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Controlled Clinical Trial
. 2023 Nov 1;6(11):e2341165.
doi: 10.1001/jamanetworkopen.2023.41165.

Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial

Thierry André  1 , Dominique Berton  2 , Giuseppe Curigliano  3   4 , Renaud Sabatier  5 , Anna V Tinker  6 , Ana Oaknin  7 , Susan Ellard  8 , Filippo de Braud  9 , Hendrik-Tobias Arkenau  10 , José Trigo  11 , Adriano Gravina  12 , Rebecca Kristeleit  13 , Victor Moreno  14 , Cyril Abdeddaim  15 , Yann-Alexandre Vano  16 , Vanessa Samouëlian  17 , Rowan Miller  18 , Valentina Boni  19 , Antonio Antón Torres  20 , Lucy Gilbert  21 , Jubilee Brown  22 , Ninad Dewal  23 , Christine Dabrowski  24 , Grace Antony  25 , Eleftherios Zografos  26 , Jennifer Veneris  24 , Susana Banerjee  27
Affiliations
Controlled Clinical Trial

Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial

Thierry André et al. JAMA Netw Open. .

Abstract

Importance: Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.

Objective: To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.

Design, setting, and participants: The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability-high (MSI-H) or polymerase epsilon (POLE)-altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months.

Interventions: Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal.

Main outcomes and measures: The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.

Results: The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified.

Conclusions and relevance: In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need.

