Cyclin Kinases inhibitors and beyond Patrizia Vici

Cooperation between ER and Cyclin D1 pathways enhances proliferation in “luminal”breast cancer

165 pts Amplif cyclin D1, loss p16 or both

Hypothesis: Can the Amplification of Cyclin D1 Predict Sensitivity?

(No differences between cohorts) PFS (ITT) Palbo+Letroz better (No differences between cohorts) 20.2 vs 10.2mo closed

Clinical benefit: 81% vs 58% p 0.0009 trend in ORR: 43% vs 33% p 0.13 OS Clinical benefit: 81% vs 58% p 0.0009

Palbo+letrozole as first-line: No neutropenic fever Palbo+letrozole as first-line: longer PFS, safety predictable and manageable

Phase III 1°-line

PALOMA 2: Baseline Characteristics (ITT) Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222) Median age, yrs (range) 65 yrs or older, % 62 (30-89) 41 61 (28-88) 36 Race, % White/Black/Asian/other 77/2/15/6 77/1/14/8 ECOG PS, % 0/1/2 58/40/2 46/53/1 Disease site, % Visceral Nonvisceral Bone only 48 52 23 50 22 Disease-free interval, % > 12 mos ≤ 12 mos De novo advanced disease 40 38 42 Prior (neo)adjuvant hormonal therapy, % 56 57 ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status. Finn R, et al. ASCO 2016. Abstract 507.

PFS 24.8 vs 14.5mo Primary objective M f up duration 23 mo

PALOMA 2

Confirmed phase II trial results

Neutropenia any grade: 79.5% Febrile neutropenia 1.8% vs none

PALOMA 2: Conclusions First-line palbociclib + letrozole significantly improved median PFS vs placebo + letrozole in women with ER+/HER2- advanced breast cancer Median PFS improved by > 10 mos compared to placebo 24.8 mos vs 14.5 mos, HR: 0.58 (95% CI: 0.46-0.72; P < .0001) Palbociclib clinical benefit observed in all prespecified subgroups Palbociclib well tolerated with neutropenia, leukopenia the most frequently reported Aes PALOMA-2[1] data confirm PALOMA-1[2] results and constitute the longest median PFS improvement to date in the front-line setting in advanced ER+ breast cancer AE, adverse event; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2. 1. Finn R, et al. ASCO 2016. Abstract 507. 2. Finn RS, et al. Lancet Oncol. 2015;16:25-35. OS: too early

Qualitative analysis Quantitative analysis Finn R, San Antonio 2016

521 pretreat pts PALOMA-3: Interim anal. Premenopausal + goserelin Fulv+palbo vs Fulv+plac

Response Rate 10.4% vs 6.3% (p=0.16) Clin Benefit 34.0% vs 19.0% (p<0.001)

ITT Previous adj/neoadjuvant only Previous CT/ET for advanced disease

PALOMA-3 Final Analysis: Effect by ER and PR Expression Level in Patients With HR-Positive MBC

PIK3CA Mutation and Resistance to CDK4/6 Inhibitors

ESR1 Mutations and Resistance to CDK4/6 Inhibitors

from PALOMA 3: 5 months advantage with palbociclib ESR1 status

1° line MONALEESA 2 Letrozole+ ribociclib vs Letrozole+placebo Phase III 668 pts 1° line Letrozole+ ribociclib vs Letrozole+placebo Stopped at pre-planned interim analysis (m fup 15.3mo)

ITT-Investigators assessment Not reached 14.7mo

Nausea, elevated liver transaminases, QTc prolongation

MONALEESA: Biomarkers analysis (AACR 2017) Exploratory endpoint Archival/fresh tumor samples (>400 pts): Rb expression P16 CDKN2A, CCND1, ESR1 Ki 67 PIK3CA No differences in PFS: the benefit with ribociclib was seen in all subgroups

