Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor–Positive/HER2-Negative Advanced or Metastatic Breast Cancer

Bora Lim, David A. Potter, Mohamad A. Salkeni, Paula Silverman, Tufia C. Haddad, Frederic Forget, Ahmad Awada, Jean-luc Canon, Michael Danso, Alain Lortholary, Hugues Bourgeois, Elizabeth Tan-chiu, Sylvie Vincent, Brittany Bahamon, Kevin J. Galinsky, Chirag Patel, Rachel Neuwirth, E. Jane Leonard, Jennifer R. Diamond

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Abstract

Purpose: This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer. Patients and Methods: Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16). Results: Overall, 118 patients enrolled in phase IB (n=24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus- sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262). Conclusions: Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausalwomen with pretreated everolimus-sensitive or everolimus-resistant breast cancer.

Original languageEnglish (US)
Pages (from-to)3329-3338
Number of pages10
JournalClinical Cancer Research
Volume27
Issue number12
DOIs
StatePublished - Jun 15 2021

Bibliographical note

Funding Information:
The authors thank all patients included in this study and their families, as well as all physicians, nurses, study coordinators, and study center staff participating in the study. The authors would like to thank the Personal Genome Diagnostic group for ctDNA sequencing, particularly Donna Nichol, PhD, and Eric Kong, PhD. They also acknowledge writing support from Helen Wilkinson and Helen Kitchen (FireKite, an Ashfield company, part of UDG Healthcare plc), which was funded

Funding Information:
B. Lim reports grants from Takeda Oncology during the conduct of the study, as well as grants from Merck, Puma Biotechnology, and Genentech outside the submitted work. D.A. Potter reports grants from Takeda during the conduct of the study, grants from ImmunoMet Therapeutics outside the submitted work, and has a patent for Therapeutic Compounds and Methods issued and a patent for BIGUANIDE COMPOUNDS pending. M.A. Salkeni reports grants from Takeda/Millennium during the conduct of the study, grants from Pfizer outside the submitted work, and research funding paid to WVU Research Corp. for the conduction of clinical trials. T.C. Haddad reports grants from Takeda Oncology during the conduct of the study, as well as grants from Takeda Oncology outside the submitted work. A. Awada reports grants from Roche and BMS, as well as personal fees from Lilly, Amgen, ESAI, Pfizer, Novartis, Genomic Health, Ipsen, Bayer, Leo Pharma, Merck, Daiichi, and Seattle Genetics outside the submitted work. J.-L. Canon has received personal fees and nonfinancial support from Roche, Pfizer, and Eli Lilly. S. Vincent reports other from Takeda during the conduct of the study, as well as other from Takeda outside the submitted work. B. Bahamon reports personal fees from Millennium Pharmaceuticals Inc. during the conduct of the study. E.J. Leonard reports other from Takeda Pharmaceuticals outside the submitted work. J.R. Diamond reports other from Takeda during the conduct of the study, as well as grants and other from Takeda outside the submitted work. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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