Vincenzo Adamo Luminal Metastatic Breast Cancer: role of CDK4/6 inhibitors from preclinical data to clinical practice Vincenzo Adamo Oncologia Medica AO Papardo & Università degli Studi di Messina vadamo@unime.it

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice Final Remarkers

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice Final Remarkers

“Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC” “Treatment recommendations should be based on type of adjuvant treatment, disease-free interval and organ function” “Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women” Rugo H, et al. JCO 2016;34:3069-3103

Top Line recomendations from ESO-ESMO ABC4 panel (Lisbona 2017) “Endocrine therapy plus a CDK4-6 inhibitor, is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance” courtesy by A. Prat

Evolution of therapy for Endocrine-sensitive Metastatic Breast Cancer

Evolution of therapy for Endocrine Resistant Metastatic Breast Cancer

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice Final Remarkers

Cyclin-dependent protein kinase (CDK) 4/6 Inhibitors Palbociclib Abemaciclib Ribociclib Lange CA, et al. Endocr Relat Cancer 2011

ER and CDK4/6 are two distinct target for controlling cancer cell growth

Palbociclib preferentially inhibits proliferation of luminal ER+ human breast cancer cell lines in vitro

Palbociclib Acts Synergistically with Tamoxifen in ER+ Breast Cancer Cell Lines Finn R, Breast Cancer Res 2009

Tumour Growth Inhibition: Synergy Between Palbociclib and Letrozole in ER+ Xenograft Model Lee, AACR 2014

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice Final Remarkers

Selective CDK4/6 Inhibitors IC50 Palbociclib Ribociclib Abemaciclib CDK4 9–11 nM 10 nM 2 nM CDK6 15 nM 39 nM 5 nM CDK2 >10 µM >50 µM >500 nM CDK9 ND 57 nM Kinase selectivity tree: Bigger circles = more inhibition Chen P, et al. Mol Cancer Ther 2016. Asghar U, et al. Nat Rev Drug Discov 2015

Clinical data for CDK4/6 inhibitors in HR+/HER2-MBC Palbociclib: NCT00721409, NCT01740427, NCT01942135 Abemaciclib: NCT02102490, Ribociclib: NCT01958021, NCT02107703, NCT02246621 NCT02278120 PALOMA-1 PALOMA-2 MONALEESA-2 MONARCH 3 1L ER+, HER2– mBC Palbociclib + AI (letrozole) 1L ER+, HER2– mBC Palbociclib + AI (letrozole) 1L ER+, HER2– ABC Ribociclib + letrozole 1L ER+, HER2– mBC Abemaciclib + NSAI 2014 2015 2016 2017 Data read-out dates PALOMA-3 MONARCH 1 MONARCH 2 MONALEESA-7 2L Recurrent HR+, HER2– mBC Palbociclib + fulvestrant 3L Recurrent ER+, HER2– mBC Abemaciclib ET resistant Or ER+, HER2– 1LmBC Abemaciclib + fulvestrant 1L ER+ HER2– pre/peri- menopausal ABC Ribociclib + goserelin + tamoxifen / NSAI www.clinicaltrials.gov 16 16

Endocrine Sensitive Disease

RCTs of 1st Line Endocrine Therapy with CDK4/6 inhibitors for HR+/HER2-ve ABC PALOMA-2 MONALEESA-2 MONARCH-3 Let+ Palbo Let + Plac Let + Ribo NSAI+ Abema NSAI + Plac Pts 444 222 334 328 165 mPFSmo 24.8 (HR 0.58) 14.5 25.3 (HR 0.56) 16 NR (HR 0.54) 14.7 mOS mo NA ORR% 42 35 41 28 48 CBR% 85 70 80 72 78

All subgroups equally benefit from a CDK4/6i

MONARCH 3: exploratory analyses Treatment-free interval <36 mos vs. ≥36 mos “...Our exploratory subgroup analyses suggest that patients with indicators of poor prognosis had substantial benefit from the addition of abemaciclib, while in patients with a long treatment-free interval or bone-only disease, single agent endocrine therapy may be an appropriate initial therapy...” Patients with/without bone only disease Patients with/without liver metastases Di Leo A, et al. ESMO 2017; Goetz MP, et al. JCO 2017

Endocrine Resistant Disease

Endocrine Resistant Disease

RCTs with CDK4/6 i in Endocrine Resistant Disease PALOMA-3 MONARCH-2 Fulv +Palbo Fulv + Plac Fulv+ Abema Fulv+ Plac Pts# 347 174 446 223 Prior Chemo for ABC % 30.8 36.2 Median PFS mo 9.2 (HR 0.42) 3.8 16.4 (HR 0.55) Median OS mo NA ORR% 10.4 6.2 35.2 16.1 CBR% 34 19 72.2 56.1

