4 th international conference TRANSLATIONAL RESEARCH IN ONCOLOGY Meldola- Forli’ 8 -11 November 2016 Cell cycle checkpoints (CDK4/6) inhibitors Luca Malorni MD, PhD “ Sandro Pitigliani ” Oncology Unit and Translational Research Unit Hospital of Prato, Italy “ Lester and Sue Smith ” Breast Center, Baylor College of Medicine, Houston (TX)
Outline • CDK 4/6 inhibitors: MoA and pre-clinical data • Clinical data in ER+/HER2 neg metastatic breast cancer • Biomarkers
CDK 4/6 as a key regulator of cell cycle Cyclin B CDK 1 M G1 CDK 4/6 Cyclin D1 S G2 Cyclin A CDK 1 Cyclin E/A CDK 2
RB E2F Cyclin D1/D2/D3 CDK 4/6 P P P E2F P RB inactive CoA DNA replication, Cell cycle entry E2F E2F Proliferation Invasiveness
Integrins GFRs HER 1/2 FAK RB PI3K ERK1/2 E2F p38 JNK Cyclin D1/D2/D3 CDK 4/6 P P P E2F P RB inactive CoA DNA replication, Cell cycle entry E2F E2F Proliferation Invasiveness
Integrins GFRs HER 1/2 p16 FAK p21 RB PI3K ERK1/2 E2F p38 JNK Cyclin D1/D2/D3 CDK 4/6 P P P E2F P RB inactive CoA DNA replication, Cell cycle entry E2F E2F Proliferation Invasiveness
Cell cycle regulation: embryonic development Adapted from Malumbres M. and Barbacid M.
Cell cycle regulation: embryonic development • Transgenic mice lacking either CDK4 or CDK6 do not show embryonic lethality • CDK4 and CDK6 are not essential for embryonic development Adapted from Malumbres M. and Barbacid M.
Cell cycle regulation: embryonic development • However, CDK4 and CDK6 are important for “specialized” cell cycles such as those of hematopoietic and pancreatic beta-cells Adapted from Malumbres M. and Barbacid M.
Cell cycle regulation: CANCER • Mice models of breast cancer induced by specific oncogenes are prevented by CyclinD1 ablation • In particular, neu (HER2) and ras induced breast cancer models are completely dependent on CyclinD1 • Although non essential in physiologic conditions, CDK4/6 and CyclinD1 may represent unique targets in cancer.
Deregulation of CDK 4/6 pathway in BC subtypes Luminal A Luminal B HER2 enriched Basal-like Cyclin D1 amp Cyclin D1 amp Cyclin D1 amp Cyclin E1 amp (29%) (58%) (38%) (9%) CDK4 gain CDK4 gain CDK4 gain (14%) (25%) (24%) 11q13.3 amp 11q13.3 amp (24%) (51%) RB1 mut/loss (20%) Low expression High FOXM1 High of p18/high expression of expression of p16/ low RB1 expression of RB1 The Cancer Genome Atlas Network, Nature 2012
Modern CDK 4/6 inhibitors Sherr CJ, Cancer Discovery 2016
CDK4/6i are preferentially active in Luminal type BC cell lines Subtype Subtype 1000 Luminal Non- luminal/post EMT Non- luminal/post EMT Luminal 900 HER2 Amplified Non - luminal Non-luminal HER2 Amplified Immortalized Immortalized 800 700 600 500 400 300 200 100 0 EFM19 CAMA-1 HCC202 UACC-893 EFM192A HCC1500 HCC1419 HCC38 MCF-10A UACC-812 HCC2218 MDAMB453 T47D MCF7 BT-20 MDAMB435 SKBR3 KPL-1 HCC1143 MDAMB231 HCC1395 SUM-225 HS578T UACC732 CAL-51 COLO824 DU4475 HCC1187 HCC1569 HCC1806 HCC1937 HCC1954 HCC70 MDAMB468 MB-175 ZR75-30 MB134 SUM190 MB-361 MB-415 ZR75-1 184A1 BT474 184B5 BT549 MB-436 MB157 CDK 4-6 inhibitors have shown activity preferentially on ER+, luminal breast cancer cell lines with or without HER2 amplification. Finn et al, BCR 2011
Cross-talks of the CDK 4/6 and ER pathways Integrins GFRs HER 1/2 p16 FAK p21 RB PI3K ERK1/2 E2F p38 JNK Cyclin D1/D2/D3 CDK 4/6 P P P E2F P RB inactive P CoA ER DNA replication, CyclinD1 , CoA Cell cycle entry AP-1 P E2Fs, E2F E2F E FOXM1 ER TRE Proliferation Invasiveness ERE Proliferation Proliferation Proliferation FOXM1 Invasiveness Invasiveness Invasiveness Dahlman-Wright K. et al., Carcinogenesis 2012
CDK 4/6 inhibitor + Endocrine therapy PD-0332991 alone Tamoxifen alone PD-0332991/Tamoxifen combination MCF7 100 100 CI m = 0.37 ± 0.04 80 Inhibition (%) 60 40 CDK4/6i Acts Synergistically with Tamoxifen 20 in ER+ Breast Cancer Cell Lines 0 Tamoxifen 10000 5000 2500 1250 625 312 PD-0332991 100 50 25 12.5 6.25 3.125 Concentration nM Finn et al, BCR 2011 CDK4/6i improves efficacy of Fulvestrant and Letrozole in Luminal BC models Koehler M. et al, IMPAKT meeting 2014