>9 months advantage with ribociclib

Less neutropenia, more diarrhea, cross blood-brain barrier, single-agent active

Abemaciclib: Breast Cancer Clinical Program (1 of 2) Study1 Clinicaltrials.gov # Disease Treatment Groups JPBA2 Phase 1 NCT01394016 Metastatic breast cancera abemaciclib (Cohort D) abemaciclib + fulvestrant (Cohort G) JPBH3 NCT02057133 Metastatic breast cancer abemaciclib + letrozole abemaciclib + anastrozole abemaciclib + tamoxifen abemaciclib + exemestane abemaciclib + exemestane + everolimus abemaciclib + trastuzumab JPBO4 Phase 2 NCT02308020 HR+ breast cancer with brain metastasesa abemaciclib JPBN5 MONARCH 1 Phase 2 NCT02102490 Recurrent metastatic breast cancer after progression on hormone and chemotherapy treatment JPBL: MONARCH 2 Phase 3 NCT02107703 HR+, HER2- locally advanced or metastatic breast cancer after progression on endocrine therapy abemaciclib + fulvestrant placebo + fulvestrant Abbreviations: HER2=human epidermal growth factor receptor 2; HR+=hormone receptor positive Key Points: JPBA1 Abemaciclib in combination with hormone therapies for metastatic breast cancer. JPBH1 A study of abemaciclib in combination with hormone therapies for breast cancer that has spread. JPBO1 Phase 2 study of abemaciclib in patients with brain metastases secondary to hormone receptor positive breast cancer, non-small cell lung cancer, or melanoma. JPBN1 (MONARCH 1)1 Phase 2, open-label study of abemaciclib to assess the efficacy of abemaciclib in patients with recurrent metastatic breast cancer that have previously progressed on hormone and chemotherapy treatments. JPBL1 (MONARCH 2)1 Phase 3, randomized, double-blind, placebo-controlled, study of fulvestrant with or without abemaciclib in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer. I3Y-MC-JPBA, Clinicaltrials.gov identifier: NCT01394016; I3Y-MC-JPBH, Clinicaltrials.gov identifier: NCT02057133; I3Y-MC-JPBN, Clinicaltrials.gov identifier: NCT02102490; I3Y-MC-JPBL, Clinicaltrials.gov identifier: NCT02107703 References: https://clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT01394016. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02057133. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02308020. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02102490. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02107703. Last accessed: March 22, 2016. Patnaik A, Rosen LS, et al. Efficacy and safety of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discovery 2016;(Ahead of print). Tolaney SM, Beeram M, et al. A phase Ib study of abemaciclib with therapies for metastatic breast cancer. Poster presented at American Society of Clinical Oncology; 2015. Abstract 522. Sahebjam S, Le Run E, et al. Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer. Poster presented at ASCO 2016. Abstract 526. Dickler MN, Tolaney SM, et al. Results from a Phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for metastatic disease. Presented at ASCO Annual Meeting 2016, Chicago, IL; Abstract 510. Abem-00068032 aMultiple-cohort study with disease indications in addition to breast cancer https://clinicaltrials.gov Sahebjam S et al. Poster presented at ASCO 2016. Abstract 526 Patnaik A et al. Cancer Discovery 2016;(Ahead of print) Dickler MN et al. Presented at ASCO 2016 Tolaney SM et al. Poster presented at ASCO 2015. Abstract 522 © 2016 Eli Lilly and Company

Abemaciclib: Breast Cancer Clinical Program (2 of 2) Study Clinicaltrials.gov # Disease Treatment Groups JPBM: MONARCH 3 Phase 3 NCT02246621 HR+, HER2 negative locally advanced or metastatic breast cancer initial therapy in PMP women abemaciclib + anastrozole or letrozole placebo + anastrozole or letrozole JPBY: neoMONARCH Phase 2 NCT02441946 HR+, HER2 negative, early stage breast cancer in PMP women abemaciclib + anastrozole anastrozole abemaciclib JPBZ: monarcHER Phase 2 NCT02675231 HR+, HER2 positive, locally advanced or metastatic breast cancer in PMP women abemaciclib + fulvestrant + trastuzumab abemaciclib + trastuzumab trastuzumab + single-agent chemotherapy JPCG: nextMONARCH1 Phase 2 NCT02747004 HR+, HER2 negative, metastatic breast cancer in women abemaciclib + tamoxifen abemaciclib + prophylatic loperamide JPCE: Phase 2 NCT02779751 HR+, HER2 negative breast cancera abemaciclib + pembrolizumab Abbreviations: HER2=human epidermal growth factor receptor 2; HR+=hormone receptor positive; NSCLC=non-small cell lung cancer; PMP=postmenopausal Key Points: JPBM1 (MONARCH 3)1 Phase 3, randomized, double-blind, placebo-controlled study of nonsteroidal aromatase inhibitors (anastrozole or letrozole) plus abemaciclib or placebo in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer. JPBY1 (neoMONARCH)1 Phase 2 neoadjuvant trial comparing the biological effects of 2 weeks of abemaciclib (ly2835219) in combination with anastrozole to those of abemaciclib monotherapy and anastrozole monotherapy in postmenopausal women with hormone receptor positive, HER2 negative breast cancer. JPBZ1 (monarcHER)1 Phase 2, randomized, multicenter, 3-arm, open-label study to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant to standard-of-care chemotherapy of physician's choice plus trastuzumab in women with HR+, HER2+ locally advanced or metastatic breast cancer. JPCG1: nextMONARCH1 Phase 2, randomized, open-label, study of abemaciclib plus tamoxifen or abemaciclib alone, in women with previously treated HR+, HER2-, metastatic breast cancer. JPCE1 Phase 2 study of abemaciclib in combination with pembrolizumab for patients with Stage IV NSCLC or HR+, HER2- breast cancer. I3Y-MC-JPBN, Clinicaltrials.gov identifier: NCT02246621; I3Y-MC-JPBY, Clinicaltrials.gov identifier: NCT02441946; I3Y-MC-JPBZ, Clinicaltrials.gov identifier: NCT02675231; I3Y-MC-JPCG, Clinicaltrials.gov identifier: NCT02747004; I3Y-MC-JPCE, Clinicaltrials.gov identifier: NCT02779751 References: https://clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT02246621. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02441946. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02675231. Last accessed: March 22, 2016. https://clinicaltrials.gov/ct2/show/NCT02747004. Last accessed: June 6, 2016. https://clinicaltrials.gov/ct2/show/NCT02779751. Last accessed: June 6, 2016. Abem-00068032 aStudy with NSCLC cohorts in addition to breast cancer https://clinicaltrials.gov © 2016 Eli Lilly and Company

