Overcoming Endocrine Resistance in ER+ Breast Cancer

Transcription

1 Overcoming Endocrine Resistance in ER+ Breast Cancer Richard S. Finn, MD Associate Professor of Medicine Division of Hematology/Oncology Director Signal Transduction and Therapeutics Program Jonsson Comprehensive Cancer Center Geffen School of Medicine at UCLA

2 HR+ Metastatic Breast Cancer The most common subset of breast cancer HR+ disease comprises 65-70% of patients with metastatic breast cancer Prognosis highly variable and dependent on hormone responsiveness Median survival ranges from 3 4 years 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

3 Goals and Challenges: HR+ Metastatic Breast Cancer Live as long as possible with the best quality of life Challenges Improve response to hormone therapy Prolong the duration of PFS Delay start of chemotherapy Preserve or improve QOL Improve outcome without adverse impact on quality of life Use evidence based on tumor biology to choose the most effective treatment approach Delay development of resistance to hormone therapy Overcome upfront resistance

4 Clinical Resistance is Regularly Seen Kaufmann 2000 Osborne 2002 Johnston 2014 Di Leo 2010 Bonneterre 2001 Nabholtz 2000

5 Clinical Markers Predictors of Resistance Disease free interval from adjuvant therapy Duration of response Prior treatment HER2 amplification Lower ER expression Lower PR expression Key: baseline clinical characteristics of population will dictate response/outcome

6 Pietras & Marquez, 2008

7 Pietras & Marquez, 2008

8 Numerous Molecularly Targeted Agents Evaluated but without Success Receptor Tyrosine Kinase Inhibitors EGFR (gefitinib, erlotinib, laptinib) IGFR (AMG 479) FGFR Src (dasatinib) Anti-angiogeneis sorafenib sunitinib bevacizumab

9 EGF30008 Phase III Study Design Locally tested ER+ and/or PgR+ Postmenopausal HER2+, HER2-, HER2 unknown Stage IIIb/IIIc, IV No prior treatment for MBC Stratification: Disease sites Bone only /Other Time since prior adj hormone tx < 6 mos / > 6 mos R A N D O M I Z E Letrozole 2.5mg daily + Lapatinib 1500 mg daily Letrozole 2.5mg daily + Placebo Primary endpoint: Investigator assessed PFS Johnston JCO 2009 N = 1286 of which 219 were Her2+ 9

10 EGF30008 Phase III Study Design HER2+ Johnston JCO 2009

11 EGF30008 Phase III Study Design PFS: HER2-ve Patients (N=952) 6 Mo Since D/C of Tam (33%) or No Tam (67%) Median tam duration 5 y Median time since d/c 3.5 y < 6 Mo Since D/C of Tam Median tam duration 2.8 y Median time since d/c 1 mo Let (N=370) Let + Lap (N=382) Median PFS, mo Hazard ratio (95% CI), p-value 0.94 (0.79, 1.13); p=0.522 Let (N=104) Let + Lap (N=96) Median PFS, mo Hazard ratio (95% CI), p-value 0.78 (0.57, 1.07); p=0.117 Johnston JCO

12 EGF30008 Phase III Study Design 4A. ER Quartile 1: H-Score <160 4B. ER Quartiles 2 and 3: H-Score 160 and <250 Cumulative progression-free survival Cumulative progression-free survival 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 4C. ER Quartile 4: H-Score % 90% 80% 70% 60% 50% 40% 30% 20% 10% L + Lapatinib L + Placebo L + Lapatinib L + Placebo Events, N Median, months 95% CI HR (95% CI) P value 0% Time, months Events, N Median, months 95% CI HR (95% CI) P value 0% Time, months Finn RS et al Clin Can Res 2014 Lapatinib n= , 17.2 Lapatinib n= , , (0.75,1.23) , (0.47,0.9).01 Placebo n=97 77 Placebo n= Cumulative progression-free survival 100% 90% 80% 70% 60% 50% 40% 30% Events, N Median, months 95% CI HR (95% CI) P value 20% L + Lapatinib L + Lapatinib 10% L + Placebo 0% L + Placebo Time, months Lapatinib n= , 16.4 Figures 4A, 4B, and 4C. PFS by treatment arm: grouped by ER quartile Patients treated with letrozole + lapatinib with low ER expression had a significant benefit from the addition of lapatinib vs placebo: , (0.75,1.23) Median PFS was 13.6 months with letrozole + lapatinib vs 6.6 months letrozole + placebo (HR [95% CI] = 0.65 [0.47, 0.9], P<.05).77 Placebo n=

13 Newer Agents in Development ER+ PI3k/ mtor HDAC CDK

14 PI3-Kinase Targeting

15 BOLERO-2: Study Design N = 724 Postmenopausal women ER +, HER2 unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole Randomize 2:1 Endpoints Primary: PFS (local assessment) Secondary: OS, ORR, CBR, QOL, safety, PK Exploratory: Biomarkers EVE 10 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 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. N Engl J Med. 2012;366(6):

16 Baseline Characteristics: BOLERO2 Baselga J, et al. N Engl J Med. 2012;366(6):

17 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 HR = 0.45 (95% CI, ) Log-rank P <.0001 Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months Censoring times EVE+EXE (n/n = 310/485) PBO+EXE (n/n = 200/239) No. 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. 2013;30(10):