Outline • CDK 4/6 inhibitors: MoA and pre-clinical data • Clinical data in ER+/HER2 neg metastatic breast cancer • Biomarkers
CDK 4/6 inhibitors in HR+/HER2 – mBC Feb 2016 Feb 2015 Approved: Approved: Palbociclib* + Palbociclib* + Letrozole Fulvestrant Apr 2013 Based on PALOMA 1 Based on PALOMA 3 Palbociclib* BTD Oct 2015 Aug 2016 Abemaciclib* BTD Ribociclib* BTD FDA 2015 2013 2016 EMA Sep 2016 Aug 2015 Palbociclib* Palbociclib* CHMP submission to EMA Positive opinion
CDK 4/6 inhibitors in the first line MBC setting (ER+/HER2neg) N=666 Primary endpoint PALOMA-2 Palbociclib (125 mg QD, 2:1 Investigator-assessed PFS 3/1 schedule) + letrozole Secondary endpoints RANDOMISATION • Postmenopausal (2.5 mg QD) Response, OS, safety, biomarkers, patient-reported outcomes • ER+, HER2 – advanced breast cancer • No prior treatment for advanced Stratification factors – disease Disease site (visceral, non- Placebo visceral) • AI-resistant patients excluded – (3/1 schedule) Disease-free interval (de novo metastatic; ≤12 mo, >12 mo) + letrozole – Prior (neo)adjuvant hormonal Finn RS, et al. Presented at the ASCO Annual (2.5 mg QD) therapy (yes, no) Meeting 2016. Abstract 507. N=668 Primary endpoint MONALEESA-2 1:1 Ribociclib (600 mg/day) • PFS (locally assessed) 3/1 schedule + RANDOMISATION Letrozole (2.5 mg/day) Secondary endpoints • Postmenopausal women with • Overall survival (key) HR+/HER2 – advanced breast cancer • Overall response rate • No prior therapy for advanced • Clinical benefit rate • Safety disease Placebo + Letrozole (2.5 mg/day) Hortobagyi GN, et al. NEJM 2016- Presented Stratified by the presence/absence at 2016 ESMO of liver and/or lung metastases
PFS (Investigators assessed) in PALOMA-2 and MONALEESA-2 Finn RS, et al. Presented at the ASCO Annual Meeting 2016. Abstract 507. 100 80 Probability of PFSl (%) 60 40 Ribociclib + Let Placebo + Let (n=334) (n=334) Number of events, n (%) 93 (28) 150 (45) 20 NR (19.3 – NR) 14.7 (13.0 – 16.5) Median (95% CI) PFS 0.56 (0.43 – 0.72); P =0.00000329 HR (95% CI); 1-sided P -value 0 0 4 8 12 16 20 24 Time (months) No. of patients at risk Ribo + Let 334 294 277 257 240 226 164 119 68 20 6 1 0 Hortobagyi GN, et al. NEJM 2016- Presented at 2016 ESMO Plac + Let 334 279 264 237 217 192 143 88 44 23 5 0 0
Subgroup analyses in PALOMA-2 and MONALEESA-2 Favors Ribociclib + Let Favors Placebo + Let Hazard Ratio (95% CI) Subgroup n (%) 0.556 (0.429 – 0.720) All patients 668 (100) 0.523 (0.378 – 0.723) <65 years 373 (56) Age 0.608 (0.394 – 0.937) ≥65 years 295 (44) 0.387 (0.166 – 0.906) Asian 51 (7.6) Race 0.607 (0.459 – 0.804) Non-Asian 568 (85) 0.588 (0.422 – 0.820) 0 407 (61) ECOG PS 0.528 (0.348 – 0.801) 1 261 (39) 0.616 (0.461 – 0.823) ER+ and PgR+ 546 (82) ER/PgR status 0.358 (0.198 – 0.647) Other 122 (18) 0.547 (0.360 – 0.832) Liver or lung No 295 (44) 0.569 (0.409 – 0.792) involvement Yes 373 (56) 0.541 (0.405 – 0.723) No 521 (78) Bone-only disease 0.690 (0.381 – 1.249) Yes 147 (22) 0.603 (0.447 – 0.814) No 441 (66) De novo disease 0.448 (0.267 – 0.750) Yes 227 (34) 0.448 (0.193 – 1.038) NSAI and others* 53 (7.9) 0.570 (0.393 – 0.826) Prior (neo)adjuvant Tam or Exe 293 (44) endocrine therapy 0.570 (0.380 – 0.854) None 322 (48) 0.548 (0.373 – 0.806) Prior (neo)adjuvant No 377 (56) 0.548 (0.384 – 0.780) chemotherapy Yes 291 (44) 0.556 0.556 0,1 1 10 Finn RS, et al. Presented at the ASCO Annual Meeting 2016. Abstract 507. Hortobagyi GN, et al. NEJM 2016- Presented at 2016 ESMO
Hematological AE in PALOMA-2 and MONALEESA-2 Finn RS, et al. Presented at the ASCO Annual Meeting 2016. Abstract 507. – Febrile neutropenia occurred in 5 (1.5%)* patients in the ribociclib arm vs. none in the placebo arm Hortobagyi GN, et al. NEJM 2016- Presented at 2016 ESMO
Non-hematological AE in PALOMA-2 and MONALEESA-2 Finn RS, et al. Presented at the ASCO Annual Meeting 2016. Abstract 507. Hortobagyi GN, et al. NEJM 2016- Presented at 2016 ESMO In the ribociclib arm 10 (3.0%) patients experienced Grade 2 QTcF (481 – 500 ms) and 1 (0.3%) patient experienced Grade 3 QTcF (>500 ms); no dose reductions were required
Recommend
More recommend
