Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials

Matthew P Goetz, Meena Okera, Hans Wildiers, Mario Campone, Eva-Maria Grischke, Luis Manso, Valérie A M André, Nadia Chouaki, Belén San Antonio, Masakazu Toi, George W Sledge Jr, Matthew P Goetz, Meena Okera, Hans Wildiers, Mario Campone, Eva-Maria Grischke, Luis Manso, Valérie A M André, Nadia Chouaki, Belén San Antonio, Masakazu Toi, George W Sledge Jr

Abstract

Purpose: Abemaciclib in combination with endocrine therapy (ET) has demonstrated significant efficacy benefits in HR+ , HER2- advanced breast cancer patients in the Phase 3 studies MONARCH 2 (fulvestrant as ET) and MONARCH 3 (letrozole or anastrozole as ET). Here, we report age-specific safety and efficacy outcomes.

Methods: Exploratory analyses of MONARCH 2 and 3 were performed for 3 age groups (<65, 65-74, and ≥75 years). For safety, data were pooled from both studies; for efficacy, a subgroup analysis of PFS was performed for each trial independently.

Results: Pooled safety data were available for 1152 patients. Clinically relevant diarrhea (Grade 2/3) was higher in older patients receiving abemaciclib + ET (<65, 39.5%; 65-74, 45.2%; ≥75, 55.4%) versus placebo + ET (<65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Nausea, decreased appetite, and venous thromboembolic events were all moderately higher in older patients. Neutropenia (Grade ≥ 3) did not differ as a function of age in the abemaciclib + ET arm (<65, 25.8%; 65-74, 27.4%; ≥75, 18.1%). Dose adjustments and discontinuation rates were slightly higher in older patients. Abemaciclib + ET improved PFS compared with placebo + ET independent of patient age, with no significant difference in abemaciclib treatment effect between the 3 age groups (MONARCH 2: interaction p-value, 0.695; MONARCH 3: interaction p-value, 0.634). Estimated hazard ratios ranged from 0.523-0.633 (MONARCH 2) and 0.480-0.635 (MONARCH 3).

Conclusions: While higher rates of adverse events were reported in older patients, they were manageable with dose adjustments and concomitant medication. Importantly, a consistent efficacy benefit was observed across all age groups.

Clinical trial registration: ClinicalTrials.gov: NCT02107703 (first posted April 8, 2014) and NCT02246621 (first posted September 23, 2014).

Keywords: Abemaciclib; Age; Endocrine therapy; HER2−; HR+; Metastatic breast cancer.

Conflict of interest statement

Funding M.P. Goetz reports research funding from the National Cancer Institute, National Institutes of Health, Department of Defense, Mayo Development, Eli Lilly, Pfizer, Alliance Foundation Trials, Sermonix Pharmaceutical, Translational Breast Cancer Research Consortium, and Minnesota Partnership for Biotechnology and Medical Genomics. H. Wildiers reports consulting fees and honoraria from AstraZeneca, Biocartis, Lilly, Novartis, Pfizer, PUMA Biotechnology, Roche, Sirtex, and Daiiji (all to institution); research grants from Roche and Novartis (all to institution); and travel support from Roche and Pfizer (to H.W). M. Campone received travel support from Pfizer, Novartis, Roche, and AstraZeneca. L. Manso reports consulting fees from Roche, Astra, Novartis, Tesaro, and Pfizer. M. Toi reports research funding from Takeda, Chugai, Pfizer, Taiho, Kyowa-Kirin, Eisai, JBCRG association, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Nippon Kayaku, and AFI technology. G. Sledge Jr. reports research support from Eli Lilly and Company; research support from Pfizer. Financial interests M.P. Goetz reports consulting fees (all to institution) from Eagle Pharmaceuticals, Eli Lilly, Biovica, Novartis, Sermonix, Context Pharm, Pfizer, and Biotheranostics. M. Toi reports consultation fees from Kyowa-Kirin, Daiichi-Sankyo, Konica-Minolta, BMS, Athenex Oncology, and Bertis; and lecture fees from Takeda, Chugai, Eli Lilly Pfizer, Taiho, Kyowa-Kirin, Eisai, Daiichi-Sankyo, MSD, AstraZeneca, Astellas, Shimadzu, Genomic Health, Novartis, Yakult, and Nippon Kayaku. V.A-M. André, N. Chouaki, and B. San Antonio report stocks/shares in Eli Lilly and Company. Non-financial interests M.P. Goetz has consulted for or is/was a board member of NCI Breast Cancer Steering Committee, Translational Breast Cancer Research Consortium, NCCN Breast Cancer Panel, Clinical Pharmacogenetics Implementation Consortium Guide for CYP2D6 and Tamoxifen, NCI SPORE Special Emphasis Panel, and Academic and Community Cancer Research United. M. Campone has consulted for Pierre Fabre Oncology, Sanofi, Novartis, and Servier; speakers’ bureau, Novartis. M. Toi has served on Editorial Boards for Breast Cancer Research and Treatment, Scientific Reports, Frontier Oncology, Cancer Science, International Journal of Clinical Oncology, Asian Journal of Surgery, and International Journal of Biological Markers; and is/was a member of the Board of Directors for Japanese Breast Cancer Research group association, Kyoto Breast Cancer Research network, and Organisation for Oncology and Translational Research. G. Sledge Jr. reports consulting for Syndax, Symphogen, Verseau Therapeutics, and Eli Lilly and Company; Board of Directors for Tessa Therapeutics. Employment V.A-M. André, N. Chouaki, and B. San Antonio are employees of Eli Lilly and Company. M. Okera declares no competing interests. E-M. Grischke declares no competing interests.