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice Final Remarkers

Different Safety Profile of CDK4/6 inhibitors Barros-Sousa, et al. Breast Care 2016

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice Final Remarkers

Premenopausal women and clinical trials Premenopausal women generally excluded from large registrational trials HR+ ABC. Clinical data limited to only a few small phase 2 trials. PALOMA-3 included 108 premenopausal women ad is the only phase 3 study to date to report outcomes data for fulvestrant 500 mg with ovarian suppression in premenopausal patients. MONALEESA-7 is the only phase 3 trial conducted in premenopausal women and is the only phase 3 trial to date report outcomes data in this populations.

Palbociclib + Fulvestrant in premenopausal women: a subset analysis of PALOMA-3 trial 108 premenopausal women HER2-/HR+ MBC ORR: 25.0% vs. 11.1% CBR: 69.4% vs. 44.4% “...These findings show that the addition of palbociclib had no impact on the concentration of fulvestrant, complete ovarian suppression was maintained, and no additional toxicities were evident with the addition of a LHRH agonist, all factors important for the investigation of palbociclib in early stage breast cancer. The results support the use of palbociclib in combination with fulvestrant and goserelin for women with HR+ ABC, and these findings have expanded the treatment options for premenopausal women...” Loibl S, et al. Oncologist 2017

Placebo + tamoxifen/NSAI + goserelin* n=337 MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/NSAI + goserelin Pre/perimenopausal women with HR+, HER2– ABC No prior endocrine therapy for advanced disease ≤1 line of chemotherapy for advanced disease N=672 Ribociclib (600 mg/day; 3-weeks-on/1-week- off) + tamoxifen/NSAI + goserelin* n=335 Primary endpoint PFS (locally assessed per RECIST v1.1)‡ Secondary endpoints Overall survival (key) Overall response rate Clinical benefit rate Safety Patient-reported outcomes Randomization (1:1) Placebo + tamoxifen/NSAI + goserelin* n=337 Stratified by: Presence/absence of liver/lung metastases Prior chemotherapy for advanced disease Endocrine therapy partner (tamoxifen vs NSAI) Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter Primary analysis planned after ~329 PFS events 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm1,2), and a sample size of 660 patients Triphaty D, SABCS 2017

MONALEESA-7: Primary Endpoint: PFS 100 90 80 70 60 Probability of PFS (%) 50 40 30 PFS (investigator assessment) Ribociclib + tamoxifen/NSAI n=335 Placebo + tamoxifen/NSAI n=337 Number of events, n (%) 131 (39.1) 187 (55.5) Median PFS, months (95% CI) 23.8 (19.2–NR) 13.0 (11.0–16.4) Hazard ratio (95% CI) 0.553 (0.441–0.694) One-sided p value 0.0000000983 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 No. at risk Time (months) Ribociclib + tamoxifen/NSAI 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 Placebo + tamoxifen/NSAI 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 Triphaty D, SABCS 2017

MONALEESA-7: PFS by Endocrine Therapy Partner (investigator-assessed) PFS (investigator assessment) Tamoxifen NSAI Ribociclib arm n=87 Placebo arm n=90 Ribociclib arm n=248 Placebo arm n=247 Number of events, n 39 55 92 132 Median PFS, months (95% CI) 22.1 (16.6–24.7) 11.0 (9.1–16.4) 27.5 (19.1–NR) 13.8 (12.6–17.4) Hazard ratio (95% CI) 0.585 (0.387–0.884) 0.569 (0.436–0.743) Triphaty D, SABCS 2017

MONALEESA-7: Secondary Endpoints All patients Rate (%) Patients with measurable disease Rate (%) p=0.000317 p=0.00098 Ribociclib + tamoxifen/NSAI Placebo + tamoxifen/NSAI The CBR in patients with measurable disease was 79.9% for ribociclib + tamoxifen/NSAI vs 67.3% for placebo + tamoxifen/NSAI (p=0.000340) Overall survival data were immature at the cut-off date Triphaty D, SABCS 2017

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice The Future Final Remarkers

ABC 4 guidelines (Lisbona 2017): Postmenopausal patients with ER+/HER2‒ ABC courtesy by A. Prat

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice The Future Final Remarkers

The Future Integration of CDK 4/6 inhibitors in EBC setting, in HER2 positive disease and beyond second line setting

OUTLINE Therapeutic landscape of HR+HER2-MBC Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data The CDK 4/6 inhibitors program Toxicity Premenopausal women Positioning of CDK4/6 inhibitors in standard clinical practice The Future Final Remarkers

