CDK 46 Inhibitors in Breast Cancer Expert Perspectives on New Data Faculty Javier Cortes MD PhD Head Breast Cancer Program Oncology Department Ramon y Cajal University Hospital Madrid Spain ID: 761355
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CDK 4/6 Inhibitors in Breast Cancer Expert Perspectives on New Data Faculty Javier Cortes, MD, PhDHeadBreast Cancer ProgramOncology DepartmentRamon y Cajal University HospitalMadrid, Spain Fabrice André, MD, PhD Professor Chairman, Inserm Unit U981 Institut Gustave Roussy Villejuif , France
Program Overview In this program, we will discuss The evolution of the treatment of HR+, HER2- MBC The role of CDK 4/6 inhibitors, including recently presented data on their efficacy, safety, and use in clinical practice
a. Finn RS, et al. Lancet Oncol. 2015;16:25-35; b. Turner NC, et al. N Engl J Med. 2015;373:209-219; c. Finn RS, et al. N Engl J Med. 2016;375:1925-1936; d. Hortobagyi GN, et al. Ann Oncol. 2018;29:1541-1547; e. Tripathy D, et al. Lancet Oncol. 2018;19:904-915; f. Slamon DJ, et al. J Clin Oncol. 2018;36:2465-2472; g. Sledge GW Jr, et al. J Clin Oncol. 2017;35:2875-2884; h. Dickler MN, et al. Clin Cancer Res. 2017;23:5218- 5224; i. Goetz MP, et al. J Clin Oncol. 2017;35:3638-3646. CDK 4/6 Inhibitors: Consistency of Response
N = 521 patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy. Absolute improvement in median OS in the palbociclib arm vs the placebo arm was 6.9 months. From N Engl J Med, Nicholas C. Turner, M.D, et al., Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. PALOMA-3: OS (ITT)
PALOMA-3: OS by Sensitivity to Prior ET From N Engl J Med , Nicholas C. Turner, M.D, et al., Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Patients With Sensitivity to Previous ETPatients Without Sensitivity to Previous ET
In patients who achieved an OR, median DOR was longer with palbociclib plus letrozole (27.7 months; 95% CI: 24.7, 36.1) vs placebo plus letrozole (20.9 months; 95% CI: 16.5, 27.6). Rugo HS, et al. 2018 ESMO Congress. Poster 332P. Clinical Outcomes in Patients With or Without OR: Results From PALOMA-2
a. André F, et al. 2018 ESMO Congress. Abstract LBA3; b. Sabine VS, et al. J Clin Oncol. 2014;32:2951-2958; c. Lee JJ, et al. Cancer Biol Med . 2015;12:342-354. SOLAR-1: Alpelisib + Fulvestrant for HR+, HER2- ABCPhase 3 randomized, double-blind, placebo-controlled trial evaluating the safety/efficacy of alpelisib in addition to fluvestrant in men and postmenopausal women with HR+, HER2- ABC, who received prior treatment with an AI, with or without a CDK 4/6 inhibitor[a]Approximately 40% of patients with HR+ ABC have PIK3CA mutations[b,c]The PI3K pathway is the most commonly mutated pathway associated with tumor progression in HR+ ABC
PFS determined by local assessment. There was no advantage to alpelisib on median PFS in patients without a PIK3CA mutation.André F, et al. 2018 ESMO Congress. Abstract LBA3. SOLAR-1: Median PFS in Patients With PIK3CA Mutations HR (95% CI): 0.65 (0.50, 0.85) P = . 00065
Implications of SOLAR-1 Trial Results In the future, may consider different treatment options based on genomic testing results, as well as estrogen-receptor positivity Genomic testing is used in other fields of cancer medicineIt is expected that other drugs will show efficacy according to genomic segments in the future
Risk of VTE in Patients Receiving CDK 4/6 Inhibitors: Updated Meta-Analysis 6 studies (PALOMA-1, PALOMA-2, PALOMA-3, MONARCH-2, MONARCH-3, MONALEESA-2) with a total of 3159 eligible patients. Thein KZ, et al. 2018 ESMO Congress. Poster 1691P. Homogeneity existed between RCTsPatients receiving CDK 4/6 inhibitors experienced an increase in VTE risk vs control groupPooled RR: 3.56 (95% CI: 1.57, 8.06; P = .002)
CDK 4/6 Inhibitors and the Risk for VTE: Implications of Meta-Analysis Although the risk of VTE was higher in patients who received a CDK 4/6 inhibitor, overall incidence was low Evaluate other factors, which may contribute to increased VTE risk in patients receiving CDK 4/6 inhibitors
Khozin S, et al. J Natl Cancer Inst . 2017;109. Importance of Real-World Data in Oncology Support active pharmacovigilance Develop external control arms Enable evidence generation based on pragmatic clinical trials Support randomized study designs Expand clinical research to point of care May help increase access to experimental therapies Increase patient participation in clinical trials
