Targeting CDK 4/6. Jee Hyun Kim, M.D., Ph.D. Seoul National University College of Medicine

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1 GBCC Education Symposium Targeting CDK 4/6 Jee Hyun Kim, M.D., Ph.D. Seoul National University College of Medicine

2 Contents Cyclins -CDKs in cell cycle control CDK 4/6 in breast cancer Preclinical development of CDK inhibitors Clinical development of CDK inhibitors and ongoing trials Future implications

3 Cell cycle & cyclin dependent kinases Cell cycle : tightly regulated in normal conditions with well defined phases Cyclin Dependent Kinases: Family of serine/threonine protein kinases, that are activated on interaction with their partner cyclins CDK1-4, 6 : regulate transition through specific checkpoints in the cell cycle CDK4 & 6 cyclin D, CDK2 cyclin E then A CDK7-9 : involved in regulation of the transcriptional machinery CDK5 : involved in neuron-specific functions

4 Cell cycle regulation by Cyclin CDK INK4 family Negative regulators of CDK4/6 signalling INK 4 family: p15, 16, 18, 19 CIP/KIP (p21, p27, p57) CDK4/6 & Cyclin D have a crucial role in regulation of G1/S transition

5 Cell cycle dysregulation Dysregulated cell division resulting in uncontrolled cellular proliferation : one of the key hallmarks of cancer Rb Loss/mutation Cyclin D1 amplification Altered expression of cyclins Altered expression or mutation in CDKs Loss of CDK suppressor function CDK inhibition has long been ideal targets for drug development

6 O Leary B, et al. Nature Rev Clin Oncol 2016 Finn RS, et al. Breast Cancer Res 2016 Cyclin D CDK 4/6 alterations in breast cancer In luminal ER positive breast cancer, ER signaling activates the CCND1 promoter Cyclin D1 binds to ER and facilitates ER transcriptional activity Cyclin D1 is expressed at a high level, with or without CCND1 gene amplification in many ER positive breast cancers Amplification of CDK4 and cyclin D1 reported in 15-25% breast cancer Cyclin D1 overexpression occur in over half of all breast cancers Amplification of both cyclin D1 and CDK4 is especially high in luminal B (58% and 25%) and HER2 positive subtypes (29% and 14%) Endocrine resistance is associated with persistent cyclin D1 expression and RB phosphorylation.

7 First generation CDK inhibitors Pan-CDK inhibitors, not specific for single CDK enzyme Flavopiridol Minimal single agent activity Severe toxicities: infusion site irritation, GI toxicity, severe neutropenia Unacceptable rate of neutropenia in MBC, probably d/t inhibition of transcription by the compounds effects on CDK9 and possibly 7 UCN-01 Stausporine analog, G1/S phase cell cycle arrest Severe DLTs : hyperglycemia, arrhythmia, pulmonary dysfunction

PD0332991 (palbociclib) inhibits proliferation of luminal ER-positive human

8 PD (palbociclib) inhibits proliferation of luminal ER-positive human breast cancer cell lines in vitro Clin Cancer Res 2014, Finn RS Breast Cancer Res 2009

9 Effects of palbociclib on phosphorylation of Rb gene product Finn RS Breast Cancer Res 2009

10 Palbociclib induces cell cycle arrest in sensitive cell lines but not in resistant control Sensitive treated G0/G1 S G2 Resistant Finn RS Breast Cancer Res 2009

11 % inhibition Trastuz umab Palbociclib + Trastuzumab Palbociclib Palbociclib + Tamoxifen Tamoxifen Palbociclib

12 Combination of palbociclib and anti -estrogens Phase 1 Clinical study to test safety and efficacy of CDK4/6 inhibition by palbociclib in combination with anti-estrogen drugs in ER positive breast ca Dose : oral palbociclib 125mg once daily Schedule : 3 weeks on followed by 1 week off treatment in a 28-day cycle No drug-drug interactions Most common adverse events : neutropenia, leucopenia, and fatigue

