 8

9 FALCO: PRIMARY EDPOIT, PFS 1..9 Fulvestrant (n=23) Anastrozole (n=232) Proportion of patients alive and progression free HR.797 (95% CI.637,.999); p=.486 Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months. umber of patients at risk: Fulvestrant 23 Anastrozole Time (months) A circle represents a censored observation FALCO: PFS I PATIETS WITH OR WITHOUT VISCERAL DISEASE Without visceral disease With visceral disease 1..9 Fulvestrant (n=95) Anastrozole (n=113) 1..9 Fulvestrant (n=135) Anastrozole (n=119) Proportion of patients alive and progression-free HR.59 (95% CI.42,.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Proportion of patients alive and progression-free HR.99 (95% CI.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months Time (months) Time (months) Post hoc interaction test p<.1 A circle represents a censored observation 9

10 FALCO: OS (31% MATURITY) 1..9 Fulvestrant (=23) Anastrozole (=232).8.7 Proportion of patients alive HR.88 (95% CI.63, 1.22); p=.428 umber of patients at risk: Fulvestrant Anastrozole Time (months) Median follow up 25. months A circle represents a censored observation FALCO: MOST COMMO AEs (FREQUECY >5%; SAFETY AALYSIS POPULATIO) umber (%) of patients MedDRA preferred term Fulvestrant (=228) Anastrozole (=232) Patients with any AE 166 (72.8) 173 (74.6) Arthralgia 38 (16.7) 24 (1.3) Hot flush 26 (11.4) 24 (1.3) ausea 24 (1.5) 24 (1.3) Fatigue 26 (11.4) 16 (6.9) Hypertension 15 (6.6) 21 (9.1) Back pain 21 (9.2) 14 (6.) Anaemia 9 (3.9) 2 (8.6) Insomnia 15 (6.6) 13 (5.6) Diarrhoea 14 (6.1) 13 (5.6) Constipation 13 (5.7) 11 (4.7) Myalgia 16 (7.) 8 (3.4) ALT increased 16 (7.) 7 (3.) Pain in extremity 13 (5.7) 1 (4.3) Dyspnoea 9 (3.9) 13 (5.6) Oedema peripheral 9 (3.9) 13 (5.6) AST increased 12 (5.3) 8 (3.4) Cough 12 (5.3) 8 (3.4) 1

11 ew Agents in Development for Metastatic HR+ Breast Cancer PI3k/ mtor HDAC CDK 4/6 Other RTKs (HER/IGFR) Estrogen Receptor Signaling Pietras & Marquez, 28 11

12 BOLERO-2: Study Design = 724 Postmenopausal women ER +, HER2 unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole Randomize 2:1 EVE 1 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) Stratification: Sensitivity to prior hormone therapy Presence of visceral metastases Endpoints Primary: PFS (local assessment) Secondary: OS, ORR, CBR, QOL, safety, PK Exploratory: Biomarkers Abbreviations: BC, breast cancer; CBR, clinical benefit rate; ER +, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; HER2, human epidermal growth factor receptor-2 negative; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life. Baselga J, et al. Engl J Med. 212;366(6): BOLERO-2 (18-mo): Final PFS Analysis Based on Local Assessment Met Primary Endpoint (4.6-mo Prolongation of PFS) Probability of Progression-Free Survival Censoring times EVE+EXE (n/ = 31/485) PBO+EXE (n/ = 2/239) HR =.45 (95% CI, ) Log-rank P <.1 Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months o. at risk EVE+EXE PBO+EXE Time, months Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Yardley DA, et al. Adv Ther. 213;3(1):

13 11. BOLERO-2 (39-mo): Final OS Analysis Probability of Overall Survival Censoring times EVE+EXE (n/ = 267/485) PBO+EXE (n/ = 143/239). E+E censored P+E 8. censored Time, months o. at risk EVE+EXE PBO+EXE HR =.89 (95% CI, ) Log-rank P =.14 Kaplan-Meier medians EVE+EXE: 3.98 months PBO+EXE: months At 39 months median follow-up, 41 deaths had occurred (data cutoff date: 3 October 213) 267 deaths (55%) in the EVE+EXE arm vs 143 deaths (6%) in the PBO+EXE arm One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS. Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS, Interactive Voice and Web Response System; PBO, placebo. Piccart et alpresented at EBCC-9; March 214; Glasgow, Scotland. Abstract 1LBA. 2 5 Toxicity: Everolimus and Exemestane Baselga EJM

