ODAC: Single-arm trial data will suffice for dostarlimab in rectal cancer subgroup
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Data from a pair of single-arm clinical trials will be sufficient to illustrate the benefits and risks of dostarlimab-gxly for a subgroup of patients with rectal cancer, according to the FDA’s Oncologic Drugs Advisory Committee.
The panel voted 8-5 that the studies, set to enroll a total of 130 patients, would provide adequate data on use of the anti-PD-1 monoclonal antibody in the curative-intent setting for patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) disease. The data would support a biologics license application submission to the FDA for accelerated approval of dostarlimab-gxly (Jemperli, GlaxoSmithKline) for this indication.
Rationale
About 20,000 individuals in the United States are diagnosed annually with locally advanced rectal cancer, and among them only 5% to 10% have dMMR/MSI-H disease, according to Andrea Cercek, MD, medical oncologist, section head of colorectal cancer and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center. Current standard of care consists of trimodality treatment with neoadjuvant chemotherapy, chemoradiation and surgery, which has been associated with significant toxicities and impaired quality of life.
Dostarlimab has demonstrated efficacy in various dMMR/MSI-H tumors. The agent has received FDA accelerated approval for adults with dMMR solid tumors that progressed on or after previous therapy with no acceptable alternative treatment options. On Thursday, FDA announced that it converted a separate accelerated approval of dostarlimab to regular approval for women with dMMR recurrent or advanced endometrial cancer that progressed on or after a platinum-containing regimen in any setting who are not candidates for curative surgery or radiation.
The proposed clinical development program for dostarlimab in dMMR/MSI-H locally advanced rectal cancer includes a single-arm phase 2 study at Memorial Sloan Kettering Cancer Center that will enroll 30 patients and a single-arm, multi-institution, GSK-initiated phase 2 study that would enroll 100 patients. Clinical complete response rate (cCR) at 12 months has been designated as the primary endpoint of both studies, with overall response rate as a co-primary endpoint of the Memorial Sloan Kettering study and cCR at 36 months and EFS at 3 years per investigator assessment as key secondary endpoints of the GSK-initiated study. Those who achieve a cCR would proceed to nonoperative management.
Data from the ongoing Memorial Sloan Kettering study, presented at last year’s ASCO Annual Meeting in June, showed a cCR of 100% among 14 patients with at least 6 months of follow-up. Updated data through December showed all 18 patients enrolled in the trial at that point achieved and maintained a cCR.
“These unprecedented results and the potential for off-label use resulting from commercial availability of dostarlimab may result in challenges in recruitment and retention in the control arm of a randomized study,” GlaxoSmithKline stated in its sponsor briefing document.
Discussion points
Topics for ODAC discussion included the adequacy of proposed single-arm trials to assess the efficacy and safety of dostarlimab, the adequacy of the proposed clinical endpoints such as cCR and EFS to verify and characterize benefit, the use of a nonoperative management approach for the study population, and the potential impact of variations in care and expertise across study staff and sites on conduct of the studies and outcomes.
Committee member Jorge J. Nieva, MD, associate professor of clinical medicine at Keck School of Medicine of USC, said he would like to see a higher benchmark for cCR than the proposed 35% and “great vigilance to prevent [certain] biases from entering into the clinical trial.” He urged careful analysis of the data.
Some committee members expressed concern about whether cCR at 12 months served as a high enough bar for a clinical endpoint, whereas others supported the endpoint.
“Monitoring that 3-year event-free survival will be very critical, but given the compelling nature of the current data, I think this warrants moving forward,” said committee member George J. Chang, MD, MS, professor and chair ad interim in the department of colon and rectal surgery and Sue and Radcliffe Killam chair and associated vice president of regional surgery strategy at The University of Texas MD Anderson Cancer Center.
“Accelerated approval is for patients, and this feels like a condition and a potentially enormous step up in care for patients that’s worth going with the proposed trial design, not waiting 3 to 5 years,” said committee consumer representative David E. Mitchell, founder of Patients for Affordable Drugs.
References:
- Cercek A, et al. Abstract LBA5. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
- FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer (press release). Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-dostarlimab-gxly-dmmr-endometrial-cancer?utm_medium=email&utm_source=govdelivery. Published Feb. 9, 2023. Accessed Feb. 9, 2023.
- February 9, 2023 meeting of the Oncologic Drugs Advisory Committee (ODAC). Available at: www.youtube.com/watch?v=-iHseGn2LhQ. Accessed Feb. 9, 2023.
- Study design to evaluate dostarlimab in treatment-naive dMMR/MSI-H locally advanced rectal cancer. Sponsor briefing document. Available at: www.fda.gov/media/165221/download. Accessed Feb. 9, 2023.
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