18 BOLERO-2 (39-mo): Final OS Analysis HR = 0.89 (95% CI, ) Log-rank P =.14 Kaplan-Meier medians EVE+EXE: months PBO+EXE: months Censoring times No. at risk EVE+EXE PBO+EXE At 39 months median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013) 267 deaths (55%) in the EVE+EXE arm vs 143 deaths (60%) 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 2014; Glasgow, Scotland. Abstract 1LBA. 18

19 Baselga NEJM 2012 Toxicity: Everolimus and Exemestane

20 SWISH Study Rugo et al. The Lancet Oncology , DOI: ( /S (17) )

21 21

22 San Antonio Breast Cancer Symposium, December 6-10, 2016 PrECOG0102: Study Schema Induction Phase Continuation Phase 1:1 Randomization Stratify: ECOG PS: 0 vs. 1 Measurable Disease (y/n) Prior Chemo for Mets (y/n) Arm A Fulvestrant 500 mg day 1 and 15 of cycle 1, then day 1 of cycles 2-12 (28d cycles) Everolimus 10 mg PO QD Arm A & B (week 48) Arm B Fulvestrant 500 mg day 1 and 15 of cycle 1, then day 1 of cycles 2-12 (28d cycles) Placebo PO QD Unblind and continue Fulvestrant +/- Everolimus Induction Phase: Treat until evidence of progressive disease or unacceptable toxicity for a maximum of 12 cycles (48 weeks) Continuation Phase: If no disease progression or unacceptable toxicity after 12 cycles, unblind and continue fulvestrant +/- everolimus Treatment Plan: Tumor measurements every 12 weeks (+/- 1 week) by local treating physician Supportive Care: Corticosteroid mouthwash prophylaxis was not used Kornblum et al SABCS 2016

23 San Antonio Breast Cancer Symposium, December 6-10, 2016 PrECOG0102: Key Eligibility Criteria Post-menopausal women HR-positive, HER2-negative (ASCO-CAP) Inoperable locally advanced or metastatic breast cancer AI resistant disease: Relapse while receiving adjuvant AI therapy Progression after one or more AIs for metastatic disease ECOG PS 0-1 Normal organ function < 1 prior chemotherapy regimen for metastasis Measurable and/or non-measurable disease (RECIST 1.1) 2 doses of fulvestrant permitted within 28d prior to randomization Kornblum et al SABCS 2016

24 San Antonio Breast Cancer Symposium, December 6-10, 2016 Characteristic Fulvestrant + Everolimus Fulvestrant + Placebo Number of Randomized Patients (treated) 66 (64) 65 (65) Age (Median/Range) 64 (39-92) 59 (35-85) ECOG Performance Status: (61%) 26 (39%) 38 (58%) 27 (41%) Measurable Disease 44 (67%) 42 (65%) Metastatic Disease Site Bone 43 (65%) 46 (71%) Lung 28 (42%) 22 (34%) Liver 18 (27%) 17 (26%) Lymph Nodes 27 (41%) 28 (43%) Prior Therapy PrECOG0102: Patient Characteristics Prior Chemo for Metastatic Disease 11 (17%) 12 (18%) Fulvestrant prior to C1D1 6 (9%) 5 (8%) Prior CDK4/6 Inhibitor 0 2 (3%) Kornblum et al SABCS 2016

25 San Antonio Breast Cancer Symposium, December 6-10, 2016 Progression Free Survival (by investigator assessment primary study endpoint) Proportion Alive and Progression-Free Hazard Ratio 0.60, 95% CI Stratified Log rank p = 0.02 Everolimus (45 events/66 pts), Median PFS 10.4 mos Placebo (56 events/65 pts), Median PFS 5.1 mos Months No. at Risk Everolimus Placebo Kornblum et al SABCS 2016

26 PI3K ER+ Studies BELLE-3 BELLE-2

27 FERGI Study Design Part I 27 ER+, HER2-, postmenopausal women with advanced or MBC Prior aromatase inhibitor in adjuvant (PD<6mo) or metastatic setting ECOG PS 0, 1 No diabetic patients 0-1 chemotherapy or 2 prior endocrine therapies R N = 168 1:1 Fulvestrant 500mg 1 + pictilisib (GDC-0941) 340 mg QD Fulvestrant 500 mg 1 + placebo QD Treat to PD 2 Treat to PD 2 Cross Over pictilisib + fulvestrant Stratification factors 1 objective 2 objectives PIK3CA-MT and PTEN loss 3 Measurable disease 1 o vs. 2 o resistance 4 Median duration of follow up 17.5 months PFS in the ITT PFS in PIK3CA-MT pts Safety Objective response rate Duration of objective response PK 1 Administered on D1 of each 28 day cycle and C1D15; 2 Tumor assessments performed every 8 weeks; 3 Exons 9 and 20 in the codons encoding amino acids E542, E545, and H1047 were detected by RT-PCR; 4 Disease relapse during or within 6 months of completing AI treatment in the adjuvant setting, or disease progression within 6 months of starting AI treatment in the metastatic setting. 5 Data presented is with an additional year of follow up per-protocol primary analysis Krop I, Lancet Onc 2016

