Cyclin CDK 4/6 inhibitors in breast cancer treatment Agustí Barnadas Medical Oncology Department Hospital Sant Pau Barcelona Agenda • Cell-cycle pathway • Cyclin CDK 4/6 inhibitors: – Palbociclib • Clinical efficacy • Safety • Clinical development – Other inhibitors • Conclusions Cyclin-dependent kinase 4/6-Rb protein: a key pathway in cell cycle progression From Rocca A, et al. Expert Opin Pharmacother 2013 Synergy Between ER and CDK4/6: Critical for Efficacy of Combinations in ER+ Tumours • Cyclin D1 is a direct transcriptional target of ER. • Inhibition of cyclin D1 inhibits oestrogen-induced S-phase entry. • Endocrine resistance is associated with persistent cyclin D1 expression and RB phosphorylation. • CDK4/6 inhibitors are most effective in tumours with gene amplification and overexpression of cyclin D1, which is common in ER+ breast cancer. M B ZR 175 75 C 30 AM A M -1 B 13 H C 4 U C2 AC 0 C 2 -8 9 EF 3 M SU 19 M EF 19 M 0 19 M 2A B H -36 CC 1 1 H 50 CC 0 14 1 H 9 CC M 38 B M 415 C F U -1 AC 0A C H -81 CC 2 22 Z 18 M R7 D AM 5-1 B 45 18 3 4A 1 T4 7D M C F7 B M T D AM -20 B 43 B 5 T4 7 SK 4 BR K 3 H PLCC 1 M D 114 AM 3 B H 23 CC 1 1 SU 39 M 5 -2 H 25 S5 78 18 T 4 U AC B5 C 7 C 32 AL -5 B 1 T C 54 O LO 9 8 D 24 U4 4 H CC 75 1 H 18 CC 7 1 H 56 CC 9 1 H 80 CC 6 H 193 CC 7 19 5 H 4 CC M 70 B -4 3 M 6 M B 15 D AM 7 B 46 8 IC50, nM Palbociclib Preferentially Inhibits Proliferation of Luminal Oestrogen Receptor-Positive Human Breast Cancer Cell Lines in Vitro 1000 900 800 700 Enriched in RE+ luminal cell 600 500 400 300 200 100 0 Subtype Luminal HER2 amplified Non-luminal/post EMT Non-luminal Immortalised Finn RS, et al. Breast Cancer Res. 2009;11(5):R77. ER+ breast cancer: related sensitivity markers to palbociclib Sensitive cell lines: •76% luminal genes (0% in resistant cell lines) • 0% non-luminal gene (59% in resistant cell lines) • RB − upregulated • cyclin D1 − upregulated • p16 − downregulated Molecular Mechanisms of Palbociclib Combined With ER Antagonists in ER+ Breast Cancer Combined inhibition of CDK4/6 and ER signalling increases senescence in ER+ breast cancer cell lines SA**-bGal activity in T47D treated with ER antagonists and palbociclib Normalized b-Gal Activity 2.50 2.00 * * 1.50 1.00 0.50 0.00 *P<0.001 vs. single agents **SA= Senescence Associated Finn RS, et al. Breast Cancer Res. 2009;11(5):R77. Differential response to CDK4/6 inhibition in breast cancer explants Dean JL et al. Cell Cycle 2012; 11: 2756 CDK4/6 inhibitors in CDK4/6-dependent murine model of BC Roberts PJ, et al. J Natl Cancer Inst 2012 Abstract S1-6 Results of a Randomized Phase 2 Study of PD 0332991, a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole vs Letrozole Alone for FirstLine Treatment of ER+, HER2– Advanced Breast Cancer (TRIO-18) RS Finn,1 JP Crown,2 I Lang,3 K Boer,4 IM Bondarenko,5 SO Kulyk,6 J Ettl,7 R Patel,8 T Pinter,9 M Schmidt,10 Y Shparyk,11 AR Thummala,12 NL Voitko,13 A Breazna,14 ST Kim,15 S Randolph,15 DJ Slamon1 1University of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research Group, Dublin, Ireland; 3Orszagos Onkologiai Intezet, Budapest, Hungary; 4Szent Margit Korhaz, Onkologia, Budapest, Hungary; 5Dnipropetrovsk City MultipleDiscipline Clinical Hospital, Dnipropetrovsk, Ukraine; 6Municipal Treatment-and-Prophylactic Institution, Donetsk, Ukraine; 7Technical University of Munich, Munich, Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA, USA; 9Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary; 10University Hospital Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV, USA; 13Kyiv City Clinical Oncology Center, Ukraine; 14Pfizer Oncology, New York, NY, USA; 15Pfizer Oncology, La Jolla, CA, USA Presented at SABCS 2012; December 5, 2012; San Antonio, TX, USA Phase 2 Design Part 1 ER+, HER2– BC R A N D O M I S A T I O N N = 66 