Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study.

Abstract

9 Background: Dostarlimab is a humanized anti–PD-1 monoclonal antibody that binds the PD-1 receptor, blocking interaction with ligands PD-L1 and PD-L2. The ongoing phase 1 GARNET study (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F of the GARNET trial enrolled pts with dMMR or POLEmut non-endometrial solid tumors; the majority were gastrointestinal (GI) in origin. Pts must have progressed per blinded independent central review (BICR) following prior systemic therapy for advanced disease and had dMMR status by local immunohistochemistry. Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W until discontinuation. Objective response rate (ORR) and duration of response (DOR) were assessed by BICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and 6 mo of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 144 pts were included in the safety analysis, with 106 dMMR pts in the efficacy analysis (1 POLEmut pt with a confirmed PR was not included in this population). Of the 106 pts, 99 (93.4%) had GI tumors. Confirmed ORR in dMMR pts was 38.7% (95% CI: 29.4, 48.6), with a complete response rate of 7.5%. ORR was consistent across tumor type (Table). At the data cutoff, median duration of follow-up (n = 107; dMMR and POLEmut pts) was 12.4 months and median DOR was not reached. The Kaplan–Meier estimated probability of maintaining response at 12 and 18 months was 91.0% and 80.9% respectively. Treatment-related adverse events (TRAEs) were reported in 68.8% of pts; 8.3% of pts experienced at least 1 grade ≥3 TRAE. The most common was lipase increased in 2 (1.4%) pts. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers. The safety profile was consistent with other cohorts in GARNET, with immune-related TRAEs infrequent and low grade. Clinical trial information: NCT02715284. [Table: see text]

Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

“…The median DOR was not reached and grade ≥ 3 TRAEs were 8%. Within the 69 (65%) mCRC enrolled, ORR was 36.2%, matching the results of other anti-PD-1 antibodies (nivolumab and pembrolizumab) in pre-treated dMMR/MSI-H mCRC [42][43][44]. These results confirm the activity of anti-PD-1 antibodies in pre-treated MSI-High/dMMR mCRC.…”

The New Era of Immunotherapy in Gastric Cancer

“…In addition, post-hoc analysis of KEYNOTE-061 and KEYNOTE-062 suggested remarkable survival benefit for pembrolizumab in MSI-H patients. Most recently, the GARNET study (Cohort F) of dostarlimab (anti-PD-1 antibody) showed ORR of 38.7% in MMR-D patients with non-endometrial solid tumors (ORR of 37.5% for AGC) [ 16 ], leading to FDA accelerated approval to dostarlimab for advanced dMMR solid tumors with VENTANA MMR RxDx Panel. Currently, MSI-H/MMR-D is one of the most consistent predictive biomarkers for ICIs.…”

“…Another anti-PD-1 antibody, nivolumab, showed a survival benefit in third-line or subsequent treatment in an Asian patient population irrespective of PD-L1 expression (ATTRACTION-2) or in first-line treatment combined with standard cytotoxic agents (CheckMate-649) [ 14 , 15 ]. On the other hand, dostarlimab, an anti-PD-1 antibody, demonstrated a favorable ORR in the GARNET trial in MMR-D patients with non-endometrial solid tumors [ 16 ], and was granted accelerated approval by the FDA. Furthermore, clinical trials of several investigational immunotherapies are ongoing in AGC, including anti-PD-1 antibody plus anti-CTLA4 antibody, ICIs plus other targeted agents, and chimeric antigen receptor T (CAR-T) cell therapies.…”

Advances in immuno-oncology and precision oncology: Where are we heading?

“…The latest addition to the list of tumor agnostic approval is dostarlimab-gxly for adults with MSI high tumors based on the results of GARNET trial. [6] For patients with localized esophageal or esophagogastric junction cancer who have residual disease in the surgical specimen after initial chemoradiotherapy, adjuvant nivolumab for 1 year has been approved recently. [7] Similarly, for renal cell carcinoma, KEYNOTE-564 showed 1 year of adjuvant pembrolizumab improved disease-free survival (DFS) compared with placebo (2-year DFS 77% vs. 68%).…”