Figures

Fig. 1
Fig. 1
Study design. Data cutoff for MONARCH 2 was Feb 14, 2017; MONARCH 3 data cutoff was Nov 3, 2017. BID twice daily, ET endocrine therapy, HR+ hormone receptor-positive, HER2− human epidermal growth factor receptor 2 negative, ITT intent to treat, M2 MONARCH 2, M3 MONARCH 3, n number of patients, N total population
Fig. 2
Fig. 2
PFS by age subgroup in a MONARCH 2 and b MONARCH 3. HR hazard ratio, NSAI nonsteroidal aromatase inhibitor

References

    1. SEER cancer statistics: common cancer sites (2019) National Cancer Institute.
    1. Battisti NML, De Glas N, Sedrak MS, Loh KP, Liposits G, Soto-Perez-de-Celis E, Krok-Schoen JL, Menjak IB, Ring A. Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper. Ther Adv Med Oncol. 2018;10:1–26. doi: 10.1177/1758835918809610.
    1. Cancer stat facts: female breast cancer (2019) National Cancer Institute, SEER Program.
    1. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, Cronin KA. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Nat Cancer Inst. 2014 doi: 10.1093/jnci/dju055.
    1. Howie LJ, Singh H, Bloomquist E, Wedam S, Amiri-Kordestani L, Tang S, Sridhara R, Sanchez J, Prowell TM, Kluetz PG, King-Kallimanis BL, Gao JJ, Ibrahim A, Goldberg KB, Theoret M, Pazdur R, Beaver JA. Outcomes of older women with hormone receptor-positive, human epidermal growth factor receptor-negative metastatic breast cancer treated with a CDK4/6 inhibitor and an aromatase inhibitor: an FDA pooled analysis. J Clin Oncol. 2019;37(36):3475–3483. doi: 10.1200/JCO.18.02217.
    1. Scotté F, Bossi P, Carola E, Cudennec T, Dielenseger P, Gomes F, Knox S, Strasser F. Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide. Ann Oncol. 2018;29(8):1718–1726. doi: 10.1093/annonc/mdy228.
    1. Singh H, Hurria A, Klepin HD (2018) Progress through collaboration: an ASCO and U.S. Food and Drug Administration workshop to improve the evidence base for treating older adults with cancer. 2018 ASCO educational book
    1. Riseberg D. Treating elderly patients with hormone receptor-positive advanced breast cancer. Clin Med Insights Oncol. 2015;9:65–73. doi: 10.4137/cmo.s26067.
    1. Savard M-F, Khan O, Hunt KK, Verma S. Redrawing the lines: the next generation of treatment in metastatic breast cancer. Am Soc Clin Oncol Educ Book. 2019;39:e8–e21. doi: 10.1200/edbk_237419.
    1. NCCN Clinical Practice Guidelines in Oncology: breast cancer (Version 2.2020) (2020). National Comprehensive Cancer Network (NCCN).
    1. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortés J, Curigliano G, Diéras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP. 4th ESO-ESMO international consensus guidelines for advanced breast Cancer (ABC 4) Ann Oncol. 2018;29(8):1634–1657. doi: 10.1093/annonc/mdy192.
    1. Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, Bachelot T, De Laurentiis M, Thomas G, De Placido P, Arpino G, De Placido S, Cristofanilli M, Giordano A, Puglisi F, Pistilli B, Prat A, Del Mastro L, Venturini S, Generali D. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019;20(10):1360–1369. doi: 10.1016/s1470-2045(19)30420-6.
    1. Eggersmann TK, Degenhardt T, Gluz O, Wuerstlein R, Harbeck N. CDK4/6 inhibitors expand the therapeutic options in breast cancer: palbociclib, ribociclib and abemaciclib. Biodrugs. 2019;33(2):125–135. doi: 10.1007/s40259-019-00337-6.