13 PALOMA-1: Phase 2 Design Finn RS Lancet Oncol 2014

14 PALOMA-1 Study Statistical Analyses Primary Endpoint Progression-free survival (PFS) Designed to detect 50% improvement in median PFS from 9 to 13.5 months (80% power, 1-sided = 10%) : 150 patients Interim Analysis 1 (Part 1) Statistically significant improvement in PFS(HR = 0.35;P =0.006) Exploratory biomarkers for CCND1 gains or p16 loss did not add to ER+ alone as a selection marker Interim Analysis 2 (combined Part 1 + Part 2) ~50% of total events (57 PFS events), data cutoff July 2012 Final Analysis (combined Part 1 + Part 2) 114 PFS events needed

15 Baseline Characteristics Palbociclib + Letrozole (n=84) Letrozole (n=81) Median Age, years(range) 62(41-89) 64(38-84) ECOG PS, n(%) 0 46(55) 45(56) 1 38(45) 36(44) Disease Site Visceral 37(44) 43(53) Bone only 18(21) 12(15) Other (Non-Visceral) 29(34) 26(32) Disease-Free Interval, n(%) >12 months from adjuvant to recurrence 34(29) 30(37) 12 months form adjuvant to recurrence 60(71) 51(63) Prior Systemic Treatment, n(%) None 44(52) 37(36) Chemotherapy 34(40) 37(46) Hormonal 26(31) 28(35)

16 Progression free Survival HR (95% CI: ) P= Median PFS: 10.2 vs 20.2 months Finn RS Lancet Oncol 2014

17 Overall survival Finn RS Lancet Oncol 2014

18 Treatment-Related Adverse Events

19 PALOMA-2 Study design ER+, HER2- BC Locoregionally recurrent or metastatic disease No prior systemic therapy R A N D O M I Z A T I O N 2:1 Palbociclib + Letorozole Placebo + Letrozole N=650 Postmenopausal women only Primary endpoint: PFS

20 Palbociclib + Fulvestrant (n=347) Placebo + Fulvestrant (n=174) Median Age, years(range) ECOG PS, n(%) 0 207(59.7) 115(66.1) 1 140(40.3) 48(33.9) HR status ER positive and PR positive 238 (68.6) 111 (63.8) ER positive and PR negative 91 (26.2) 48 (27.6) Menopausal status at entry Premenopausal or perimenopausal 72 (20.7) 36 (20.7) Postmenopausal 275 (79.3) 138 (79.3) Visceral metastases, n(%) 206 (59.4) 105 (60.3) Disease-Free Interval, n(%) 24 months 42/235 (17.9) 23/124 (18.5) >24 months 186/235 (79,1) 95/124(76.6) Prior Systemic Treatment, n(%) None 44(52) 37(36) Chemotherapy 34(40) 37(46) Hormonal 26(31) 28(35)

21 RESULTS : Efficacy of Palbociclib in Combination with Fulvestrant Turner NC, et al. NEJM 2015

22 RESULTS : Efficacy of Palbociclib in Combination with Fulvestrant

24 RESULTS : Adverse Events Turner NC, et al. NEJM 2015

25 RESULTS : Adverse Events Turner NC, et al. NEJM 2015

26 Neutropenia associated with CDK inhibitors Differs from that seen with cytotoxic chemotherapy Transient, reversible, does not lead to febrile neutropenia Hu W, et al. CCR 2016

27 Anti-proliferative, apoptotic, DNA damage response, and cellular senescence effects of palbociclib, doxorubicin, and paclitaxel Hu W, et al. CCR 2016

28 CDK inhibitors Palbociclib Abemaciclib Ribociclib T1/ hr 17-38h 24-36hr Dosing CDK in vitro inhibition profile (IC50) 125mg po qd D1-21, q 4 weeks CDK1 10µM CDK2 10µM CDK4 (cyclin D1):11nM CDK4 (cyclin D3): 9nM CDK5 10µM CDK6 (CyclinD2):15nM 150mg po bid CDK1 1µM CDK2 500nM CDK4 (cyclin D1): 2nM CDK6: 5nM CDK7: 300nM CDK9: 57nM Phase Approved Ⅲ Ⅲ Major AEs Other Neutropenia Thrombocytopenia Fatigue Diarrhea Neutropenia` Crosses BBB 600mg po qd CDK1 100µM CDK2 50µM CDK4 (cyclin D1): 10nM CDK6 (Cyclin D2):40nM Neutropenia Thrombocytopenia QTc interval