28 Progression-Free Survival in the ITT Population 28 Krop I, Lancet Onc 2016

29 Progression-Free Survival Based on Tumor PIK3CA Mutation Status 29 PIK3CA-Mutant Population PIK3CA Wild-Type Population PIK3CA mutation status does not predict benefit of the addition of pictilisib to fulvestrant Krop I, Lancet Onc 2016

30 BELLE-2 Study Design and Endpoints 30 Postmenopausal women with HR+/HER2 locally advanced or metastatic breast cancer that progressed on/after AI therapy N=1147 Randomization (1:1) Stratification by PI3K pathway* and visceral disease status Buparlisib (100 mg/day) + fulvestrant (500 mg) n=576 Placebo + fulvestrant (500 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 PTEN 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 ctdna PIK3CA mutation status BELLE-2: ClinicalTrials.gov NCT AI, aromatase inhibitor; BEAMing, beads, emulsification, amplification, and magnetics; ctdna, circulating tumor DNA; 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 20) and/or loss of PTEN expression by immunohistochemistry (1+ expression in <10% of cells); ctdna PIK3CA status was assessed by BEAMing technology. Baselga et al 2015

31 BELLE-2 Safety Profile Was Characterized by Hyperglycemia, Transaminitis, Rash, and Mood Disorders ALT, alanine aminotransferase; AST, aspartate aminotransferase. Buparlisib + Fulvestrant n=573 Placebo + Fulvestrant n=570 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 Nausea Decreased appetite Serious adverse events occurred in 23.4% of patients in the buparlisib arm vs 15.8% in the placebo arm 12 on-treatment deaths (2.1%) were reported in each arm in the full population, the majority due to disease progression 3 1

32 Probability of Progression-free Survival, % BELLE-2 Met the Primary Endpoint for Statistically Significant PFS Improvement in the Full and Main Population Buparlisib + fulvestrant (n/n=349/576) Placebo + fulvestrant (n/n=435/571) Full Population (N=1047) Buparlisib + Fulvestrant n=576 Placebo + Fulvestra nt n= Time (Months) Median PFS, months (95% CI) 6.9 ( ) 5.0 ( ) HR (95% CI) 0.78 ( ) One-sided P value <0.001 A similar PFS improvement was observed in the main population (HR 0.80 [95% CI: ]; one-sided P value 0.003) 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. 3 2

33 Probability of Progression-free Survival, % PFS Increase in the PI3K Activated Group Was Not Statistically Significant Buparlisib + fulvestrant (n/n=116/188) Placebo + fulvestrant (n/n=144/184) Time (Months) PI3K Activated Group (N=372) Median PFS, months (95% CI) Buparlisi b + Fulvestr ant n= ( ) Placebo + Fulvestr ant n= ( ) HR (95% CI) 0.76 ( ) One-sided P value* *PFS in the PI3K activated group was tested at a one-sided α=0.01 level of significance. CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase.

34 Probability of Progression-free Survival, % San Antonio Breast Cancer Symposium December 8 12, 2015 Buparlisib and Fulvestrant Produced a Clinically Meaningful PFS Improvement in Patients With ctdna PIK3CA Mutations Probability of Progression-free Survival, % ctdna PIK3CA Mutant n=200 Median PFS, months (95% CI) Buparlisib + Fulvestrant n= ( ) Placebo + Fulvestra nt n= ( ) HR (95% CI) 0.56 ( ) One-sided nominal P value < Buparlisib + fulvestrant (n/n=48/87) Placebo + fulvestrant (n/n=90/113) ctdna PIK3CA Non-mutant n=387 Median PFS, months (95% CI) Buparlisib + Fulvestrant n= ( ) Placebo + Fulvestra nt n= ( ) HR (95% CI) 1.05 ( ) One-sided nominal P value Buparlisib + fulvestrant (n/n=124/199) Placebo + fulvestrant (n/n=126/188) CI, confidence interval; ctdna, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival Time (Months) This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission Time to reprint (Months) and/or distribute. 34

35 San Antonio Breast Cancer Symposium December 8 12, 2015 BELLE-3 Study Design and Endpoints This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission to reprint and/or distribute. 3 5

36 San Antonio Breast Cancer Symposium December 8 12, 2015 BELLE-3 Study Baseline Characteristics This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission to reprint and/or distribute. 3 6

37 San Antonio Breast Cancer Symposium December 8 12, 2015 BELLE-3 Primary Endpoint: Investigator PFS This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission to reprint and/or distribute. 3 7

38 San Antonio Breast Cancer Symposium December 8 12, 2015 BELLE-3 PFS by PIK3CA Status This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission to reprint and/or distribute. 3 8

39 San Antonio Breast Cancer Symposium December 8 12, 2015 BELLE-3 :Adverse Events (>10% regardless of cause) This presentation is the intellectual property of the author/presenter. Contact them at baselgaj@mskcc.org for permission to reprint and/or distribute. 3 9