a Schedule 3/1. Part 2 PD 0332991 125 mg QDa + Letrozole 2.5 mg daily 1:1 Letrozole 2.5 mg daily ER+, HER2– BC with CCND1 amp and/or loss of p16 R A N D O M I S A T I O N PD 0332991 125 mg QDa + Letrozole 2.5 mg QD 1:1 Letrozole 2.5 mg QD N = 99 Stratification Factors • Disease Site (Visceral vs Bone only vs Other) • Disease-Free Interval (>12 vs ≤12 mo from end of adjuvant to recurrence or de novo advanced disease) Best Overall Response (ITT) PD 991 + LET (n = 84) LET (n = 81) 84 81 Objective Response Rate, % (95% CI) Complete Response, n (%) Partial Response, n (%) 34 (24-46) 0 29 (34) 26 (17-37) 1 (1) 20 (25) Patients with measurable disease, n (%) 64 (76) 65 (80) Objective Response Rate, % (95% CI) Complete Response, n (%) Partial Response, n (%) 45 (33-58) 0 29 (45) 31 (20-43) 0 20 (31) Stable Disease ≥24 weeks, n (%) 30 (36) 15 (18) Clinical Benefit Rate, n (%)* 59 (70) 36 (44) Stable Disease <24 weeks, n (%) 14 (17) 22 (27) Progressive Disease, n (%) 3 (4) 17 (21) Indeterminable, n (%) 8 (10) 6 (7) All randomised patients, n * Complete response + partial response + stable disease ≥24 weeks. Progression-Free Survival Probability Progression-Free Survival LET (n = 81) 1.0 Number of Events (%) 21 (25) 40 (49) 0.9 Median PFS, months (95% CI) 26.1 (12.7, 26.1) 7.5 (5.6, 12.6) 0.8 Hazard Ratio (95% CI) 0.7 P value 0.37 (0.21, 0.63) <0.001 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 84 81 75 57 12 14 16 18 20 22 24 26 14 4 9 3 5 3 3 1 1 1 Time (Month) Number of patients at risk PD991+LET LET PD 991 + LET (n = 84) 60 38 53 29 43 22 35 17 25 11 18 6 15 5 28 Treatment Administration (AT) PD 991 + LET (n = 83) LET (n = 77) 8.9 (<1 – 25.9) 5.1 (<1 – 29.0) Dose Interruptions During Cycles, n (%) 59 (71) 17 (22) Cycle Delays, n (%) 62 (75) NA Dose Reductions, n (%) 29 (35) NA Median Duration of Treatment, months (range) AT = as treated. Most Common Treatment-Related Adverse Events ≥10% (AT) PD 991 + LET (n = 83) LET (n = 77) Grade 1/2 Grade 3 Grade 4 Grade 1/2 Grade 3 Grade 4 Neutropenia 19 46 5 1 1 0 Leukopenia 24 14 0 0 0 0 Anaemia 19 4 1 0 0 0 Fatigue 17 2 0 13 0 0 Alopecia 18 0 0 3 0 0 Hot flushes 17 0 0 10 0 0 Arthralgia 16 0 0 10 0 0 Nausea 12 2 0 1 0 0 Thrombocytopenia 11 1 0 0 0 0 Palbociclib - Predictive biomarkers Rb nuclear score 1.00 Negative Intermediate/equivocal Positive Progression-free survival 0.90 0.80 0.70 0.60 0.50 Rb Nuclear Score Negative Equivocal Positive HR (95% CI) 1 1.02 (0.34, 2.99) 0.82 (0.28, 2.43) 600 1000 0.40 0.30 0.20 0.10 0.00 0 200 400 800 Time on study (days) Clark AS, et al. SABCS 2013 Palbociclib predictive markers % p16 nuclear staining positive negative 1.00 0% 1-24% 25-75% 0.90 0.80 0.70 0.60 % p16 Nuclear Staining 0% 1-24% 25-75% 0.50 0.40 HR (95% CI) 1 0.64 (0.22, 1.83) 2.42 (0.67, 8.68) 0.30 0.20 0.10 0.00 0 200 400 600 Time on study (days) 800 1000 Clark AS, et al. SABCS 2013 Palbociclib: ongoing studies in endocrine-sensitive tumours Phase III, PALOMA-2 (1008) N:465 • Post-menopausal • HR+, HER2− MBC • No previous treatment for advanced disease • AI-resistant patients excluded Primary endpoint: PFS Secondary endpoints: ORR SV Safety Biomarkers Palbociclib (125 mg /daily, 3/1 schedule) + letrozole(2.5 mg daily) R 2:1 Placebo (3/1 schedule) + letrozole(2.5 mg daily) Stratification factors - disease site - disease-free interval - previous hormonal therapy Palbociclib: ongoing studies in endocrine-resistant tumours Phase III, PALOMA-3 (1023) N:417 • HR+, HER2− MBC Palbociclib (125 mg daily, 3/1 schedule) + Fulvestrant (500 mg IM q4wk) • Pre-menopausal or post-menopausal • Failure of previous hormonal treatment: • Progressed on or ≤12 months after end of adjuvant therapy (AI or tamoxifen) • Progressed on or ≤1 month after end of treatment with AI/other endocrine therapy for advanced disease • 1 previous chemotherapy