14 PrECOG 12 Evaluated everolimus and fulvestrant vs fulvestrant + placebo (=131) Advanced ER+, HER2-, post menopausal Previously treated with AI, or relapsing on AI PFS: 1.4 mos vs 5.1 mos (p=.2) Expected toxicities Kornblum SABCS 216 PI3-Kinase Targeting pilaralisib buparlisib pictisilib alpelisib 14

15 PI3K ER+ Studies BELLE-3 BELLE-2 15

16 FERGI: PFS Krop SABCS 214 San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-2 Study Design and Endpoints Postmenopausal women with HR+/HER2 locally advanced or metastatic breast cancer that progressed on/after AI therapy =1147 Randomization (1:1) Stratification by PI3K pathway* and visceral disease status Buparlisib (1 mg/day) + fulvestrant (5 mg) n=576 Placebo + fulvestrant (5 mg) n=571 Primary Endpoints PFS in the main population (PI3K activated and non-activated, excluding status unknown*) PFS in the PI3K activated group* (PIK3CA mutation and/or PTE loss in archival tissue) PFS in the full population (local assessment) Key Secondary Endpoint Overall survival Other Secondary Endpoints Overall response rate Clinical benefit rate Safety, pharmacokinetics, quality of life Exploratory Endpoint PFS by ctda PIK3CA mutation status BELLE-2: ClinicalTrials.gov CT AI, aromatase inhibitor; BEAMing, beads, emulsification, amplification, and magnetics; ctda, circulating tumor DA; HER2, human epidermal growth factor receptor 2 negative; HR+, hormone receptor-positive; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase. *PI3K pathway activation (activated, non-activated, unknown) was assessed in archival tumor tissue provided at screening, defined as PIK3CA mutation by Sanger sequencing (any mutations in exons 1, 7, 9, or 2) and/or loss of PTE expression by immunohistochemistry (1+ expression in <1% of cells); ctda PIK3CA status was assessed by BEAMing technology. This presentation is the intellectual property of Dr. Ian Krop; contact at ikrop@partners.org for permission to reprint and/or distribute 16

17 San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-2 Met the Primary Endpoint for Statistically Significant PFS Improvement in the Full and Main Population Probability of Progression-free Survival, % Buparlisib + fulvestrant (n/=349/576) Placebo + fulvestrant (n/=435/571) Full Population (=147) Median PFS, months (95% CI) Buparlisi b + Fulvestr ant n= ( ) Placebo + Fulvestr ant n= (4. 5.2) HR (95% CI).78 (.67.89) One-sided P value <.1 Time (Months) A similar PFS improvement was observed in the main population (HR.8 [95% CI:.68.94]; one-sided P value.3) Follow-up for OS analysis is ongoing, with a pre-specified target of 588 deaths in the full population At the time of primary PFS analysis, OS data were immature (281 deaths in the full population), with a trend in favor of the buparlisib arm CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. This presentation is the intellectual property of Dr. Ian Krop; contact at ikrop@partners.org for permission to reprint and/or distribute 3 3 San Antonio Breast Cancer Symposium December 8 12, 215 Buparlisib and Fulvestrant Produced a Clinically Meaningful PFS Improvement in Patients With ctda PIK3CA Mutations ctda PIK3CA Mutant n=2 Median PFS, months (95% CI) Buparlisib + Fulvestrant n=87 7. (5. 1.) Placebo + Fulvestra nt n= (2. 5.1) HR (95% CI).56 (.39.8) 1 One-sided nominal P value <.1 Buparlisib + fulvestrant (n/=48/87) Placebo + fulvestrant (n/=9/113) ctda PIK3CA on-mutant n=387 Median PFS, months (95% CI) Buparlisib + Fulvestrant n= ( ) Placebo + Fulvestra nt n= ( ) HR (95% CI) 1.5 ( ) 1 One-sided nominal P value.642 Buparlisib + fulvestrant (n/=124/199) Placebo + fulvestrant (n/=126/188) Probability of Progression-free Survival, % Probability of Progression-free Survival, % Time (Months) Time (Months) CI, confidence interval; ctda, circulating tumor DA; HR, hazard ratio; PFS, progression-free survival. This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission to reprint and/or distribute

