Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors
Authors: André Thierry , Berton Dominique , Curigliano Giuseppe , Sabatier Renaud , Tinker Anna V. , Oaknin Ana , Ellard Susan , de Braud Filippo , Arkenau Hendrik-Tobias , Trigo José , Gravina Adriano , Kristeleit Rebecca , Moreno Victor , Abdeddaim Cyril , Vano Yann-Alexandre , Samouëlian Vanessa , Miller Rowan , Boni Valentina , Torres Antonio Antón , Gilbert Lucy , Brown Jubilee , Dewal Ninad , Dabrowski Christine , Antony Grace , Zografos Eleftherios , Veneris Jennifer , Banerjee Susana 
Published: November 2023

ImportanceMismatch 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.ObjectiveTo assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.Design, Setting, And ParticipantsThe 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.InterventionsPatients 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 MeasuresThe 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.ResultsThe 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT02715284