Perspectives: Identifying patients with primary resistance to CDK 4-6 inhibitors. The Rb Sig E2F1 and E2F2 high vs low breast cancers in the TCGA Expression data Differential gene expression analysis (METABRIC) Functional Rbsig loss of function Correlation with palbociclib activity (in-vitro) Prognostic value (in-silico analysis) Malorni L et al, Oncotarget 2016

Functional RBsig discriminates palbociclib sensitive vs resistant BC cell lines AUC = 0.93 Malorni L et al, Oncotarget 2016

RFS: RBsig loss of function is prognostic in pts with ER+ tumors Untreated LOW expression-> better RFS ER+ Luminal A Luminal B Endocrine treated only Malorni L et al, Oncotarget 2016

CDK4/6 inhibitors may overcome resistance to HER-2 blocking agents Not only ER+/Her2neg…. CDK4/6 inhibitors may overcome resistance to HER-2 blocking agents Rbsig predictive of resistance in neoadjuvant CT/Trast Her2+ Studies ongoing

TAMRAD Ph II: TAM +/- everolimus CB 61% vs 42% TTP 8.6 vs 4.5mo

>12mo previous adjuvant NSAI allowed

buparlisib 2° line (after AIs) Baselga J et al, proc. SABCS, 2015

Primary tumor archival tissue (mutations exons 7,9,20, PTEN loss) Baselga J et al, proc. SABCS, 2015

Fulvestrant alone doesn’t work in ctDNA PIK3CA mut pts Baselga J et al, Proc. SABCS, 2015

Phase 3 SANDPIPER trial (fulvestrant +/- taselisib) ONGOING alpelisib Phase 3 SANDPIPER trial (fulvestrant +/- taselisib) ONGOING

PI3K Pathway Inhibitors in Clinical Development in Breast Cancer Drug Source Target(s) GDC-0032 Genentech PI3Kα MLN-1117 Millenium BYL719 Novartis GS-1101 Gilead PI3Kd XL-147/SA245408 Exelixis/Sanofi Pan-PI3K BKM120 GDC-0941 PF-05212384/PKI-587 Pfizer XL-765/SAR245409 PI3K/mTOR BEZ235 GDC-0980 MLN-128/MLN0128 TORC1/2 OSI-027 OSI Pharma AZD2014 AstraZeneca AZD5363 AKT (catalytic) MK2206 Merck AKT (allosteric) GDC-0068 ClinicalTrials.gov. From: www.clinicaltrials.gov. Accessed August 2013. 59

more and more…… “Targetable” genomic alterations Growth-factors receptor TK inhibitors: sorafenib/letrozole; vandetanib/fulvestrant; dovitinib/fulvestrant, lucitinib, fulv +/-pictilisib Src inhibitors: dasatinib/letrozole PD-1 inhibitors: pembrolizumab + vorinostat Proteasome inhibitors: bortezomib/fulvestrant Epigenetic modifiers: azacitidine/fulvestrant; entinostat/exemestane; azacitidine/entinostat; decitabine/panobinostat/TAM “Targetable” genomic alterations

Conclusions Thanks for your attention ! CDK 4/6 inhibitors - New standard first/second line in HR positive advanced breast cancer - Efficacy and manageable toxicity No predictive biomarkers Many trials ongoing How endocrine therapy or chemotherapy work after CDK 4/6 inhibitors ? PI3K/mTOR pathway inhibitors -Everolimus in combination with AI other than exe, as 1°line, independently on previous PD to adjuvant NSAIs Buparlisib: efficacy, high toxicity; efficacy in PIK3CA mutated and visceral disease Studies with more selective agents ongoing “Targetable” genomic alteration….. Thanks for your attention !