Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study

David M O'Malley, Giovanni Mendonca Bariani, Philippe A Cassier, Aurelien Marabelle, Aaron R Hansen, Ana De Jesus Acosta, Wilson H Miller Jr, Tamar Safra, Antoine Italiano, Linda Mileshkin, Lei Xu, Fan Jin, Kevin Norwood, Michele Maio, David M O'Malley, Giovanni Mendonca Bariani, Philippe A Cassier, Aurelien Marabelle, Aaron R Hansen, Ana De Jesus Acosta, Wilson H Miller Jr, Tamar Safra, Antoine Italiano, Linda Mileshkin, Lei Xu, Fan Jin, Kevin Norwood, Michele Maio

Abstract

Purpose: Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158.

Methods: Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety.

Results: As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up; N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events).

Conclusion: Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer.

Conflict of interest statement

David M. O'MalleyConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute, Agenus, Marker Therapeutics, Eisai, Genelux, Iovance Biotherapeutics, Ambry Genetics, Tarveda Therapeutics, Leap Therapeutics, Myriad Genetics, GlaxoSmithKline, Regeneron, Sorrento Therapeutics, Rubius Therapeutics, Elevar Therapeutics, Novartis, Seattle Genetics, BBI Healthcare, Arquer Diagnostics, Toray Medical, Takeda, InxMed, Celsion, Roche Diagnostics MSAResearch Funding: Amgen (Inst), AstraZeneca (Inst), Genentech/Roche (Inst), Regeneron (Inst), Immunogen (Inst), Janssen Research & Development (Inst), Clovis Oncology (Inst), EMD Serono (Inst), Ergomed (Inst), Ajinomoto (Inst), Immunogen (Inst), Cerulean Pharma (Inst), PharmaMar (Inst), Array BioPharma (Inst), Bristol Myers Squibb (Inst), Agenus (Inst), Tesaro (Inst), TRACON Pharma (Inst), Genmab (Inst), Seattle Genetics (Inst), Iovance Biotherapeutics (Inst), Leap Therapeutics (Inst), Merck (Inst), AbbVie/Stemcentrx (Inst), AbbVie (Inst), Mersana (Inst), Eisai (Inst), BBI Healthcare (Inst), Sumitomo Dainippon Pharma Oncology (Inst) Giovanni Mendonca BarianiConsulting or Advisory Role: LibbsResearch Funding: mAbxience, Merck Sharp & Dohme, Bristol Myers SquibbTravel, Accommodations, Expenses: Lilly Philippe A. CassierHonoraria: Novartis, Roche/Genentech, Amgen, AstraZeneca, Merck SeronoResearch Funding: Novartis (Inst), Roche/Genentech (Inst), Lilly (Inst), Blueprint Medicines (Inst), Bayer (Inst), AstraZeneca (Inst), Celgene (Inst), Plexxikon (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Merck Serono (Inst), Merck Sharp & Dohme (Inst), Taiho Pharmaceutical (Inst), Toray Industries (Inst), Transgene (Inst), Loxo (Inst), GlaxoSmithKline (Inst), Innate Pharma (Inst), Janssen (Inst)Travel, Accommodations, Expenses: Roche, Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Netris Pharma, Bayer, Merck Serono Aurelien MarabelleStock and Other Ownership Interests: PEGASCY (Inst), HiFiBiO Therapeutics, Shattuck Labs, Centessa Pharmaceuticals (Inst)Honoraria: Bristol Myers Squibb, AstraZeneca/MedImmune, OncovirConsulting or Advisory Role: Lytix Biopharma, EISAI, Pierre Fabre, AstraZeneca, Servier, Roche, Redx Pharma, Sotio, Innate Pharma, ImCheck therapeutics, MSD, OSE Immunotherapeutics, HiFiBiO Therapeutics, MedinCell, Centessa PharmaceuticalsSpeakers' Bureau: BMSResearch Funding: Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Transgene (Inst), MSD (Inst)Patents, Royalties, Other Intellectual Property: Monoclonal antibodies against CD81 (Stanford University)Travel, Accommodations, Expenses: MSD, AstraZeneca Aaron R. HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol Myers Squibb, Eisai, Novartis, AstraZenecaResearch Funding: Karyopharm Therapeutics (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim, GlaxoSmithKline (Inst), Roche/Genentech (Inst), Janssen (Inst), AstraZeneca/MedImmune (Inst), Astellas Pharma (Inst), BioNTech (Inst), Pfizer/EMD Serono (Inst), Neoleukin Therapeutics (Inst) Ana De Jesus AcostaConsulting or Advisory Role: MerckResearch Funding: Merck (Inst), AstraZeneca (Inst) Wilson H. Miller JrHonoraria: Bristol Myers Squibb Foundation, Merck, Roche, Novartis, GlaxoSmithKline, Mylan, EMD Serono, AmgenConsulting or Advisory Role: Bristol Myers Squibb, Merck, Roche, Novartis, Amgen, GlaxoSmithKline, Mylan, EMD SeronoResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Roche (Inst), AstraZeneca (Inst), Merck (Inst), MethylGene (Inst), Bayer (Inst), Amgen (Inst), MedImmune (Inst), Pfizer (Inst), Esperas Pharma (Inst), Astellas Pharma (Inst), Sanofi (Inst), Incyte (Inst), Array BioPharma (Inst), Exelixis (Inst), Mimic Technologies (Inst), Ocellaris Pharma (Inst), Canadian Institutes of Health Research (CIHR) (Inst), Canadian Research Society (Inst), Terry Fox Research Institute (Inst), Samuel Waxman Cancer Research Foundation (Inst), Canadian Cancer Society Research Institute (CCSRI) (Inst) Antoine ItalianoHonoraria: Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche, IPSENConsulting or Advisory Role: Roche, Daiichi Sankyo, Immune Design, Epizyme, Bayer, LillyResearch Funding: Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck SeronoPatents, Royalties, Other Intellectual Property: BMS Lei XuEmployment: MerckStock and Other Ownership Interests: Merck Fan JinEmployment: MerckStock and Other Ownership Interests: MerckTravel, Accommodations, Expenses: Merck Kevin NorwoodEmployment: Merck Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA Hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, AlfasigmaNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Disposition of patients' study medication status in the safety population (ie, all patients who received ≥ 1 dose of pembrolizumab). aIncludes patients with clinical and radiographic progression. bTwo patients received a second course of pembrolizumab, one of whom had second course up to cycle 3 and the other had second course up to cycle 12. cPatients who received ≥ 1 dose of pembrolizumab and had been enrolled ≥ 26 weeks before data cutoff. AE, adverse event; CR, complete response; dMMR; mismatch repair deficiency; MSI-H, high levels of microsatellite instability.
FIG 2.
FIG 2.
(A) Best percentage change from baseline in target lesion size. (B) Time to response and duration of response for patients with a response. (C) Kaplan-Meier analysis of duration of response per RECIST version 1.1. Light blue lines indicate 95% confidence bands. For each figure, all assessments are per RECIST version 1.1 by independent central review. aCR was the last overall response before data cutoff and was not confirmed as of the data cutoff date. CR, complete response; NR, not reached; PD, progressive disease; PR, partial response.
FIG 3.
FIG 3.
Kaplan-Meier analysis of (A) PFS per RECIST version 1.1 by independent central radiologic review in the efficacy analysis population and (B) OS in the efficacy analysis population. Light blue lines indicate 95% confidence bands. NR, not reached; OS, overall survival; PFS, progression-free survival.