40 Gene Expression and Cancer Mechanisms of Epigenetic Modulation HDAC Histone deacetylation prevents gene expression Histone acetylation allows gene expression HAT TF Ac Ac Ac Deacetylation Acetylation Ac: acetyl group TF: transcription factors HDAC depicts a class I deacetylase Normal Cell Marks PA et al. J Natl Cancer Inst 2000;92:

41 Etinostat and Exemestane Post-menopausal ER+ advanced breast cancer Progressed on/or relapsed while taking a NSAI 1:1 NSAI setting Bone only Region exemestane +etinostat exemestane +placebo N= 130 Yardley et al 2013

42 Etinostat and Exemestane PFS: 2.3 mos to 4.3 mos HR % CI mos: 19.8 mos to 28.1 mos HR % CI Yardley et al 2013

43 Etinostat and Exemestane: Toxicity Yardley et al 2013

44 Etinostat and Exemestane: Phase III

45 Finn RS et al Breast Can Res i

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47 PALOMA-2: Demographics and Baseline Characteristics (ITT Population) Palbociclib + letrozole (N=444) a Visceral disease was defined as: any lung (including pleura) and/or liver involvement b Time since completion of (neo)adjuvant therapy and onset of recurrence; percentage calculated based on number of patients who received (neo)adjuvant therapy Patients who progressed while receiving or 12 months from completion of prior anastrozole or letrozole were excluded Placebo + letrozole (N=222) Age, n (%) Median (range) 62 (30 89) 61 (28 88) <65 years 263 (59.2) 141 (63.5) 65 years 181 (40.8) 81 (36.5) Race, n (%) White 344 (77.5) 172 (77.5) Asian 65 (14.6) 30 (13.5) Black 8 (1.8) 3 (1.4) Other 27 (6.1) 17 (7.7) ECOG PS, n (%) (57.9) 102 (45.9) (40.1) 117 (52.7) 2 9 (2.0) 3 (1.4) Disease site, n (%) Visceral a 214 (48.2) 110 (49.5) Non-visceral 230 (51.8) 112 (50.5) Bone-only 103 (23.2) 48 (21.6) No. of disease sites (31.1) 66 (29.7) (26.4) 52 (23.4) (25.2) 61 (27.5) 4 77 (17.3) 43 (19.4) Disease-free interval, b n (%) Newly metastatic disease 167 (37.6) 81 (36.5) 12 months 99 (22.3) 48 (21.6) >12 months 178 (40.1) 93 (41.9) Finn RS, et al. N Engl J Med 2016 Nov 17;375(20):

48 Subgroup PALOMA-2: PFS Subgroup Analysis (ITT, Investigator Assessment) Palbociclib Letrozole, n (%) Placebo Letrozole, n (%) HR (95% CI) All randomized patients 444 (100) 222 (100) 0.58 ( ) Age <65 years 65 years 263 (59.2) 181 (40.8) 141 (63.5) 81 (36.5) 0.57 ( ) 0.57 ( ) Race White Asian 344 (77.5) 65 (14.6) 172 (77.5) 30 (13.5) 0.58 ( ) 0.48 ( ) Site of metastatic disease at baseline Visceral a Non-visceral 214 (48.2) 230 (51.8) 110 (49.5) 112 (50.5) 0.63 ( ) 0.50 ( ) Prior hormonal therapy Yes No 249 (56.1) 195 (43.9) 126 (56.8) 96 (43.2) 0.53 ( ) 0.63 ( ) Disease-free interval Newly metastatic disease 12 months >12 months 167 (37.6) 99 (22.3) 178 (40.1) 81 (36.5) 48 (21.6) 93 (41.9) 0.67 ( ) 0.50 ( ) 0.52 ( ) Region North America Europe Asia/Pacific 168 (37.8) 212 (47.7) 64 (14.4) 99 (44.6) 95 (42.8) 28 (12.6) 0.61 ( ) 0.57 ( ) 0.49 ( ) ECOG performance status 0 1/2 257 (57.9) 187 (42.1) 102 (45.9) 120 (54.1) 0.65 ( ) 0.53 ( ) Bone-only disease at baseline Yes No 103 (23.2) 341 (76.8) 48 (21.6) 174 (78.4) 0.36 ( ) 0.65 ( ) Measurable disease Yes No 338 (76.1) 106 (23.9) 171 (77.0) 51 (23.0) 0.66 ( ) 0.35 ( ) Prior chemotherapy Yes No 213 (48.0) 231 (52.0) 109 (49.1) 113 (50.9) 0.53 ( ) 0.61 ( ) Most recent therapy Aromatase inhibitor Antiestrogen 91 (20.5) 154 (34.7) 44 (19.8) 75 (33.8) 0.55 ( ) 0.56 ( ) Number of disease sites (31.1) 306 (68.9) 66 (29.7) 156 (70.3) 0.51 ( ) 0.61 ( ) Histopathological classification Ductal carcinoma Lobular carcinoma 356 (80.2) 68 (15.3) a Visceral disease was defined as: any lung (including pleura) and/or liver involvement CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group In favor of PAL + LET In favor of PCB + LET Performance Status; HR, hazard ratio; ITT, intention to treat; LET, letrozole; PAL, palbociclib; PCB, placebo; PFS, progression-free survival Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): (82.9) 30 (13.5) 0.59 ( ) 0.46 ( )