    1. Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer. 2019;5(1):27. doi: 10.1038/s41523-019-0121-y.
    1. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Tredan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638–3646. doi: 10.1200/jco.2017.75.6155.
    1. Sledge GWJ, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke E-M, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–2884. doi: 10.1200/jco.2017.73.7585.
    1. Johnston S, Martin M, Di Leo A, Im S-A, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5(1):5. doi: 10.1038/s41523-018-0097-z.
    1. Sledge GW, Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Conte P, Lu Y, Barriga S, Hurt K, Frenzel M, Johnston S, Llombart-Cussac A. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 2019;6(1):116–124. doi: 10.1001/jamaoncol.2019.4782.
    1. Dickler MN, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt D, Wildiers H, Hudis CA, O'Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR(+)/HER2(−) metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218–5224. doi: 10.1158/1078-0432.ccr-17-0754.
    1. Rugo HS, Huober J, Garcia-Saenz JA, Masuda N, Sohn JH, Andre VAM, Barriga S, Cox J, Goetz M (2020) Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3. Oncologist Epub ahead of print. doi:10.1002/onco.13531
    1. Soto-Perez-De-Celis E, Lichtman SM. Considerations for clinical trial design in older adults with cancer. Expert Opin Investig Drugs. 2017;26(10):1099–1102. doi: 10.1080/13543784.2017.1369043.
    1. Wildiers H, de Glas NA. Anticancer drugs are not well tolerated in all older patients with cancer. Lancet Healthy Longev. 2020;1:e43–47. doi: 10.1016/S2666-7568(20)30001-5.
    1. Spring LM, Wander SA, Zangardi M, Bardia A. CDK 4/6 inhibitors in breast cancer: current controversies and future directions. Curr Oncol Rep. 2019;21(3):25. doi: 10.1007/s11912-019-0769-3.
    1. Thein K, Zaw M, Tun A, Jones C, Radhi S, Hardwicke F, Oo T (2018) Abstract P3-14-02: incidence of venous thromboembolism in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: a systematic review and meta- analysis of randomized controlled trials. Cancer Res 78(4 Supplement):P3-14-02–P13-14-02. doi:10.1158/1538-7445.sabcs17-p3-14-02
    1. FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer (2019) U.S. food and drug administration.
    1. Wildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen ML, Extermann M, Falandry C, Artz A, Brain E, Colloca G, Flamaing J, Karnakis T, Kenis C, Audisio RA, Mohile S, Repetto L, Van Leeuwen B, Milisen K, Hurria A. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32(24):2595–2603. doi: 10.1200/jco.2013.54.8347.
    1. Simcock R, Wright J. Beyond performance status. Clin Oncol (Royal College of Radiologists) 2020;32(9):553–561. doi: 10.1016/j.clon.2020.06.016.
    1. Kalsi T, Babic-Illman G, Fields P, Hughes S, Maisey N, Ross P, Wang Y, Harari D. The impact of low-grade toxicity in older people with cancer undergoing chemotherapy. Br J Cancer. 2014;111(12):2224–2228. doi: 10.1038/bjc.2014.496.
    1. . Abemaciclib monotherapy in treating older patients with hormone receptor positive metastatic breast cancer (NCT04305834). Available at . Accessed October 30 2020

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