The US Food and Drug Administration (FDA) has granted accelerated approval to dostarlimab (Jemperli, GSK) for adults with stage 2/3 Locally Advanced Rectal Cancer (LARC) that is microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), as determined by an FDA-authoried test for solid tumors.

Efficacy was evaluated in AZUR-1 (NCT05723562), a multicenter, single-arm, open-label trial in 154 patients with previously untreated, histologically confirmed, MSI-H/dMMR, Stage 2/3 LARC.

Patients received dostarlimab 500 mg intravenously every 3 weeks for 9 cycles unless unacceptable toxicity or disease progression occurred. Tumor response was assessed using a combination of endoscopy, rectal MRI, and CT scans of the chest, abdomen, and pelvis at week 6, week 12, and approximately 3 weeks after completing treatment.

Patients who achieved a clinical Complete Response (cCR) at either of the first 2 post-treatment assessments entered a non-operative management period, during which they were closely monitored for recurrence through regular multi-modal assessments conducted every 4 months for the first 2 years and every 6 months thereafter.

Patients who did not experience cCR, or whose disease recurred or progressed, were evaluated for Standard of Care (SoC) management at investigator discretion.

The primary efficacy outcome measure was sustained cCR for 12 months (cCR12) per Independent Central Review (ICR) measured from the first disease assessment after the last dose of dostarlimab where cCR was observed. Additional efficacy outcome measures included cCR12 based on investigator assessments and Objective Response Rate (ORR) as per ICR and per investigator.

Of 154 treated patients, 110 (71 percent) were treated with dostarlimab alone, did not receive any additional form of treatment, and did not experience disease progression; 26 (17 percent) underwent surgery (with or without additional systemic therapy or radiation); 13 (8 percent) received additional systemic therapy or radiation; 1 (0.6 percent) had progressive disease without further treatment; and 4 (2.5 percent) withdrew or were lost to follow-up.

In 116 ICR-evaluable patients, the cCR12 was 47 percent (95 percent CI: 27 percent, 56 percent). In addition, there are 38 (33 percent) patients who achieved cCR by ICR and have less than 12 months of follow-up at the time of the data cutoff, and 44 (38 percent) patients had near CR.

With a median follow up of 26.3 months, none of the patients with cCR12, cCR, or nCR experienced disease progression. The ORR per ICR was 79 percent (95 percent CI: 71 percent, 85 percent).

In 144 investigator-evaluable patients, the cCR12 rate was 68 percent (95 percent CI: 60 percent, 76 percent) and the ORR was 82 percent (95 percent CI: 75 percent, 88 percent).

Of the 15 patients who underwent surgery after dostarlimab alone, based on imaging findings suggesting incomplete response, pathological complete response was reported in 12 patients.

In addition, FDA reviewed an investigator-led, multicenter, single-arm, open-label trial (NCT04165772) that assessed dostarlimab 500 mg intravenously every 3 weeks for 9 cycles in 50 patients with previously untreated, MSI-H/dMMR, stage 2/3 LARC. The cCR12 rate was 93 percent (95 percent CI: 82 percent, 99 percent) and the ORR was 100 percent (95 percent CI: 93 percent, 100 percent).

No patients received chemoradiation and/or rectal cancer surgery as part of the treatment of LARC.

Of the 27 patients who have been followed for at least 3 years, 1 patient had a local recurrence treated with lymphadenectomy, 1 patient withdrew, and 1 patient died unrelated to disease under study.

The prescribing information includes warnings and precautions for immune-mediated Adverse Reactions (ARs), infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.

The recommended dostarlimab dose is 500 mg every 3 weeks until disease progression or unacceptable toxicity, for up to 9 cycles.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (CoE).

Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Health Canada (HC), Israel’s Ministry of Health (IMoH), Switzerland’s Swissmedic (SMC), and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) program, which streamlined data submission prior to the filing of the entire application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 4 months ahead of the FDA goal date.

This application is part of the FDA Commissioner’s National Priority Review Voucher (CNPV) pilot program, which is designed to accelerate the review of products with the potential to address key national priorities.

This application was granted Priority Review (PR).

Dostarlimab received Breakthrough Therapy Designation (BTD). A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.