49 PFS (%) PFS in Patients with Visceral Disease a,b PAL + LET (n=214) PBO + LET (n=110) Median (95% CI) PFS, months 19.3 ( ) 12.9 ( ) HR (95% CI) 0.63 ( ) P value < PAL + LET PBO + LET Censored No. at risk PAL + LET PBO + LET Time (months) Data cutoff: February 26, 2016 a ITT population; b Investigator assessment CI, confidence interval; HR, hazard ratio; ITT, intention to treat; LET, letrozole; PAL, palbociclib; PBO, placebo; PFS, progression-free survival Finn RS, et al. Poster presented at ASCO 2017 (Abstract 1039)

50 PFS (%) PFS in Patients with Non-Visceral Disease a,b 100 PAL + LET (n=230) PBO + LET (n=112) Median (95% CI) PFS, months NR (25.1 NR) 16.8 ( ) HR (95% CI) 0.50 ( ) P value < PAL + LET PBO + LET Censored No. at risk PAL + LET PBO + LET Time (months) Data cutoff: February 26, 2016 a ITT population; b Investigator assessment CI, confidence interval; HR, hazard ratio; ITT, intention to treat; LET, letrozole; NR, not reached; PAL, palbociclib; PBO, placebo; PFS, progression-free survival Finn RS, et al. Poster presented at ASCO 2017 (Abstract 1039)

51 PFS (%) PFS in Patients with Bone-Only Disease a,b PAL + LET (n=103) PBO + LET (n=48) Median (95% CI) PFS, months NR (24.8 NR) 11.2 ( ) 100 HR (95% CI) 0.36 ( ) P value < PAL + LET PBO + LET Censored No. at risk PAL + LET PBO + LET Time (months) Data cutoff: February 26, 2016 a ITT population; b Investigator assessment CI, confidence interval; HR, hazard ratio; ITT, intention to treat; LET, letrozole; NR, not reached; PAL, palbociclib; PBO, placebo; PFS, progression-free survival Finn RS, et al. Poster presented at ASCO 2017 (Abstract 1039)

52 Design of Phase III Study in Recurrent MBC (1023)- PALOMA-3 HR+, HER2 ABC Pre-/peri-* or post-menopausal Progressed on prior endocrine therapy: 2:1 Randomization N=521 n=347 Palbociclib (125 mg QD; 3 wks on/1 wk off) + Fulvestrant (500 mg IM q4w) On or within 12 mo adjuvant On therapy for ABC Stratification: 1 prior chemotherapy regimen for advanced cancer *All received goserelin. Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs Post-menopausal n=174 Placebo (3 wks on/ 1wk off) + Fulvestrant (500 mg IM q4w) Post-menopausal patients must have progressed on prior aromatase inhibitor therapy. administered on Days 1 and 15 of Cycle 1. Clinicaltrials.gov NCT

53 Adverse Events All Cause AE, % Palbociclib + Fulvestrant (n=345) Any Grade Grade 3 Grade 4 Placebo + Fulvestrant (n=172) Any Grade Grade Grade 3 4 Any AE Neutropenia Leukopenia Anemia Thrombocytopenia Fatigue Nausea Headache 21 < Upper respiratory infection a 19 < Diarrhea Constipation Alopecia AE=adverse event. AEs with 15% incidence in the palbociclib + fulvestrant group reported. a Upper respiratory infection includes influenza, influenza-like illness, laryngitis, nasopharyngitis or pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection.

54 PFS (%) PALOMA-3 Final Analysis: Investigator-assessed PFS (ITT Population) PAL + FUL (n=347) PBO + FUL (n=174) Median PFS, months (95% CI) 9.5 ( ) 4.6 ( ) HR (95% CI) 0.46 ( ) P value < Palbociclib + fulvestrant Placebo + fulvestrant No. at risk Palbociclib + fulvestrant Placebo + fulvestrant Time (months) FUL, fulvestrant; HR, hazard ratio; PAL, palbociclib; PBO, placebo Cristofanilli M, et al. Lancet Oncol Apr;17(4):425 39

55 PFS (%) PFS (%) PALOMA-3 Final Analysis: PFS in Patients by PIK3CA Status PIK3CA status did not influence the magnitude of PFS benefit from palbociclib (HR=0.45 for PIK3CA WT, HR=0.48 for PIK3CA mutation positive, P interaction =0.83) PIK3CA-WT patients (n=266) Patients with PIK3CA mutations (n=129) PAL + FUL (n=180 ) PBO + FUL (n=86) PAL + FUL (n=85 ) PBO + FUL (n=44) Median PFS, months (95% CI) 9.9 ( ) 4.6 ( ) Median PFS, months (95% CI) 9.5 ( ) 3.6 ( ) HR (95% CI) 0.45 ( ) HR (95% CI) 0.48 ( ) 100 P value < P value Palbociclib + fulvestrant (n=180) Placebo + fulvestrant (n=86) Time (months) No. at risk Palbociclib + fulvestrant Placebo + fulvestrant Palbociclib + fulvestrant (n=85) Placebo + fulvestrant (n=44) Time (months) No. at risk Palbociclib + fulvestrant Placebo + fulvestrant FUL, fulvestrant; HR, hazard ratio; PAL, palbociclib; PBO, placebo; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Cristofanilli M, et al. Lancet Oncol Apr;17(4):425 39

