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Ref Type Journal Article
PMID (37917058)
Authors André T, Berton D, Curigliano G, Sabatier R, Tinker AV, Oaknin A, Ellard S, de Braud F, Arkenau HT, Trigo J, Gravina A, Kristeleit R, Moreno V, Abdeddaim C, Vano YA, Samouëlian V, Miller R, Boni V, Torres AA, Gilbert L, Brown J, Dewal N, Dabrowski C, Antony G, Zografos E, Veneris J, Banerjee S
Title Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial.
Journal Vol Issue Date Pages Journal Short Title
JAMA network open 6 11 2023 Nov 01 e2341165 JAMA Netw Open
URL
Abstract Text 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.To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.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.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.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.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.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.ClinicalTrials.gov Identifier: NCT02715284.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MSH6 negative Advanced Solid Tumor sensitive Dostarlimab-gxly FDA approved - On Companion Diagnostic Actionable In a Phase I trial (GARNET) that supported FDA approval, Jemperli (dostarlimab-gxly) treatment demonstrated acceptable safety profile, and resulted in an objective response rate of 44.0% (144/327), with a median progression-free survival of 7.0 mo, and median overall survival and duration of response not reached in patients with advanced mismatch repair deficient (dMMR) solid tumors, as indicated by a loss of MLH1, PMS2, MSH2, or MSH6 expression in an FDA-approved IHC test (PMID: 37917058; NCT02715284). detail... detail... 37917058
MLH1 negative Advanced Solid Tumor sensitive Dostarlimab-gxly FDA approved - On Companion Diagnostic Actionable In a Phase I trial (GARNET) that supported FDA approval, Jemperli (dostarlimab-gxly) treatment demonstrated acceptable safety profile, and resulted in an objective response rate of 44.0% (144/327), with a median progression-free survival of 7.0 mo, and median overall survival and duration of response not reached in patients with advanced mismatch repair deficient (dMMR) solid tumors, as indicated by a loss of MLH1, PMS2, MSH2, or MSH6 expression in an FDA-approved IHC test (PMID: 37917058; NCT02715284). 37917058 detail... detail...
PMS2 negative Advanced Solid Tumor sensitive Dostarlimab-gxly FDA approved - On Companion Diagnostic Actionable In a Phase I trial (GARNET) that supported FDA approval, Jemperli (dostarlimab-gxly) treatment demonstrated acceptable safety profile, and resulted in an objective response rate of 44.0% (144/327), with a median progression-free survival of 7.0 mo, and median overall survival and duration of response not reached in patients with advanced mismatch repair deficient (dMMR) solid tumors, as indicated by a loss of MLH1, PMS2, MSH2, or MSH6 expression in an FDA-approved IHC test (PMID: 37917058; NCT02715284). 37917058 detail... detail...
POLE inact mut Advanced Solid Tumor predicted - sensitive Dostarlimab-gxly Case Reports/Case Series Actionable In a Phase I trial (GARNET), Jemperli (dostarlimab-gxly) treatment demonstrated acceptable safety, and resulted in an objective response rate (ORR) of 44.1% (153/347) in patients with mismatch repair deficient (dMMR), microsatellite high (MSI-H), or POLE-altered advanced solid tumors, with an ORR of 54.5% (6/11, 1 complete, 5 partial responses) and median duration of response and median overall survival not reached in patients with pathogenic POLE exonuclease domain mutations (PMID: 37917058; NCT02715284). 37917058
MSH2 negative Advanced Solid Tumor sensitive Dostarlimab-gxly FDA approved - On Companion Diagnostic Actionable In a Phase I trial (GARNET) that supported FDA approval, Jemperli (dostarlimab-gxly) treatment demonstrated acceptable safety profile, and resulted in an objective response rate of 44.0% (144/327), with a median progression-free survival of 7.0 mo, and median overall survival and duration of response not reached in patients with advanced mismatch repair deficient (dMMR) solid tumors, as indicated by a loss of MLH1, PMS2, MSH2, or MSH6 expression in an FDA-approved IHC test (PMID: 37917058; NCT02715284). detail... detail... 37917058