References

    1. Bray F, Ferlay J, Soerjomataram I, et al. : Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394-424, 2018
    1. Zhang S, Gong TT, Liu FH, et al. : Global, regional, and national burden of endometrial cancer, 1990-2017: Results from the Global Burden of Disease study, 2017. Front Oncol 9:1440, 2019
    1. National Comprehensive Cancer Network (NCCN) : NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Uterine Neoplasms. Version 2.2021.
    1. Miller DS, Filiaci VL, Mannel RS, et al. : Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol 38:3841-3850, 2020
    1. Fleming GF: Second-line therapy for endometrial cancer: The need for better options. J Clin Oncol 33:3535-3540, 2015
    1. Siegel RL, Miller KD, Fuchs HE, et al. : Cancer statistics, 2021. CA Cancer J Clin 71:7-33, 2021
    1. Ryan NAJ, Glaire MA, Blake D, et al. : The proportion of endometrial cancers associated with Lynch syndrome: A systematic review of the literature and meta-analysis. Genet Med 21:2167-2180, 2019
    1. Bonneville R, Krook MA, Kautto EA, et al. : Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol
    1. Pakish JB, Zhang Q, Chen Z, et al. : Immune microenvironment in microsatellite-instable endometrial cancers: Hereditary or sporadic origin matters. Clin Cancer Res 23:4473-4481, 2017
    1. Meyer LA, Broaddus RR, Lu KH: Endometrial cancer and Lynch syndrome: Clinical and pathologic considerations. Cancer Control 16:14-22, 2009
    1. Le DT, Uram JN, Wang H, et al. : PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509-2520, 2015
    1. Howitt BE, Shukla SA, Sholl LM, et al. : Association of polymerase E-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol 1:1319-1323, 2015
    1. Ott PA, Bang YJ, Berton-Rigaud D, et al. : Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: Results from the KEYNOTE-028 study. J Clin Oncol 35:2535-2541, 2017
    1. Le DT, Durham JN, Smith KN, et al. : Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409-413, 2017
    1. Marabelle A, Le DT, Ascierto PA, et al. : Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 38:1-10, 2020
    1. O'Malley D, Marabelle A, De Jesus-Acosta A, et al. : Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEYNOTE-158 study. Ann Oncol 30:v425-v426, 2019
    1. Chung HC, Ros W, Delord JP, et al. : Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 37:1470-1478, 2019
    1. KEYTRUDA® (Pembrolizumab). Full Prescribing Information. Merck Sharp & Dohme Corp, Whitehouse Station, NJ, 2021
    1. Mok TSK, Wu YL, Kudaba I, et al. : Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 393:1819-1830, 2019
    1. Herbst RS, Baas P, Kim DW, et al. : Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non–small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387:1540-1550, 2016
    1. Ott PA, Bang YJ, Piha-Paul SA, et al. : T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol 37:318-327, 2019
    1. Miller DS, Scambia G, Bondarenko I, et al. : ZoptEC: Phase III randomized controlled study comparing zoptarelin with doxorubicin as second line therapy for locally advanced, recurrent, or metastatic endometrial cancer (NCT01767155). Presented at American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 1-5, 2018
    1. Oaknin A, Gilbert L, Tinker AV, et al. : Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and proficient (MMRp) endometrial cancer cohorts from the GARNET study. Presented at Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer, March 9-25, 2021; Virtual
    1. Oaknin A, Tinker AV, Gilbert L, et al. : Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: A nonrandomized phase 1 clinical trial. JAMA Oncol 6:1-7, 2020
    1. US Food and Drug Administration : FDA Grants Accelerated Approval to Dostarlimab-Gxly for dMMR Endometrial Cancer.
    1. Antill YC, Kok PS, Robledo K, et al. : Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601). J Clin Oncol 37, 2019. (suppl; abstr 5501)
    1. Konstantinopoulos PA, Luo W, Liu JF, et al. : Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer. J Clin Oncol 37:2786-2794, 2019
    1. Makker V, Taylor MH, Aghajanian C, et al. : Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol 38:2981-2992, 2020
    1. Makker V, Colombo N, Casado Herraez A, et al. : A multicenter, open-label, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer. Presented at Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer, March 9-25, 2021; Virtual
    1. Luchini C, Bibeau F, Ligtenberg MJL, et al. : ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: A systematic review-based approach. Ann Oncol 30:1232-1243, 2019

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