18 San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-2 Safety Profile Was Characterized by Hyperglycemia, Transaminitis, Rash, and Mood Disorders Buparlisib + Fulvestrant Placebo + Fulvestrant n=573 n=57 Adverse event, % All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Total Increased ALT Increased AST Hyperglycemia Rash Anxiety Fatigue Depression Diarrhea Asthenia Stomatitis ausea Serious adverse events occurred in 23.4% of patients in the buparlisib arm vs 15.8% in the placebo arm Decreased 12 on-treatment deaths (2.1%) 29.8were reported 1.6in each arm in the full population, 11.1the majority due.2to disease progression appetite ALT, alanine aminotransferase; AST, aspartate aminotransferase. This presentation is the intellectual property of Dr. Ian Krop; contact at ikrop@partners.org for permission to reprint and/or distribute 3 5 San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-3 Study Design and Endpoints 36 This presentation is the intellectual property of Dr. Ian Krop; contact at ikrop@partners.org for permission to reprint and/or distribute 18

19 San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-3 Primary Endpoint: Investigator PFS 37 This presentation is the intellectual property of Dr. Ian Krop; contact at for permission to reprint and/or distribute San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-3 PFS by PIK3CA Status 38 This presentation is the intellectual property of Dr. Ian Krop; contact at for permission to reprint and/or distribute 19

20 San Antonio Breast Cancer Symposium, Dec 9-13, 214 BELLE-3 :Adverse Events (>1% regardless of cause) 39 This presentation is the intellectual property of Dr. Ian Krop; contact at for permission to reprint and/or distribute Gene Expression and Cancer Mechanisms of Epigenetic Modulation Histone deacetylation prevents gene expression HDAC Histone acetylation allows gene expression HAT Ac TF Ac Ac Deacetylation Acetylation Ac: acetyl group TF: transcription factors HDAC depicts a class I deacetylase ormal Cell Marks PA et al. J atl Cancer Inst 2;92:

21 Reversible Histone Acetylation Regulates Gene Expression HAT Transcriptional Factors Core histones Histone acetylation Ac - Ac - Ac - Pol2 Ac - Ac - Ac - HDAC Inhibitor mra Histone deacetylation HDACs Cofactors Repressed Chromatin (hypo-acetylated histones) Ac - Ac - Activated Chromatin (hyper-acetylated histones) Repressed Chromatin Yoo CB and Jones PA. at Rev Drug Discov. 26;5:37 Entinostat and Exemestane Post-menopausal ER+ advanced breast cancer Progressed on/or relapsed while taking a SAI 1:1 SAI setting Bone only Region exemestane +entinostat exemestane +placebo = 13 Yardley et al

22 Entinostat and Exemestane PFS: 2.3 mos to 4.3 mos HR.73 95% CI mos: 19.8 mos to 28.1 mos HR.59 95% CI Yardley et al 213 Entinostat and Exemestane: Toxicity Yardley et al

23 Entinostat and Exemestane: Phase III Palbociclib: an Oral Selective CDK 4/6 Kinase Inhibitor Inhibits cell proliferation and cellular DA synthesis by preventing cellcycle progression from G1 to S phase In vitro activity in retinoblastoma-positive tumor cell lines and primary tumors Low nanomolar concentrations block Rb phosphorylation, inducing G1 arrest in sensitive cell lines CDK (partner) Specific cell cycle arrest in G1 phase IC 5 (mm) O CDK4 (cyclin D1).11 CDK4 (cyclin D3).9 H O CDK6 (cyclin D2).15 CDK2 (cyclin A) >1 CDK1 (cyclin B) >1 CDK5 (p25) >1 + H 2 Palbociclib (PD ) Fry DW, et al. Mol Cancer Ther 24;3: / Menu E, et al. Cancer Res 28;68: Sutherland RL, Musgrove EA. Breast Cancer Res 29;11:112 23

24 Rb as Master-Regulator of the R-Point Palbociclib: CDK 4/6 Inhibitor Breast Panel Subtype Luminal HER2 amplified Immortalized on-luminal/post EMT on-luminal Finn RS, et al. Breast Cancer Res. 29;11(5):R77. 24

