Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors

Abstract

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

Tumor biomarkers for diagnosis, prognosis and targeted therapy

“… 1317 Dostarlimab (Jemperli) developed by GSK was approved in 2021 and used in patients with mismatch repair-deficient advanced solid tumors. 1318 …”

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions

“…Another PD-1 monoclonal antibody, dostarlimab, was approved in 2021 and tested in clinical trials (NCT04165772) in patients with MSI-H or dMMR CRC[ 141 ]. A high-resolution structure revealed that Dostarlimab binds to the flexible loops of PD-1, including the BC, C’D, and FG loops, in contrast to the binding modes of Pembrolizumab or Nivolumab[ 94 ].…”

Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer

“…In the second- or third-line setting, there are multiple phase I/II clinical trials reporting on the efficacy of PD-L1/PD-1 inhibitors: pembrolizumab, dostarlimab, nivolumab, and avelumab, with similar results, with an ORR between 30–38% [ 86 , 96 , 105 , 106 ]. The phase II Checkmate 142 trial tested the PD-1 and CTLA4 dual blockade in pre-treated patients, reporting a ORR of 55%, mPFS not reached [ 107 ].…”