Final Remarkers Are there clinical factors that may influence treatment decisions? DFI, tumor burden, metastatic site, menopausal status and endocrine resistance type should be included in the decision making. Are all CDK4/6 inhibitors created equal? No, but they are similar and present different safety profile. Do we have to use CDK4/6 inhibition + AI in 1st line in all pts? No, unless the OS results of PALOMA-2, MONALEESA-2, and MONARCH-3 state otherwise. CDK4/6 inhibitors induce a meaningful benefit? Yes, in 1st and 2nd line Are there predictive biomarkers? No, predictive biomarkers, all patients equally benefit from CDK4/6. Should we incorporate CDK4/6 inhibitors plus endocrine therapy at some point in the treatment of ER+ MBC? Absolutely yes! The relatively good safety profile, the long duration of clinical benefit and the delay in chemotherapy start support it !

Grazie per l’attenzione

Do we need predictive markers for targeted agents Do we need predictive markers for targeted agents? Yes, but…not yet identified and/or validated BOLERO-2 PALOMA-2 PALOMA-3 MONALEESA-2 1. Baselga J, NEJM 2012; 2. Finn RS NEJM 2016; Cristofanilli M, Lancet 2016; 4. Hortobagyi G. NEJM 2016

PALOMA-3: PI3KCA Mutation in ctDNA PFS in PIK3CA WT pts PFS All population PFS in PIK3CA mutated pts “…Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo , irrespective of hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy…” Cristofanilli M, et al. Lancet 2016

PALOMA-2: Subgroup Analysis of PFS by Biomarker “…These exploratory analyses did not identify a subgroup of ER+ pts that did not benefit from the addition of Palbociclib to Letrozole…” Finn RS, ESMO 2016

MONALEESA-2: Subgroup Analysis of PFS by Biomarker Andre et al, AACR 2017

CDK4/6 in Breast Cancer o The growth of HR+ breast cancer is dependent on Cyclin D1, a direct transcriptional target of ER Cyclin D1 activates CDK4/6 resulting in G1–S phase transition and entry into the cell cycle1 Adapted from Asghar U, Nat Rev Drug Discov 2015

Luminal MBC: Treatment Guidelines o NCCN/ASCO Pts whose tumors express any level of ER and/or PgR. Treatment recommendations should be offered on the basis of type of adjuvant treatment, disease-free interval, and extent of disease at the time of recurrence. Endocrine therapy should be recommended as initial treatment for patients with HR-positive MBC, except for patients with immediately life-threatening disease or for those experiencing rapid visceral recurrence during adjuvant endocrine therapy Sequential hormone therapy should be offered to patients with endocrine-responsive disease Treatment should be administered until there is unequivocal evidence of disease progression. ESMO/ABC3 the preferential use of endocrine therapy, even in the presence of visceral metastases, until clear evidence of endocrine resistance. Chemotherapy should be reserved for cases of rapidly progressive disease or proven endocrine resistance. Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable option, although this approach has not been assessed in randomized trials. AIOM Tumori ormonosensibili HER2 negativi, in assenza di malattia aggressiva e crisi viscerale. Il trattamento ormonale dovrebbe essere proseguito (anche con linee di terapia successive) fino a quando è possibile considerare la malattia ormonosensibile. la scelta della terapia, sia per la prima linea che per quelle successive, si basa soprattutto sullo stato menopausale della paziente e sulle terapie precedentemente eseguite in fase adiuvante o metastatica. Rugo HS, et al. JCO 2017 Cardoso F, et al. Ann Oncol 2016 Linee Guida AIOM 2016

Treatment for HR+HER2neg MBC CDK 4/6 inhibitors + AI Breast Cancer o ER+/HER2- 7% CDK4/6 + fulvestrant Toremifene Everolimus + exemestane Exemestane Letrozolo Buparlisib + fulvestrant Fulvestrant Tamoxifene 30% Anastrozolo 70% 1975 1980 1985 1990 1995 2000 2005 2010 2015 2016

RCTs of 1st Line Endocrine Therapy with CDK4/6 inhibitors for HR+/HER2-ve ABC Da togliere Trial Study Design Study Size Target Population Partner ET Primary Endpoint PALOMA-1 Phase 2 Open label 165 pts AI sensitive Treatment naïve for mBC Postmenopausal Letrozole PFS PALOMA-2 Phase 3 Placebo control 666 pts MONALEESA-2 Placebo control 668 pts MONARCH-3 Placebocontrol 496 pts NSAI (Letrozole or Anastrozole)

TOXICITY o

ASCO guidelines 2016: Endocrine therapy for patients with HR+ mBC Da togliere? Adapted from Rugo HS, J Clin Oncol 2016