25 MCF7 Palbociclib Acts Synergistically with Tamoxifen in ER+ Breast Cancer Cell Lines Inhibition (%) Palbociclib alone Tamoxifen alone Palbociclib/Tamoxifen combination CI m =.37±.4 Tamoxifen Palbociclib Concentration nm EFM CI m =.45± Tamoxifen Palbociclib Concentration nm Inhibition (%) T47D 1 8 CI m =.1± Tamoxifen Palbociclib Concentration nm Inhibition (%) Mean combination index (CI m ) <1 indicates synergy for the combinations Finn RS, et al. Breast Cancer Res. 29;11(5):R77 PALOMA-1/TRIO-18 Study Design (CT72149) Cohort 1 Cohort 2 ER+/HER2 advanced breast cancer RA D O MI ZA TI O * Palbociclib 125 mg/d + Letrozole 2.5 mg/d 1:1 Letrozole 2.5 mg/d ER+/HER2 advanced breast cancer with CCD1 amplification and/or loss of p16 RA D O MI ZA TI O * Palbociclib 125 mg/d + Letrozole 2.5 mg/d 1:1 Letrozole 2.5 mg/d n=66 n=99 Randomized phase II open-label trial involving 5 centers in 12 countries Key eligibility criteria: inoperable ER+/HER2 locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.) or bone-only disease, ECOG performance status 1, adequate bone marrow and renal function *Randomization stratified by disease site and disease-free interval. Palbociclib schedule 3/1 (28-day cycles). Finn RS, et al. Lancet Oncol. 215;16(1):

26 PALOMA-1/TRIO-18: PFS (ITT Population) 1 Progression-free survival, % Palbociclib plus letrozole Letrozole 1 umber at risk Palbociclib plus letrozole Letrozole HR.488 (95% CI ; one-sided P =.4) Time, months Finn RS, et al. Lancet Oncol. 215;16(1): PALOMA-1/TRIO-18: Overall Survival (ITT Population) 1 9 Palbociclib plus letrozole Letrozole 8 Overall survival, % umber at risk Palbociclib plus letrozole Letrozole 1 HR.813 (95% CI ; two-sided P =.42) Time, months With only 3 events in the palbociclib plus letrozole arm and 31 events in the control arm, the study was not powered to demonstrate an overall survival advantage; initial data suggest there is no detrimental effect on OS by adding palbociclib A follow-up overall survival analysis will be performed after the accrual of additional events Finn RS, et al. Lancet Oncol. 215;16(1):

27 PALOMA-1/TRIO-18: All-Causality AEs Occurring in 1% of Patients (Safety Population) (1/2) PAL + LET (n=83) LET (n=77) Adverse event, % All grades Grade 3/4 All grades Grade 3/4 Any adverse event eutropenia Leukopenia Fatigue Anemia ausea Arthralgia Alopecia 22 n/a 3 n/a Diarrhea Hot flush Thrombocytopenia Decreased appetite Dyspnea asopharyngitis 16 1 Back pain o cases of febrile neutropenia were reported One (1%) grade 5 event occurred in the PAL + LET group (from disease progression); none occurred in the LET group. Finn RS, et al. Lancet Oncol. 215;16(1): PALOMA-1/TRIO-18: All-Causality AEs Occurring in 1% of Patients (Safety Population) (2/2) PAL + LET (n=83) LET (n=77) Adverse event, % All grades Grade 3/4 All grades Grade 3/4 Any adverse event Headache 14 1 Vomiting Asthenia Bone pain Constipation 12 9 Cough 12 1 Stomatitis 12 3 Epistaxis 11 1 Influenza Musculoskeletal pain Upper respiratory tract infection Dizziness 1 4 Peripheral neuropathy 1 5 Oropharyngeal pain 1 1 Pain in extremity 1 8 SAEs occurring in >1 patient in the palbociclib plus letrozole group were pulmonary embolism (n=3 [4%]), back pain (n=2 [2%]), and diarrhea (n=2 [2%]); no SAEs occurred in the letrozole group One (1%) grade 5 event occurred in the PAL + LET group (from disease progression); none occurred in the LET group. Finn RS, et al. Lancet Oncol. 215;16(1):

28 Slide 6 Presented By Richard Finn at 216 ASCO Annual Meeting PFS: Investigator-Assessed <br />(ITT Population) Presented By Richard Finn at 216 ASCO Annual Meeting 28

29 PFS: Blinded Independent Central Review<br />Confirms PFS Advantage Observed Using Investigator Assessment Presented By Richard Finn at 216 ASCO Annual Meeting Consistency of 1o and 2o Efficacy Endpoints Across PALOMA-1 and PALOMA-2 Studies Presented By Richard Finn at 216 ASCO Annual Meeting 29

30 TEAEs Occurring in 15% of Patients All Causality <br /> Presented By Richard Finn at 216 ASCO Annual Meeting PALOMA3 Study Design Presented By icholas Turner at 215 ASCO Annual Meeting 3

31 Primary Endpoint: PFS (ITT Population) Presented By icholas Turner at 215 ASCO Annual Meeting PFS: Central Blinded Review Audit (n=211) Presented By icholas Turner at 215 ASCO Annual Meeting 31