56 PFS (%) PFS (%) ESR1 Mutations in PALOMA-3: Response by ESR1 Mutation Status The PFS benefit associated with the addition of palbociclib to fulvestrant was demonstrated regardless of ESR1 mutation status Median PFS, months (95% Cl) Palbociclib + fulvestrant (n=67) 9.4 ( ) Placebo + fulvestrant (n=39) 4.1 ( ) HR (95% CI) ( ) P value Median PFS, months (95% Cl) Palbociclib + fulvestrant (n=67) 9.5 ( ) Placebo + fulvestrant (n=39) 3.8 ( ) HR (95% CI) ( ) P value < ESR ESR No. at risk: Time (months) Palbociclib + fulvestrant Placebo + fulvestrant No. at risk: Palbociclib + fulvestrant Placebo + fulvestrant Time (months) HR, hazard ratio Turner NC, et al. J Clin Oncol 2016;34(Suppl.) (Abstract 512)

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58 RANDOMIZATION PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal Growth Factor Receptor 2 (HER2)- Negative Early Breast Cancer (PALLAS) Phase 3, PALLAS Sponsor: Alliance for Clinical Trials in Oncology Foundation, ABCSG HR+ and HER2- Stage II or III N=4600 Arm A* Palbociclib (2 Years) + Endocrine Treatment (5+ years) Diagnosis Surgery 1:1 Survival/Disease Follow-up Neo/Adjuvant Systemic Therapy Arm B** Endocrine Treatment (5+ years) *ARM A: palbociclib at a dose of 125 mg once daily, Day 1-21 in a 28-day cycle **ARM B: standard adjuvant endocrine therapy (AI; tamoxifen) FFPE Tissue Sample received at central biorepository QOL & Adherence Monitoring Stratification Factors: Pathologic stage (IIA vs IIB/III) or clinical stage if pre-operative therapy was given with the higher stage determining eligibility Neo/adjuvant chemotherapy (yes vs. no) Age (< 50 vs 50 years) Geographic region (North America vs. Europe vs. Asia)

59 CDK4/6 Inhibitors in Clinical Trials O N F N HN N N N O N N N F HN N N N N HN N N H N N N N O N N H PD (Palbociclib) 1 CDK4 IC 50 = 11 nm CDK6 IC 50 = 16 nm LY (Abemaciclib) 2 CDK4 IC 50 = 2 nm CDK6 IC 50 = 9.9 nm CDK9 IC 50 = 57 nm CDK1 IC 50 = 1,627 nm LEE011 (Ribociclib) 3 CDK4 IC 50 = 10 nm CDK6 IC 50 = 39 nm FDA Approved Positive Phase 3 Data FDA Approved 1. Fry DW et al. Mol Cancer Ther. 2004;3: Gelbert LM et al. Invest New Drugs. 2014;32: Kim S et al. Mol Cancer Ther. 2013;12(11 Suppl):PR02.

60 NCT MONALEESA-2

61

62 PATIENT DEMOGRAPHICS AND BASELINE 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) 280 (84) Asian 28 (8.4) 23 (6.9) Black 10 (3.0) 7 (2.1) Other/unknown 27 (8.1) 24 (7.2) ECOG performance status, n (%) (61) 202 (60) (39) 132 (40) 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) 10 (3.0) >12 months 216 (65) 210 (63) Prior (neo)adjuvant systemic therapy, n (%) Chemotherapy and endocrine therapy 123 (37) 120 (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.

63

64 HEMATOLOGIC ADVERSE EVENTS Regardless of study treatment relationship Adverse Event 5% in Either Arm, % Ribociclib + Letrozole n=334 Placebo + Letrozole n=330 All Grade 3 Grade 4 All Grade 3 Grade 4 Neutropenia 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.

65 NON-HEMATOLOGIC ADVERSE EVENTS Regardless of study treatment relationship Ribociclib + Letrozole Placebo + Letrozole Adverse Event n=334 n=330 15% in Either Arm, % All Grade 3 Grade 4 All Grade 3 Grade 4 Nausea Infections Fatigue Diarrhea Alopecia Vomiting Arthralgia Constipation Headache Hot flush Back pain Cough Decreased appetite Rash ALT increased AST increased In the ribociclib arm 10 (3.0%) patients experienced Grade 2 QTcF ( ms) and 1 (0.3%) patient experienced Grade 3 QTcF (>500 ms); no dose reductions were required

66 MONALEESA2 Updated Data: ASCO 2017 Hortabagyi et al ASCO 2017

67 NCT MONALEESA-3

68 NCT MONALEESA-7

69

70 MONARCH 1: Prior Therapies Median number of prior systemic regimens (any setting) was 5 (range 2-11) 100% of patients received taxanes in any setting Median number of prior systemic regimens for metastatic disease was 3 (range 1-8) Rugo et al AACR 2017

