FDA Has Concerns on 'Unprecedented' Plan for Dostarlimab in Rectal Cancer

The FDA's Oncologic Drugs Advisory Committee (ODAC) will meet Thursday and vote on whether the clinical development plans for dostarlimab (Jemperli) are sufficient to support accelerated approval of the drug for the treatment of patients with treatment-naive mismatch repair-deficient/microsatellite instability-high locally advanced rectal cancer.

In a briefing document issued in advance of the meeting, FDA reviewers expressed concerns about these plans.

GlaxoSmithKline (GSK), the maker of dostarlimab, is proposing to evaluate the PD-1-blocking IgG4 humanized monoclonal antibody in two single-arm trials -- the ongoing single-center trial by investigators at Memorial Sloan Kettering Cancer Center (MSKCC) that will enroll a total of 30 patients, and a proposed multicenter trial that will enroll 100 patients.

In both trials, patients will receive dostarlimab 500 mg intravenously every 3 weeks for 9 cycles, with a primary endpoint of clinical complete response rate at 12 months (cCR12).

Results from the MSKCC study's first 14 patients -- presented last year at the American Society of Clinical Oncology annual meeting and published in the New England Journal of Medicine -- showed that at a median follow-up of 6.8 months, all 14 patients had a clinical complete response with dostarlimab monotherapy.

Since then, four of the 14 patients have completed 12 months of follow-up and remain in clinical complete response, "thus achieving cCR12," GSK reported.

These results led to a proposed second study -- an open-label, global, multi-site, single-arm, phase II study designed to further investigate the efficacy and safety of dostarlimab monotherapy, which will also evaluate two key secondary endpoints: clinical complete response rate at 36 months and investigator-assessed event-free survival at 3 years.

According to the briefing document submitted by GSK, this study "will be single-arm due to the impracticality of conducting a randomized controlled study given likely recruitment and retention issues resulting from the publishing and wide dissemination of the MSKCC study's unprecedented results and the potential for off-label use resulting from commercial availability of the product, in addition to the rare patient population."

The primary endpoint of cCR12 is "reasonably likely to predict survival benefit in this patient population," the company noted.

Standard treatment of locally advanced rectal cancer consists of multimodality therapy that combines fluoropyrimidine-based chemotherapy, chemoradiotherapy or other short-course radiotherapy, and surgery. According to the FDA reviewers, "although administered with curative intent, this treatment is associated with both short- and long-term toxicities that adversely impact quality of life, leading to the growing interest in non-operative management of this disease."

Among the questions ODAC panelists will address Thursday are those related to the appropriateness of single-arm trials to evaluate the efficacy and safety of dostarlimab, as well as the adequacy of the endpoints to verify the benefit of the drug, and support its approval.

In the FDA briefing document, reviewers pointed out that the agency generally requires randomized trials to determine a drug's efficacy and safety in a curative setting.

While GSK said a randomized trial is not feasible, FDA reviewers suggested that the benefits and risks of dostarlimab "may not be fully evaluable in comparison to available curative treatment with the proposed study designs."

As for the proposed clinical endpoints, reviewers said that using clinical complete response as the major efficacy endpoint to support approval in oncology is "unprecedented."

They noted that evidence-based guidelines on the use of clinical complete response as an endpoint in clinical practice or in clinical trials are lacking, and that the use of this endpoint in locally advanced rectal cancer clinical decision making is based on small, mostly retrospective, uncontrolled studies that vary in design and other important factors, and limit the interpretability of findings.

'These challenges introduce uncertainty with respect to the magnitude, durability, and method of assessment of [clinical complete response], to predict clinical benefit," they wrote, adding that it is also unclear whether this endpoint reported in the MSKCC study will be replicable across other sites and, if not, "what magnitude of [clinical complete response] rate would provide a favorable benefit/risk assessment in the context of available curative-intent treatment, the known toxicities of dostarlimab, and an unclear rate of relapse."

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