32 GEICAM/213-2: Phase III study of Palbociclib (PD ) in combination with Exemestane versus chemotherapy (capecitabine) in Hormonal Receptor (HR) positive/her2 negative Metastatic Breast Cancer (MBC) patients with Resistance to nonsteroidal Aromatase inhibitors PI: M.Martin Phase 3 study Postmenopausal women with ER +/ HER2- advanced breast cancer Resistant to SAIs Measurable disease o more than 1 prior line of therapy for M1 Capecitabine 125 mg/m2/12hr x 14 days q3w =348 Exemestane 25 mg/d + palbociclib 125mg/d x 21 days q4w Primary endpoint PFS Secondary endpoints ORR, CBR, DoCR, OS, TTD, QoL, safety, PK, biomarkers 8% power to detect a difference between the control arm (median PFS of 6 months) and the experimental arm (median PFS of 8.75 months, HR of.686, with a 5% two sided significance level. 4 sites in six countries (Austria, Bosnia, Hungary, Israel, Romania and Spain); recruitment period of approximately 24 months. PEARL trial, ClinTrials.gov CT22857, EudraCT umber:

33 CDK4/6 Inhibitors in Clinical Trial O F H O F H H H O H PD (Palbociclib) 1 CDK4 IC 5 = 11 nm CDK6 IC 5 = 16 nm LY (Abemaciclib) 2 CDK4 IC 5 = 2 nm CDK6 IC 5 = 9.9 nm CDK9 IC 5 = 57 nm CDK1 IC 5 = 1,627 nm LEE11 (Ribociclib) 3 CDK4 IC 5 = 1 nm CDK6 IC 5 = 39 nm 1. Fry DW et al. Mol Cancer Ther. 24;3: Gelbert LM et al. Invest ew Drugs. 214;32: Kim S et al. Mol Cancer Ther. 213;12(11 Suppl):PR2. Additional follow up: PFS 25.3 mos vs 16. mos 33

34 PATIET DEMOGRAPHICS AD BASELIE CHARACTERISTICS Characteristic Ribociclib + Letrozole Placebo + Letrozole n=334 n=334 Median age, years (range) 62 (23 91) 63 (29 88) Race, n (%) Caucasian 269 (81) 28 (84) Asian 28 (8.4) 23 (6.9) Black 1 (3.) 7 (2.1) Other/unknown 27 (8.1) 24 (7.2) ECOG performance status, n (%) 25 (61) 22 (6) (39) 132 (4) Metastatic sites, n (%) Visceral disease 197 (59) 196 (59) Bone-only disease 69 (21) 78 (23) De novo metastatic disease, n (%) 114 (34) 113 (34) Disease-free interval since end of (neo)adjuvant therapy, n (%)* 12 months 4 (1.2) 1 (3.) >12 months 216 (65) 21 (63) Prior (neo)adjuvant systemic therapy, n (%) Chemotherapy and endocrine therapy 123 (37) 12 (36) Endocrine therapy only 52 (16) 51 (15) Chemotherapy only 23 (6.9) 25 (7.5) *1 patient in the placebo + letrozole arm had an unknown disease-free interval. HEMATOLOGIC ADVERSE EVETS Regardless of study treatment relationship Adverse Event 5% in Either Arm, % Ribociclib + Letrozole n=334 Placebo + Letrozole n=33 All Grade 3 Grade 4 All Grade 3 Grade 4 eutropenia Leukopenia Anemia Lymphopenia Thrombocytopenia Febrile neutropenia occurred in 5 (1.5%)* patients in the ribociclib arm vs. none in the placebo arm *5 cases, which includes 1 case of febrile neutropenia recorded incorrectly. 34

35 O-HEMATOLOGIC ADVERSE EVETS Regardless of study treatment relationship Ribociclib + Letrozole Placebo + Letrozole Adverse Event n=334 n=33 15% in Either Arm, % All Grade 3 Grade 4 All Grade 3 Grade 4 ausea Infections Fatigue Diarrhea Alopecia Vomiting Arthralgia Constipation Headache Hot flush Back pain Cough 2 18 Decreased appetite Rash ALT increased AST increased In the ribociclib arm 1 (3.%) patients experienced Grade 2 QTcF (481 5 ms) and 1 (.3%) patient experienced Grade 3 QTcF (>5 ms); no dose reductions were required MOALEESA-3 CT

