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Anti–PD-1 Antibody Dostarlimab Active in Mismatch Repair–Deficient Gastrointestinal Tumors


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Dostarlimab, a monoclonal antibody targeting PD-1, showed antitumor activity in patients with mismatch repair–deficient (dMMR) gastrointestinal tumors in the phase I GARNET study, reported at the 2021 Gastrointestinal Cancers Symposium by Thierry André, MD, of Sorbonne University and Saint-Antoine Hospital, Paris.1

“The majority of patients were enrolled with advanced disease that had progressed on prior therapy, and they had limited treatment options. This represents a patient group with a high unmet need,” Dr. André noted. “Dostarlimab demonstrated durable antitumor activity in a cohort with dMMR colorectal and noncolorectal cancers, and it has a convenient schedule of administration.”

Thierry André, MD

Thierry André, MD

During the discussion period, Dr. André was asked how dostarlimab differs from pembrolizumab, which is approved in the treatment of dMMR colorectal cancer. “It’s difficult to answer, but the feeling is that it has the same kind of efficacy and toxicity. The difference, however, is that the selection of patients in the dostarlimab study was more stringent,” he responded. “We needed to have proof of disease progression, and the patients had very advanced disease. It’s clear that dostarlimab works well in refractory disease and in a large panel of cancer types. It’s good news in gastrointestinal cancer.”

Phase I GARNET Study

The ongoing phase I GARNET study is evaluating dostarlimab in patients with a variety of advanced solid tumors. Dr. André presented findings from Cohort F, which included patients with locally determined dMMR or microsatellite instability–high (MSI-H) or POLE-mutated nonendometrial solid tumors, the majority of which were gastrointestinal. Other cohorts in the study have endometrial, non–small cell lung, and prostate cancers.

Patients had experienced disease progression following systemic therapy (most had two to three prior lines) and lacked satisfactory treatment options. Those with colorectal cancer were required to have progressive disease after, or to be intolerant to, fluoropyrimidines, oxaliplatin, and irinotecan.

Patients received dostarlimab at 500 mg every 3 weeks for 4 cycles and 1,000 mg of dostarlimab every 6 weeks thereafter for up to 2 years. They were included in the efficacy analysis if they received at least one dose, had measurable disease at baseline, and had 6 months of follow-up (n = 106). All who received one dose were included in the safety analysis (n = 144). In the study population, 99 patients (93.4%) had gastrointestinal tumors.

KEY POINTS

  • The novel anti–PD-1 agent dostarlimab is being evaluated in multiple tumor types in the ongoing GARNET trial.
  • In the cohort of patients with mismatch repair–deficient and gastrointestinal tumors, the response rate was 39%, and the complete response rate was 8%.
  • The drug has a convenient dosing schedule and appears to be well tolerated.

Responses and Toxicity

The confirmed objective response rate was 38.7%, with 7.5% being complete responses. For the 41 responders, the median duration of response had not been reached after 12.4 months of median follow-up. The probability of maintaining a response at 12 and 18 months was 91.0% and 80.9%, respectively. Responses were consistent and durable across colorectal and noncolorectal tumor types, Dr. André reported.

Treatment-related adverse events were reported in 69% of patients, of which 8% were grade ≥ 3. Treatment-related serious adverse events were observed in 6% of patients, and toxicities leading to treatment discontinuation occurred in 4%. No deaths associated with dostarlimab were reported. The safety profile was consistent with other cohorts in GARNET, with immune-related adverse events being infrequent and low grade, Dr. André noted.

The cohort is open for further enrollment. Data for the entire cohort with dMMR or MSI-H disease determined centrally will be reported in the future. 

DISCLOSURE: Dr. André has received honoraria from Amgen, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Pierre Fabre, Roche/Genentech, Sanofi, Servier , and Vantana; has served as a consultant or advisor to Amgen, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Clovis Oncology, Gamamabs Pharma SA, GIC Advice, HalioDX, MSD Oncology, Pierre Fabre, Servier, and Tesaro; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Bristol Myers Squibb, MSD Oncology, Roche, Roche/Genentech, and Vantana.

REFERENCE

1. André T, Berton D, Curigliano G, et al: Safety and efficacy of anti–PD-1 antibody dostarlimab in patients with mismatch repair-deficient solid cancers: Results from GARNET study. 2021 Gastrointestinal Cancers Symposium. Abstract 9. Presented January 16, 2021.

 


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