71 Change from Baseline (%) MONARCH 1: Response Summary Investigator Assessed Response a Confirmed Objective Response Rate (ORR = CR + PR) (95% CI) CR PR Abemaciclib 200 mg (N = 132) 19.7% (13.3, 27.5) 0% 19.7% Stable Disease 6 months 22.7% Clinical Benefit Rate (CBR = ORR +SD 6 mos) 42.4 % Disease Control Rate (CR + PR + SD) = 67.4% -100 Progressive disease (n = 34) Stable disease (n = 63) Partial response (n = 26) Not assessed (n = 9) Dickler M. et al. J Clin Oncol 34, 2016 (suppl; abstr 510) Rugo et al AACR 2017 a Assessments based on independent review were comparable

72 Survival Probability Survival Probability MONARCH 1: Kaplan-Meier Plots A. Progression-free Survival B. Overall Survival I I II I I I II I I Abemaciclib 200 mg Patients/Events 132/100 Median, months % CI 4.21, 7.50 I I II I I I I I I II Patients/ Events Median, months I I I I 132/ % CI 17.7, NR I I I II II II I IIIII III I IIIIIIII I III I II I II I I I I I I Months Months Pts at Risk: Pts at Risk: Pts = patients, NR = not reached Rugo et al AACR 2017

73 MONARCH 1: Most Common Adverse Events Investigator Assessed TEAEs a >20% (N=132) Grade 1 % Grade 2 % Grade 3 % Grade 4 % All Grades % Diarrhea Nausea Fatigue Decreased appetite Abdominal pain Vomiting Headache Pain Lab abnormalities b TEAEs a > 40% Creatinine increased c (CTCAE v 4.03: over baseline) White blood cell decreased Neutrophil count decreased d Anemia Lymphocyte count decreased Platelet count decreased a CTCAE Version 4.03, b N = 130 for lab abnormalities listed, except platelet count decreased (N = 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 30 day follow up window experienced febrile neutropenia

74 Randomization Study Design: MONARCH2 N = 669 HR+/HER2- ABC Pre/peri- a or postmenopausal ET resistant: Relapsed on neoadjuvant or on/within 1 yr of adjuvant ET Progressed on first-line ET No chemo for MBC No more than 1 ET for MBC ECOG PS 1 2 :1 abemaciclib: 150 mg b BID (continuous schedule) fulvestrant: 500 mg c placebo: BID (continuous schedule) fulvestrant: 500 mg c Primary endpoint: Investigator-assessed PFS Secondary endpoint: OS, Response, Clinical Benefit Rate, Safety Stratification factors: - Metastatic site - ET resistance (primary vs secondary) 4, 5 Statistics: 378 events for 90% power at one-sided α of.025 assuming a true HR of.703 Patients enrolled in 142 centers in 19 countries a Required to receive GnRH agonist b Dose reduced by protocol amendment in all new and ongoing patients from 200 mg to 150 mg BID after 178 patients enrolled c Fulvestrant administered per label 4. Cardoso F et al. The Breast 6: , 2014; 5. Cardoso F et al. Ann Oncol 25: , Sledge et al ASCO 2017, Sledge et al JCO 2017

75 Patient and Disease Characteristics abemaciclib + fulvestrant N = 446 a Data not available for all patients; b 401 (59.9%) had chemotherapy in neoadjuvant or adjuvant setting placebo + fulvestrant N = 223 Median age (range) 59 (32-91) 62 (32-87) ET resistance a Primary 111 (24.9) 58 (26.0) Secondary 326 (73.1) 163 (73.1) Neoadjuvant or Most recent 263 (59.0) 133 (59.6) ET a, b adjuvant Metastatic 171 (38.3) 85 (38.1) Prior AI Yes 316 (70.9) 149 (66.8) No 130 (29.1) 74 (33.2) PgR status a Positive 339 (76.0) 171 (76.7) Negative 96 (21.5) 44 (19.7) Visceral 245 (54.9) 128 (57.4) Metastatic site a Bone only 123 (27.6) 57 (25.6) Other (non-visceral 75 (16.8) 38 (17.0) soft tissue) Measurable disease Yes 318 (71.3) 164 (73.5) No 128 (28.7) 59 (26.5) Menopausal Pre/peri- 72 (16.1) 42 (18.8) status a Post- 371 (83.2) 180 (80.7) Sledge et al ASCO 2017, Sledge et al JCO 2017

76 Primary Endpoint: PFS (ITT) Median PFS abemaciclib + fulvestrant: 16.4 months placebo + fulvestrant: 9.3 months HR (95% CI):.553 (.449,.681) P < PFS benefit confirmed by blinded independent central review (HR:.460; 95% CI:.363,.584; P < ) Sledge et al ASCO 2017, Sledge et al JCO 2017

77 Change in Tumor Size placebo + fulvestrant placebo + fulvestrant ORR CR CBR ITT (N = 223) 16.1% 0.4 % 56.1% Measurable (n=164) 21.3% 0% 51.8% abemaciclib + fulvestrant abemaciclib + fulvestrant ORR CR CBR ITT (N = 446) 35.2%* 3.1 % 72.2% * Measurable (n = 318) 48.1%* 3.5 % 73.3% * *P<.001 Sledge et al ASCO 2017, Sledge et al JCO 2017