36 MOALEESA-7 CT MOARCH 1: Phase 2 Study Design Previouslytreated HR+/HER2- MBC Abemaciclib 2 mg orally Q12H Treatment continued until unacceptable toxicity or PD Primary objective To evaluate abemaciclib with respect to confirmed objective response rate based on investigator assessment (per RECIST v1.1) Secondary objectives Duration of response, progression-free survival, overall survival, clinical benefit rate, safety Statistical design A sample size of 128 patients provides 82% power, assuming a true response rate of 25%, to exclude an ORR of 15 % on the lower bound of the 95 % CI at 12 months follow-up Clinical trial ID: CT

37 MOARCH 1: Response Summary Change from Baseline (%) Disease Control Rate (CR + PR + SD) = 67.4% Investigator Assessed Response a Confirmed Objective Response Rate (ORR = CR + PR) (95 % CI) CR PR Abemaciclib 2 mg ( = 132) 19.7% (13.3, 27.5) % 19.7% Stable Disease 6 months 22.7% Clinical Benefit Rate (CBR = ORR +SD 42.4 % 6 mos) -1 Progressive disease (n = 34) Stable disease (n = 63) Partial response (n = 26) ot assessed (n = 9) Dickler M. et al. J Clin Oncol 34, 216 (suppl; abstr 51) a Assessments based on independent review were comparable MOARCH 1: Kaplan-Meier Plots A. Progression-free Survival B. Overall Survival Survival Probability I I II I I I II I I Abemaciclib 2 mg Patients/Eve nts 132/1 Median, months % CI 4.21, 7.5 I I II Months 1 8 I II I I I II Survival Probability I Patients/Eve nts 132/62 Median, months % CI 17.7, R I I I I Months I III II II I IIIII III I IIIIII II I III I II I II I II I I I Pts at Risk: Pts at Risk: Pts = patients, R = not reached 37

38 MOARCH 1: Most Common Adverse Events Investigator Assessed TEAEs a >2% ( = 132) Grade 1 % Grade 2 % Grade 3 % Grade 4 % All Grades % Diarrhea ausea Fatigue Decreased appetite Abdominal pain Vomiting Headache Pain Lab abnormalities b TEAEs a > 4% Creatinine increased c (CTCAE v 4.3: over baseline) White blood cell decreased eutrophil count decreased d Anemia Lymphocyte count decreased Platelet count decreased a CTCAE Version 4.3, b = 13 for lab abnormalities listed, except platelet count decreased ( = 128), c Abemaciclib is a competitive inhibitor of OCT2, MATE1, and MATE2 K, efflux transporters of creatinine; cystatin C calculated GFR was not raised, d One patient who received cytotoxic chemotherapy within the 3 day follow up d d fbl Abemaciclib (LY ): MOARCH 2 A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without LY , a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 egative Locally Advanced or Metastatic Breast Cancer LY Fulvestrant until PD Women with HR+, HER2- Locally Advanced or Metastatic Breast Cancer (=55) R 2:1 Primary endpoint: Progression-Free Survival (PFS) Placebo + Fulvestrant until PD MARCH 2, 217: Met its Primary Endpoint CT

39 Ph3 Study: MOARCH 2 A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without LY , a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 egative Locally Advanced or Metastatic Breast Cancer LY Fulvestrant until PD Women with HR+, HER2- Locally Advanced or Metastatic Breast Cancer (=55) R 2:1 Placebo + Fulvestrant until PD Primary endpoint: Progression-Free Survival (PFS) August 1: Pre-planned analysis, continue as planned CT21773 Ph3 Study: MOARCH 3 A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of onsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) plus LY , a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women with Hormone Receptor-Positive, HER2-egative Locoregionally Recurrent or Metastatic Breast Cancer with o Prior Systemic Therapy in this Disease Setting Women with HR+, HER2- Locoregionally Recurrent or Metastatic Breast Cancer with DFI>12 mos following (neo)adjuvant ET or presenting de novo with metastatic disease (=45) R 2:1 LY SAI until PD Placebo + SAI until PD Primary endpoint: Progression-Free Survival (PFS) CT

40 Genomic Data by Breast Subtype TCGA ature 212 Evolution of ER+ Breast Cancer Tamoxifen (1977) Anastrazole (1995) Letrozole (1997) Toremifene (1997) Examestane (1999) Fulvestrant 25 mg (22) Fulvestrant 5 mg (21) Everolimus (212) Palbociclib (215) Modifeid from Chemlowski epub 212 4