regimen permitted Primary endpoint: PFS Secondary endpoints: ORR SV Safety Biomarkers Quality of life R 2:1 Placebo (3/1 schedule) + Fulvestrant (500 mg IM q 4 wk) Stratification factors - visceral metastases - previous sensitivity to endocrine therapy - menopausal status - previous chemotherapy Palbociclib: ongoing studies in endocrine-resistant tumours Phase III, PEARL N:348 • Post-menopausal Palbociclib (125 mg daily, 3/1 schedule) + Exemestane (25 mg daily) • HR+, HER2− metastatic BC • Resistant to non-steroidal AIs: • Recurrence on or ≤12 months after end of adjuvant treatment with non-steroidal AI • Progression on or ≤1 month after end of treatment with non-steroidal AI for advanced disease Primary endpoint: PFS Secondary endpoints: ORR SV Safety Biomarkers Quality of life R 1:1 Capecitabine 1250 mg/m2/12 h 2/1 schedule Stratification factors - visceral metastases - previous sensitivity to endocrine therapy - menopausal status - previous chemotherapy - country Phase III Study of Palbociclib in High-risk Early BC: PENELOPE PENELOPEa Placebo (3/1 schedule) + Standard of care • Early ER+ BC “high risk” (CPS-EG ≥3) • Premenopausal/ postmenopausal • Completed taxane-based neoadjuvant therapy, surgery; +/− radiotherapy RANDOMISATION N=800 1:1 Palbociclib (125 mg daily, 3/1 schedule) + Standard of care Non-study adjuvant endocrine therapies being taken for 5–10 years after surgery were permitted during the study: • tamoxifen (pre- and postmenopausal women) • goserelin agonists (premenopausal) • aromatase inhibitors: anastrozole, letrozole (postmenopausal) *aIn collaboration with GBG (Germany) and GEICAM (Spain) Primary endpoint: iDFS Secondary endpoints: OS, iDFS excluding second nonbreast cancer, distant disease-free survival, local recurrence-free survival, iDFS by commerciallyavailable multigene assay subtyping, safety, patientreported outcomes, biomarkers Stratification factors: lymph node status, age, biomarkers (Ki-67, pRB, cyclin D), and region Phase II Study of Palbociclib with Letrozole in Neoadjuvant Treatment of Early ER+, HER2− BC: PALLET study • Localised ER+, HER− invasive early BC • Suitable for neoadjuvant therapy with letrozole Letrozole (2.5 mg daily) for 2 weeks • Post-menopausal • N=301 Palbociclib (125 mg daily) for 2 weeks Palbociclib (125 mg daily) + letrozole (2.5 mg daily) for 2 weeks Palbociclib (125 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) for 12 weeks Tumour samples: biopsies taken before treatment and at 2 and 14 weeks Surgery Letrozole (2.5 mg QD) for 14 weeks Primary endpoints: • Change in the proliferation marker Ki67 at week 14 • Clinical response at week 14 Secondary endpoints: • Ki67 at 2 weeks • ypCR after 14 weeks Stratification factor: Country Other CDK 4/6 inhibitors Other cyclin CDK 4/6 inhibitors: LEE-011 Monaleessa-1 study LEE-011 + letrozole 600 mg/d Early breast cancer Size > 1.5 cm 2.5 mg/d LEE-011 + letrozole 400 mg/d 2.5 mg/d Letrozole 2.5 mg/d S U R G E R Y 15 days Primary objective: Secondary objectives: Changes in Ki67 Safety Biological response Other cyclin CDK 4/6 inhibitors: LEE-011 Monaleessa-2 study LEE-011 + letrozole 600 mg/d 2.5 mg/d Advanced disease -RE positivity -Postmenopausal -1 measurable lesion -Non-previous treatment Letrozole 2.5 mg/d Primary objective: PFS Secondary objectives: OS Safety ORR CONCLUSIONS • The cyclin D-CDK4/6-Rb pathway is an important mediator of cell cycle regulation and is downstream of multiple mitogenic cascades. • It is an important target for anticancer therapy. • Different CDK4/6 inhibitors are being studied in combination with endocrine therapy or other targeted therapies such as anti-HER2 agents, PI3K inhibitors or mTOR inhibitors. • These drugs present a good opportunity to overcome endocrine resistance. 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