78 TEAE (Safety Population) 20 % in either arm, n (%) Any 435 (98.6) All G3 G4 All G3 G4 241 (54.6) 26 (5.9) 199 (89.2) 46 (20.6) 5 (2.2) Diarrhea a 381 (86.4) 59 (13.4) 0 55 (24.7) 1 (0.4) 0 Neutropenia b 203 (46.0) abemaciclib + fulvestrant n = (23.6) placebo + fulvestrant n = (2.9) 9 (4.0) 3 (1.3) 1 (0.4) Nausea 199 (45.1) 12 (2.7) - 51 (22.9) 2 (0.9) - Fatigue 176 (39.9) 12 (2.7) - 60 (26.9) 1 (0.4) - Abdominal pain 156 (35.4) 11 (2.5) - 35 (15.7) 2 (0.9) - Anemia 128 (29.0) 31 (7.0) 1 (0.2) 8 (3.6) 2 (0.9) 0 Leukopenia 125 (28.3) 38 (8.6) 1 (0.2) 4 (1.8) 0 0 Decreased appetite 117 (26.5) 5 (1.1) 0 27 (12.1) 1 (0.4) 0 Vomiting 114 (25.9) 4 (0.9) 0 23 (10.3) 4 (1.8) 0 Headache 89 (20.2) 3 (0.7) - 34 (15.2) 1 (0.4) - a Grade 2 diarrhea: abemaciclib + fulvestrant n = 140 (31.7 %); placebo + fulvestrant n = 11 (4.9 %). b Febrile neutropenia was uncommon [6 patients in the abemaciclib arm (1 incorrectly coded; 1 post-chemotherapy)] and was not associated with severe infection Sledge et al ASCO 2017, Sledge et al JCO 2017

79 PALOMA-3 and MONARCH 2 Characteristics PALOMA-3 1 MONARCH 2 Population HR+/HER2- HR+/HER2- Prior ET PD on previous ET on/within 1 yr of adjuvant or on therapy for ABC PD on previous ET on/within 1 yr of adjuvant or on therapy for ABC Dosing Prior chemotherapy for ABC # lines of ET in ABC ClinicalTrials.gov Identifier: NCT Palbociclib: 125 mg daily, 3 wks on, 1 wk off; Fulvestrant: 500 mg (per label) 1 Abemaciclib: 150mg BD, continuous; Fulvestrant: 500 mg (per label) Not permitted Any 1 ClinicalTrials.gov Identifier: NCT Cristofanilli M et al. Lancet Oncol 17(4):425-39, 2016

80 Ph3 Study: MONARCH 3 A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) plus LY , a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer with No 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 (N=450) R 2:1 LY NSAI until PD Placebo + NSAI until PD Primary endpoint: Progression-Free Survival (PFS) April : Met its Primary Endpoint NCT

81 Conclusions: Anti-endocrine agents have made the greatest impact in the management of ER+ breast cancer Still de novo and aquired resistance remains a problem Numerous strategies have been attempted to overcome endocrine resistance Validated molecular therapeutics HER2 mtor CDK 4/6

82 Acknowledgements Ireland J Crown, M Kennedy, J McCaffrey, C Murphy Canada P Desjardins, H Lim France F Priou, P Soulie Germany W Abenhardt, M Clemens, J Ettl, C Hanusch, A Kirsch, M Schmidt, V Schulz, C Thomssen Hungary K Boer, J Erfan, L Landherr, I Lang, T Pinter, A Weber, M Wenczl Russia M Kopp, O Lipatov, S Tjulandin, V Vladimirov US J Blum, D Chan, R Dichmann, R Finn, E Hu, W Lawler, A Montero, R Patel, N Robert, A Thummala Spain M Ruiz Borrego, EM Ciruelos Gil, JM Gil Gil, MJ Vidal Losada, M Ramos Vazquez Italy D Amadori South Africa M Coccia-Portugal South Korea SA Im, JS Ro Ukraine I Bondarenko, S Kulyk, Y Shparyk, N Voytko This study is sponsored and funded by Pfizer Inc.

83 Acknowledgements Ireland J Crown, M Kennedy, J McCaffrey, C Murphy Canada P Desjardins, H Lim US J Blum, D Chan, R Dichmann, R Finn, E Hu, W Lawler, A Montero, R Patel, N Robert, A Thummala Spain M Ruiz Borrego, EM Ciruelos Gil, JM Gil Gil, MJ Vidal Losada, M Ramos Vazquez France F Priou, P Soulie The Patients and Their Families Revlon-UCLA Women's Cancer Research Program Department of Defense Innovator Award Italy D Amadori Germany W Abenhardt, M Clemens, J Ettl, C Hanusch, A Kirsch, M Schmidt, V Schulz, C Thomssen South Africa M Coccia-Portugal Hungary K Boer, J Erfan, L Landherr, I Lang, T Pinter, A Weber, M Wenczl Russia M Kopp, O Lipatov, S Tjulandin, V Vladimirov Network of Investigators and Study Staff South Korea SA Im, JS Ro Ukraine I Bondarenko, S Kulyk, Y Shparyk, N Voytko This study is sponsored and funded by Pfizer Inc.