Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.

BACKGROUND

Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.

PATIENTS AND METHODS

Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.

RESULTS

Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.

CONCLUSIONS

Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.

CLINICAL TRIAL REGISTRATION

https://clinicaltrials.gov/, identifier NCT02057133.

Informations de copyright

Copyright © 2022 Tolaney, Beeram, Beck, Conlin, Dees, Puhalla, Rexer, Burris, Jhaveri, Helsten, Becerra, Kalinsky, Moore, Manuel, Lithio, Price, Chapman, Litchfield and Goetz.

Déclaration de conflit d'intérêts

Authors AMM, AL, GLP, SCC and LML were employed by Eli Lilly and Company. SMT received research grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Cyclacel, Eisai, Eli Lilly (outside submitted work), Exelixis, Genentech/Roche, Gilead, Merck, Nektar, Nanostring, Odonate, Pfizer, Puma, Sanofi; and personal fees from 4D Pharma, Athenex, BeyondSpring Pharma, Certara, Chugai Pharma, CytomX, Daiichi-Sankyo, Ellipses Pharma, G1 Therapeutics, Kyowa Kirin Pharmaceuticals, Mersana Therapeutics, OncoPep, OncoSec, OncXerna, Infinity Therapeutics, Samsung Bioepsis Inc., Seattle Genetics, Zentalis, and Zymeworks. MB received honoraria or research funding paid to the institution from Agios, Eli Lilly, Genentech, Johnson & Johnson, Merck, Merrimack, Mersana, Puma Biotechnology, Phoenix Molecular Designs, Zymerworks; Speaker’s Bureau paid to the institution from Bristol-Meyer-Squib, Genentech, and Merck; and travel expenses from Genentech and Merck. Consulting or advisory role payment was paid to an immediate family member from Bayer, Merck, Novartis and Seattle Genetics. ECD acted in a consulting or advisory role for Novartis, Strata Oncology, G1 Therapeutics, received research funding from Novartis, Genentech/Roche, Pfizer, Merck, H3 Biomedicine, Meryx Pharmaceuticals, and received reimbursement for travel expenses from G1 Therapeutics. HAB received research grants paid to the institution from Abbvie, Agios, Arch Oncology, ARMO Biosciences, Array BioPharma, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, BioTheryX, Boehringer Ingelheim, Bristol-Myers Squibb, CALGB, CicloMed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, Foundation Medicine, Gossamer Bio, Lilly, EMD Serono, Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon, Hengrui Therapeutics, Incyte, Janssen, Jounce, Kymab, MacroGenics, MedImmune, Merck, Millennium, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicine, Ryvu Therapeutics, SeaGen, Tesaro, TG Therapeutics, Verastem, Vertex, XBiotech, Zymeworks; uncompensated consulting for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GRAIL, Incyte, Novartis, Vincerx Pharma; and is employed by HCA Healthcare/Sarah Cannon and has Stock ownership with HCA Healthcare/Sarah Cannon. MPG received research grants paid to the institution: Biovica, Context Pharm, Eli Lilly, Novartis, Pfizer Sermonix; grants to the institution from Eli Lilly and Pfizer; and personal feed from Genentech Health. KNM served on advisory boards for Astra Zeneca, Aravive, Alkemeres, Blueprint Pharma, Eisai/Serono, Genentech/Roche, GSK/Tesoro, Hengrui, Immunogen, Inxmed, IMab, Lilly, Mereo, Merck, Mersana, Myriad, Novartis, Onconova, OncXerna, Tarveda, vBL Therapeutics. I am on SC for Genentech/Roche, Immunogen, Mersana and VBL Therapeutics. KK acted in a consulting or advisory role for 4D Pharma, AstraZeneca, Cyclocel, Eisai, Eli-Lilly, Daiichi Sankyo, Immunomedics, Merck, Novartis, Oncosec, Pfizer, Puma, and Seattle Genetics; and spouse has stock for Array BioPharma, Grail, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Eli Lilly and Company. The funder had the following involvement with the study: at the time of the study AMM, AL, GLP, LML, and SCC were employees and shareholders of Eli Lilly and Company.