Trial registration: ClinicalTrials.gov Identifier: NCT02715284.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr André reported receiving personal fees from Astellas, AstraZeneca, Aptitude Health, Bristol-Myers Squibb, Gritstone Oncology, GamaMabs Pharma SA, Gilead, GSK, Merck & Co Inc, Nordic Oncology, Pierre Fabre, Transgène, Servier, Seagen, Sanofi, Merck Serono, Amgen, and Roche/Ventana and receiving support for meetings from Bristol-Myers Squib, Merck & Co Inc and Servier outside the submitted work. Dr Curigliano reported receiving personal fees from Bristol-Myers Squibb, Ellipsis, Seattle Genetics, Roche, Novartis, Pfizer, Eli Lilly and Co, AstraZeneca, Daichii Sankyo, and Gilead during the conduct of the study. Dr Sabatier reported receiving personal fees from AstraZeneca, Eisai, Novartis, Roche, MSD, and GSK; nonfinancial support from AstraZeneca, Bristol-Myers Squibb, GSK, Pfizer, and Roche; grants from AstraZeneca, and grants to the institution from AstraZeneca and Eisai outside the submitted work. Dr Tinker reported receiving institutional grants from AstraZeneca and personal fees from GSK, Merck, Eisai, and AstraZeneca outside the submitted work. Dr Oaknin reported receiving personal fees from Agenus, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Novocure, OneXerna Therapeutics Inc, PharmaMar, Regeneron, Roche, Shattuck Labs, Seagen, and Sutro Biopharma and receiving institutional grants from AbbVie Deutschland, Ability Pharmaceuticals, Advaxis Inc, Aeterna Zentaris, Amgen, Aprea Therapeutics, Clovis Oncology, Eisai, F. Hoffmann-La Roche, GSK, ImmunoGen, Merck Sharp & Dohme de Espana, Millennium Pharmaceuticals, PharmaMar, and Regeneron Pharmaceuticals outside the submitted work. Dr Ellard reported owning stock in GSK outside the submitted work. Dr de Braud reported receiving personal fees from EMD Serono, Manarini, Novartis, MSD, Bristol-Myers Squibb, Incyte, Roche, Nerviano Medical Science, and Sanofi; receiving speakers bureau fees from AccMed, Amgen, Bristol-Myers Squibb, Healthcare Research & Pharmacoepidemiology, Incyte, Merck Group, MSD, Nadirex, Pfizer, Roche, Sanofi, and Servier; and receiving principal investigator fees from Basilea Pharmaceutica, Bristol-Myers Squibb, Exelixis, Daiichi Sankyo Development Limited, F. Hoffmann-LaRoche, Ignyta Operating, Janssen-Cilag International, Kymab, Loxo Oncology Inc, MedImmune, Merck KGAA, Merck Sharp & Dohme SpA, MSD, Novartis, Pfizer, and Tesaro outside the submitted work. Dr Trigo reported receiving institutional grants from AstraZeneca and MSD and receiving personal fees from Bristol-Myers Squibb, AstraZeneca, Boehringer, Takeda, MSD, and GSK during the conduct of the study. Dr Gravina reported receiving grants from Tesaro/GSK during the conduct of the study; receiving nonfinancial support from Pfizer; receiving grants from Janssen, AstraZeneca, Daiichi-Sankyo, Incyte, Exelixis, MSD, Pfizer, Roche, Bayer, Boehringer-Ingheleim, Hifibio, Merck, Sutro, and Taiho outside the submitted work. Dr Kristeleit reported receiving grants from Clovis Oncology and MSD; personal fees from GSK, Clovis Oncology, Tubulis, Merck, Celcuity, Leucid Bio, Duke St Bio, Seattle Genetics, Eisai, Basilea, Shattuck Labs, iTEOS, Incyte, Regeneron, AstraZeneca, PharmaMar, and MSD outside the submitted work. Dr Moreno reported receiving personal fees from Bristol-Myers Squibb, Bayer, Roche, Basilea, Janssen, Nanobiotix, Pieris, Regeneron/Sanofi, AstraZeneca, and Affimed outside the submitted work and receiving institutional funding from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, Beigene, BioInvent International, BMS, Boehringer, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Therapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Eli Lilly and Co, Loxo Oncology Inc, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, and Upshersmith outside the submitted work. Dr Abdeddaim reported receiving grants from MSD, GSK, Clovis Oncology, and AstraZeneca and receiving personal fees from AstraZeneca, Clovis Oncology, Merck, and GSK outside the submitted work. Dr Vano reported receiving personal fees from Bristol-Meyers Squibb, Janssen, Merck, Novartis, Roche, Sanofi, Viatris, Pfizer, MSD, Ipsen, and Eisai outside the submitted work. Dr Samouëlian reported receiving personal fees from Merck. Dr Miller reported receiving consultant fees from AZD, Clovis Oncology, Ellipses, GSK, MSD, and Shionogi; speakers’ bureau fees from AZD, Clovis Oncology, GSK, and Roche; travel grants from AZD and GSK; and trial funding from MSD. Dr Boni reported receiving institutional grants from AbbVie, ACEO, Adaptaimmune, Alkermes, Amcure, Amgen, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Bayer, BioNTech, CytomX, Genmab, Roche/Genentech, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Eli Lilly and Co, Loxo Oncology Inc, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, Puma, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, Daiichi, Astellas, Orca, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, and Zenith; receiving personal fees from Puma Biotechnology, Ideaya Biosciences, Loxo Oncology Inc, START, CytomX Therapeutics, Guidepoint, OncoArt, Eli Lilly and Co, Janssen, NEX Oncology, and QuironSAlud, outside the submitted work. Dr Anton Torres reported personal fees from AstraZeneca-Daichii-Sanykio and personal fees from Pfizer during the conduct of the study, personal fees from Lilly and personal fees from Gilead outside the submitted work. Dr Gilbert reported receiving personal fees from Alkermes, AstraZeneca, Eisai-Merck, GSK, Merck, Eisai, Novovure, and Kora Health; receiving grants Pfizer, Merck Sharp & Dohme, Karyopharm, Tesaro, Alkermes, AstraZeneca, Clovis, IMV, ImmunoGen, Roche, Mersana, Esperas, Novovure, Oncoquest, K-Group Beta, and GSK outside the submitted work. Dr Brown reported serving on the research steering committee for Genentech, receiving research support from Caris Life Sciences, receiving personal fees from AstraZeneca, Verastem, Clovis, Eisai, and GSK/Tesaro outside the submitted work. Drs Dewal, Dabrowski, Antony, and Zografos reported being employees of GSK during the conduct of the study. Dr Veneris reported receiving personal fees from GSK during the conduct of the study and outside the submitted work. Dr Banerjee reported receiving funding from The Royal Marsden NHS Foundation Trust during the conduct of the study and receiving grants from AstraZeneca and GSK; receiving personal fees from Amgen, Clovis Oncology, GenMab, Merck Serono, GSK, AstraZeneca, Immunogen, MSD, Mersana, Novartis, OncXerna, Seagen, Shattuck Labs, Regeneron, Epsilogen, Novacure, Takeda, Roche, Pfizer, and Verastem outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment and Outcomes
dMMR indicates mismatch repair deficient; MMRp, mismatch repair proficient; MMRunk, mismatch repair status unknown; MSI-H, microsatellite instability–high; POLE, polymerase epsilon. aSixteen patients had no measurable disease per blinded independent central review (BICR) at baseline and were excluded from the efficacy population. bAll patients with dMMR and MSI-H or POLE-altered solid tumors who had received at least 1 dose of dostarlimab, had at least 1 BICR-confirmed measurable lesion at baseline, and had the opportunity to be followed up for at least 6 months as of the data cutoff date were included in the efficacy population, regardless of whether the patient had a postbaseline tumor assessment. cTotal of 327 patients with dMMR solid tumors (including 2 who were also POLE-altered). dTotal of 106 patients with dMMR solid tumors (including 2 who also had POLE alterations). eSeven patients with MMR unknown/MSI-H tumors or MMRp tumors (including 2 who had POLE alterations).
Figure 2.
Figure 2.. Progression-Free Survival and Overall Survival for Patients With Mismatch Repair Deficient (dMMR) Solid Tumors
A, Dashed lines indicate study time points at 6, 12, 24, and 36 months. B, Dashed lines indicate study time points at 12, 24, and 36 months. Plus signs indicate censoring; NR, not reached.
See this image and copyright information in PMC

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