Real-World Use of Palbociclib i n Patients With HR+, HER2- ABC: Results From POLARIS This interim analysis includes the first 402 patients (target enrollment 1500 patients) with completed baseline case report forms from 86 sites in the United States (data cutoff, August 13, 2018). Blum JL, et al. 2018 ESMO Congress. Poster 344P. A heterogeneous population received palbociclibOlder, premenopausal, black, Latino/Hispanic, and male patients not commonly represented in clinical trials69.9% of patients received palbociclib combination as first-line ABC therapy56.6% received palbociclib in combination with letrozole or anastrozole, 39.5% with fulvestrant, and 3.9% with exemestane Disease-Free Interval, Patients Who Received Palbociclib as First-Line ABC Therapy
Evaluation of treatment patterns in patients with HR+, HER2- ABC/MBC in Germany who received palbociclib combinations (palbociclib + an AI or palbociclib + fulvestrant) in line with EMA labeled indications. Mitra D, et al. 2018 ESMO Congress. Poster 338P. Real-World Treatment With Palbociclib Therapy in Germany: Results From IRIS Overall PAL + AI PAL + FUL Total, n 257 194 63 PD following initial control/response, n (%) 5 (13.2) 3 (10.0) 2 (25.0) PD without initial control/response, n (%) 3 (7.9) 2 (6.7) 1 (12.5) Pill burden/compliance, n (%) 1 (2.6) 1 (3.3) 0 (0) Side effects/toxicity, n (%) 13 (34.2) 12 (40.0) 1 (12.5) Patient request, n (%) 7 (18.4) 5 (16.7) 2 (25.0) Other, n (%) 7 (18.4) 7 (23.3) 0 (0) Reasons for Discontinuation
Fernandes MT, et al. Drugs Context . 2018;7:212555. Treatment Landscape of HR+, HER2- MBC Evolving with recent positive advancesIn the past 3 years, CDK 4/6 inhibitors, a novel class of targeted therapy, have been approved for patients with HR+, HER2- MBCPalbociclib, ribociclib, abemaciclib
Fernandes MT, et al. Drugs Context . 2018;7:212555. Treatment Landscape of HR+, HER2- MBC (cont) Demonstrated benefit of CDK 4/6 inhibitorsAll agents exhibit PFS benefit vs standard of care Benefits also demonstrated in terms of OSCKD 4/6 inhibitors for all patients?CDK 4/6 inhibitors are efficacious among different patient subgroupsFurther studies are needed to select patients who will receive the greatest benefitCDK 4/6 inhibitors generally have fewer AEs vs traditional chemotherapeutic options
HR+, HER2- MBC Treatment: Challenges for the Future Optimizing the role of biomarkers to select patient populations that would receive the greatest benefit from CDK 4/6 inhibitors While the use of biomarkers for patient selection may not be achievable in the short term, clinicians can work to determine which patients are not receiving adequate benefit from a CKD 4/6 inhibitorConsider dynamic biomarkers
a. Turner N. ASCO® 2018. Oral presentation 1001. HR+, HER2- MBC Treatment: Challenges for the Future (cont) Determining the role of continued treatment with CDK 4/6 inhibitors after treatment progression Exploring mechanisms of resistanceMajority of mechanisms of resistance are to ET vs CDK 4/6 inhibitors, specifically[a]
a. Cardoso F, et al. Ann Oncol. 2017;28:16-33. HR+, HER2- MBC Treatment: Challenges for the Future (cont) Clarifying the role of CDK 4/6 inhibitors for patients with important visceral metastases, but not in visceral crisisGuidelines recommend ET for patients with HR+ disease, even in the presence of visceral disease, unless there is a visceral crisis[a]However, a group of patients with high disease burden, but not yet in visceral crisis existThere is a role for CKD 4/6 inhibition in this group of patientsExploring the role of CDK 4/6 inhibitors vs chemotherapy in patients with visceral crisis
Summary CDK 4/6 inhibitors are promising agents for the treatment of HR +, HER2- MBC Efficacy is similar between agentsDifferent AE profiles between agents, but with better overall tolerability profile vs traditional chemotherapeutic agentsSeveral unanswered questions remain regarding the use of CDK 4/6 inhibitorsOptimal treatment sequenceIdeal patient population
Abbreviations ABC = advanced breast cancerABE = abemaciclib AE = adverse eventAI = aromatase inhibitorCI = confidence interval CKD = cyclin-dependent kinaseCT = chemotherapyDOR = duration of responseEMA = European Medicines AgencyET = endocrine-based therapyFUL = fulvestrantHR+ = hormone receptor-positiveHR = hazard ratio ITT = intention to treatLET = letrozoleMBC = metastatic breast cancerNR = not reachedOR = objective response OS = overall survival
Abbreviations (cont )PAL = palbociclibPBO = placeboPD = progression of diseasePFS = progression-free survival RCT = randomized clinical trialsRR = risk ratioVTE = venous thromboembolism