Oncologia Medica AO Papardo & Università degli Studi di Messina vadamo@unime.it

1. 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

2. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • FinalRemarkers

3. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • FinalRemarkers

4. “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

5. 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

6. Evolution of therapy for Endocrine-sensitive MetastaticBreastCancer

7. Evolution of therapy for Endocrine ResistantMetastaticBreastCancer

8. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • FinalRemarkers

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

10. ER and CDK4/6 are twodistinct target for controllingcancercellgrowth

11. Palbociclibpreferentiallyinhibitsproliferation of luminal ER+ human breastcancercelllines in vitro

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

13. TumourGrowthInhibition: SynergyBetweenPalbociclib and Letrozole in ER+ Xenograft Model Lee, AACR 2014

14. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • FinalRemarkers

15. Selective CDK4/6 Inhibitors Chen P, et al. Mol Cancer Ther 2016. Asghar U, et al. Nat Rev Drug Discov 2015

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

17. Endocrine Sensitive Disease

19. RCTs of 1st Line Endocrine Therapy with CDK4/6 inhibitors for HR+/HER2-ve ABC

20. All subgroups equally benefit from a CDK4/6i

21. 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 onlydisease Patients with/withoutlivermetastases Di Leo A, et al. ESMO 2017; Goetz MP, et al. JCO 2017

22. Endocrine ResistantDisease

23. Endocrine ResistantDisease

24. RCTs with CDK4/6 i in Endocrine ResistantDisease

25. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • FinalRemarkers

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

27. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • FinalRemarkers

28. 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.

29. Palbociclib + Fulvestrant in premenopausalwomen: a subset analysis of PALOMA-3 trial 108 premenopausalwomen 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...” LoiblS, et al. Oncologist 2017

30. 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 • 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 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) Triphaty D, SABCS 2017

31. MONALEESA-7: Primary Endpoint: PFS 100 90 80 70 60 50 Probability of PFS (%) 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (months) No. at risk 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0 Ribociclib + tamoxifen/NSAI 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0 Placebo + tamoxifen/NSAI Triphaty D, SABCS 2017

32. MONALEESA-7: PFS by Endocrine Therapy Partner (investigator-assessed) Triphaty D, SABCS 2017

33. MONALEESA-7: Secondary Endpoints All patients Patients with measurable disease p=0.000317 p=0.00098 Ribociclib + tamoxifen/NSAI Rate (%) Rate (%) 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

34. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • The Future • FinalRemarkers

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

36. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • The Future • FinalRemarkers

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

38. OUTLINE • Therapeutic landscape of HR+HER2-MBC • Endocrine therapy plus CDK4/6 inhibitorsas a new standard of care on HR+ advancedbreastcancer-preclinical data • The CDK 4/6 inhibitorsprogram • Toxicity • Premenopausalwomen • Positioning of CDK4/6 inhibitors in standard clinicalpractice • The Future • FinalRemarkers

39. 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 !

40. Grazie per l’attenzione

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

42. 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

43. PALOMA-2: SubgroupAnalysisof PFS byBiomarker “…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

44. MONALEESA-2: SubgroupAnalysisof PFS byBiomarker Andre et al, AACR 2017

45. CDK4/6 in BreastCancer 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

46. Luminal MBC: Treatment Guidelines o Rugo HS, et al. JCO 2017 Cardoso F, et al. Ann Oncol 2016 Linee Guida AIOM 2016

47. Treatment for HR+HER2neg MBC CDK 4/6 inhibitors + AI Breast Cancer o 7% CDK4/6 + fulvestrant ER+/HER2- Toremifene Everolimus + exemestane Exemestane Letrozolo Buparlisib + fulvestrant Fulvestrant Tamoxifene 30% Anastrozolo 70%

48. RCTs of 1st Line Endocrine Therapy with CDK4/6 inhibitors for HR+/HER2-ve ABC Da togliere

49. TOXICITY o

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