A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer.

This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. ClinicalTrials.gov number, NCT02725268.

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Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Ana Oaknin reports receiving institutional funding from Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis Oncology, Eisai Co., Ltd., F. Hoffmann–La Roche Ltd., Immunogen Inc., Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc., PharmaMar SA, Regeneron Pharmaceuticals and Tesaro Inc.; personal fees for travel and/or accommodation from AstraZeneca, PharmaMar and Roche; personal fees for advisory board membership from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai Co., Ltd., EMD Serono, F. Hoffmann–La Roche Ltd., Genmab, GSK, ImmunoGen, Itheos, Merck Sharp & Dohme de España, SA, Mersana Therapeutics, Novocure, PharmaMar, Sattucklabs, Seagen, and Sutro Biopharma; membership for ASCO, GOG, and SEOM; a non-remunerated role (member and Cervix Cancer Chair on behalf of GEICO) for GCIG; and being an unpaid member, Officer, Co-Chair of the ESMO Gynaecological Cancers Congress 2023–2025, Chair of the Gynaecological Track ESMO 2019, Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, and ESMO 2022, member of the Gynaecological Cancers Faculty, and Subject Editor for the Gynaecological Clinical Practice Guidelines. Francesco Raspagliesi has received payment or honoraria from GSK, MSD, and AstraZeneca as well as support for attending meetings and/or travel from GSK. Robert M. Wenham reports receiving personal and institutional fees from Merck and Ovation Diagnostics; institutional clinical trial fees from AstraZeneca, Abbvie, Regeneron, and Eisai Co., Ltd.; personal consulting fees from Merck, Legend Biotech, Novacure, Genentech, GSK/Tesaro, AstraZeneca, Abbvie, Ovation Diagnostics, Regeneron, Seagen, Shattuck Labs, Eisai Co., Ltd., and Immunogen; speakers fees from Clovis Oncology; support for attending meetings and/or travel as part of the consulting, board participation, or abstract preparation, not in isolation; travel fees from Sonnet Biotherapeutics and Eisai Co., Ltd.; personal/DSMB fees from Seagen and GSK/Tesaro; personal/scientific advisory board fees from Sonnet Biotherapeutics; and personal stock or stock options for Ovation Diagnostics. Elena Ioana Braicu reports receiving research funding from Bayer and Tesaro; personal fees from Clovis Oncology, Tesaro, Eisai Co., Ltd., and RochePharma; and both research funding and personal fees from Roche Diagnostics, GSK, and AstraZeneca. Vicky Makker reports research funding (institution) from AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Duality, Eisai Co., Ltd., Faeth Therapeutics, Karyopharm Therapeutics, Lilly, MSD, Takeda, and Zymeworks; an unpaid consulting or advisory role for ArQule, AstraZeneca, Clovis Oncology, Duality, Eisai Co., Ltd., Faeth Therapeutics, GlaxoSmithKline, IBM, Immunocore, ITeos Therapeutics, Kartos Therapeutics, Karyopharm Therapeutics, Lilly, MSD, Moreo, Morphosys, Novartis, Takeda, and Zymeworks; support for travel, accommodations, and/or expenses from Eisai Co., Ltd. and MSD. Eva María Guerra Alía reports advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar, and Roche; speaker bureau/expert testimony honorarium from AstraZeneca-MSD, PharmaMar, Roche, and GSK-Tesaro; and support for travel, accommodation, and/or expenses from Roche, GSK-Tesaro, and Baxter. Zhenqiang Su is an employee of Takeda. Sylvie Vincent is an employee of Takeda. Farhad Sedarati is an employee of Takeda. Douglas V. Faller reports consulting fees from Viracta Therapeutics, Briacell Therapeutics, and Molecular Partners; equity from Oryzon Genomics, Phoenicia Biosciences, Viracta Therapeutics, and Briacell Therapeutics; and employment at Oryzon Genomics, Phoenicia Biosciences, and Takeda Pharmaceuticals (ended in 2022). Sileny N. Han, Amit Oza, Nicoletta Colombo, Andrea Jewell, Jonathan Krell, Jean- François Baurain, Rachel Neuwirth, and Giovanni Scambia have no disclosures to report.