29 Ongoing trials with palbociclib Trial Ph Setting Primary endpoint PALOMA-4 Ⅲ Asian MBC postmenopausal PENELOPE-B Ⅲ Adjuvant (RD after neoadjuvant chemo & surgery) Number of patients Trial status PFS 330 Recruiting Invasive DFS 1100 Recruiting PALLAS Ⅲ Adjuvant idfs 4600 Recruiting NeoPAL Ⅱ Neoadjuvant RCB Recruiting PALLET Ⅱ Neoadjuvant Ki67 change ccr 306 Recruiting PEARL Ⅲ MBC PFS 348 Recruiting Young PEARL Ⅱ MBC PFS 122 Not yet recruiting

30 Ongoing trials with abemaciclib Trial Ph Setting Primary endpoint Abemaciclib combination Number of patients Trial status Ⅰb MBC Safety 102 Completed accrual MONARCH1 Ⅱ MBC ORR 128 Completed accrual MONARCH2 (JPBL) MONARCH3 (JPBM) Ⅲ MBC PFS 630 Completed accrual Ⅲ MBC 1 st line PFS 450 Completed accrual NeoMONARCH Ⅱ Neoadjuvant Ki67 change 220 Recruiting Brain metastases Ⅱ MBC, NSCLC, Melanoma Objective intracranial RR 247 Recruiting MonarchHER Ⅱ HER2+ HR+ PFS 225 Not yet recruiting

31 Ongoing trials with ribociclib Trial Ph Setting Primary endpoint No. of patients Trial status MONALEESA-2 Ⅲ MBC, 1 st line PFS 667 Completed accrual MONALEESA-3 Ⅲ MBC PFS 660 Recruiting MONALEESA-7 Ⅲ MBC, premenopausal PFS 660 Recruiting Neoadjuvant Ⅱ Neoadjuvant PEPI score 120 Recruiting LEE011+BYL719 Ⅰ/Ⅱ MBC Safety 216 Recruiting T-DM1 + LEE011 Ⅰ/Ⅱ MBC, HER2+ MTD/CBR 86 Recruiting TRINITI-1 (everolimus + exemestane ± LEE011) Ⅰ/Ⅱ MBC after CDKi failure MTD/CBR 40 Recruiting

32 Early adaptive resistance to CDK inhibitors Resistance develop rapidly, within 72 hrs Herrera-Abreu MT, et al. Cancer Res 2016;1-13

33 Combined targeting of both CDK4/6 and PI3K can block early adaptation Herrera-Abreu MT, et al. Cancer Res 2016;1-13

34 Combined targeting of both CDK4/6 and PI3K can block early adaptation Herrera-Abreu MT, et al. Cancer Res 2016;1-13

Combination of CDK 4/6 PI3K inhibitors does not resensitize cancer with acquired resistance but prevents CDK 4/6 resistance Support clinical development of

35 Combination of CDK 4/6 PI3K inhibitors does not resensitize cancer with acquired resistance but prevents CDK 4/6 resistance Support clinical development of combinations of CDK4/6 and PI3K/mTOR inhibitors & triplet combinations (fulvestrant, CDK4/6, PI3K) in ER positive cancers. Herrera-Abreu MT, et al. Cancer Res 2016;1-13

36 Future challenges Which endocrine therapy partner in ER positive breast cancer? Aromatase inhibitor in endocrine therapy naive setting Fulvestrant in endocrine therapy pretreated breast cancer Which combination therapy? PI3K inhibitors and mtor inhibitors HER2 inhibitors

37 Summary Cyclin D- CDK 4/6 complex have pivotal role in the transition from G1 to S phase CDK inhibitors are rational targeted agent in ER positive breast cancer Cyclin D1 is expressed at a high level Endocrine resistance is associated with persistent cyclin D1 expression and RB phosphorylation in many ER positive breast cancers CDK inhibitors in combination with aromatase inhibitors or fulvestrant demonstrated significant activity in ER+ breast cancer with manageable toxicities (neutropenia without fever) CDK inhibitor clinical trials are ongoing under many different indications (neoadjuvant/adjuvant, in HER2+) and with various combinations to overcome resistance

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