Abstract
Immune checkpoint inhibitors (ICI) synergize preclinically with antibody drug conjugates (ADC), harboring anti-tubulin maytansinoid payloads. We conducted an investigator-initiated, single-arm, phase 2 trial of mirvetuximab soravtansine (MIRV), a folate receptor alpha (FOLR1/FRα)-targeting ADC with the maytansinoid payload, DM4, combined with pembrolizumab in female patients with recurrent FOLR1-expressing serous endometrial cancer (EC, NCT03835819). Co-primary objectives include objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6); secondary objectives include PFS, overall survival, duration of response and safety. Exploratory objectives include correlation of tumor genomics and immunoprofiling with clinical activity. Eighteen patients initiated protocol therapy [MIRV 6 mg/kg adjusted ideal body weight IV and pembrolizumab 200 mg IV every 3 weeks]. Confirmed ORR is 28% (1 complete and 4 partial responses, 95% CI:10-53%), Kaplan Meier estimate of PFS6 is 24.4% (95% CI:7.7-46.1%) with 4 patients progression free at 6 months; trial was closed early for feasibility (planned sample size of 35 patients not reached) and hence these results are considered preliminary. G3 treatment-related adverse effects were rare with no grade ≥4 toxicities. We report a population of high FOLR1-expressing tumor-associated macrophages (CD163 + FOLR1 + ), suggesting potential on-target, off-tumor immune editing by MIRV. A composite biomarker score derived in this cohort correlates with objective response to MIRV and pembrolizumab.
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The study protocol and the statistical analysis plan are available in the Supplementary Information file. Additional individual de-identified participant data can be shared upon request. The remaining data are available within the Article or Source Data file. Source data are provided with this paper.
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Acknowledgements
We thank all the patients and their families for their participation in this trial. This investigator-initiated study (IND holder P.A.K.) was funded by Merck and AbbVie, which also provided pembrolizumab and mirvetuximab soravtansine, respectively. We would also like to acknowledge support from the Friends of Dana Farber (R.L.P.), the Breast Cancer Research Foundation, and The Lewin Fund to Fight Women’s Cancers.
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R.L.P. and J.V. conceived the study; R.L.P. coordinated, analyzed, and interpreted all the data and wrote the manuscript. P.A.K. supervised and was the IND holder of the study. Y.Z., N.T., and N.X. performed the statistical analysis and were the lead statisticians of the study; R.L.P., E.K.L., C.K., S.C., A.A.W., J.F.L, E.H.S., S.Z., V.J., J.V., U.A.M., and P.A.K. provided clinical data and contributed to the analysis and interpretation of the data; N.E., K.L.P., and S.J.R. performed the immunoprofiling data and analysis; M.H., M.P., and H.S. were Clinical Research Project Managers for the study and coordinated the processing and distribution of the clinical trial samples. All authors contributed to the writing and editing of the manuscript.
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R.L.P. declares consulting and/or advisory board participation for Gilead, unrelated to this work; Payment for educational events: OncLive/MJH Life Sciences. E.K.L. declares advisory board participation: Oncusp Therapeutics and Genmab, unrelated to this work, and institutional research support from: Repare Therapeutics, KSQ Therapeutics, Genmab, GSK, Merck, OnCusp Therapeutics, and NiKang Therapeutics. J.F.L. declares consulting and/or advisory board participation for AbbVie, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Daiichi Sankyo, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, LoxoLilly, Merck, SystImmune, Regeneron Therapeutics, Revolution Medicine, and Zentalis Pharmaceuticals, unrelated to this work. S.J.R. declares research support from Coherus Pharmaceuticals, Delcath Pharmaceuticals, and Bristol Myers Squibb. S.R. is a member of the Scientific Advisory Board of Immunitas Therapeutics. J.V. declares current employment at GSK, unrelated to this work. U.A.M. declares participation in scientific advisory boards: NextCure, Abbvie, Immunogen, Profound Bio, Eisai, the Ovarian Cancer Research Alliance, Tango Therapeutics, Novartis, GSK, Daiichi Sankyo, DayOne Bio, and Whitehawk Therapeutics; UAM also reports participation in a data safety-monitoring board: Mural Oncology, Macrogenics, Daiichi Sankyo, Astrazseneca and Symphogen, all unrelated to this work. P.A.K. declares consulting and/or advisory board participation for AstraZeneca, Bayer, GSK, Merck, Pfizer, BMS, Repare, IMV, Artios, Kadmon, Cardiff, Immunogen, EMD Serono, Scorpion, Schrodinger, Nimbus, Mural Oncology, unrelated to this work. Y.Z., N.E., M.H., M.P., C.K., S.C., A.A.W., E.H.S., H.S., N.X., K.L.P., N.T., S.Z., V.J. declare no competing interests.
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Porter, R.L., Zhou, Y., Eskndir, N. et al. Mirvetuximab soravtansine plus pembrolizumab in recurrent folate receptor alpha-positive uterine serous carcinoma: a phase II trial. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71102-x
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DOI: https://doi.org/10.1038/s41467-026-71102-x
