Despite high-profile media coverage, FDA balks at GSK's 'unprecedented' Jemperli proposal in rectal cancer

An early-stage clinical trial of GSK’s Jemperli in rectal cancer recently attracted strong interest among media outlets aimed at the general public, including The New York Times. But the FDA isn’t convinced.

Highlighting two “unprecedented” elements, the FDA questioned whether it’s appropriate for GSK to use tumor complete response data from single-arm trials to support an approval in locally advanced rectal cancer, a setting where curing the disease is the goal. The agency raised the concerns in a briefing document prepared for a Thursday meeting of external oncology experts.

GSK plans to ask the FDA to grant Jemperli an accelerated approval for use before any treatment in early-stage rectal cancer found to have the mismatch repair deficient (dMMR) biomarker. The PD-1 inhibitor is currently approved for advanced or recurrent dMMR solid tumors, following prior treatments or in patients who have no alternative options.

Generally speaking, the agency is more open to using early tumor response signs to grant approvals in late-line cancer settings where patients have exhausted other therapies. But in early-stage cancer, where patients may be cured with existing therapies, the FDA can be demanding and typically asks for more mature patient survival data to support a drug’s application.

GSK currently has data from a very small clinical trial conducted by the Memorial Sloan Kettering Cancer Center. All patients who received the GSK drug before surgery had no evidence of any residual disease at an interim analysis of the study, according to data presented at the 2022 annual meeting of the American Society of Clinical Oncology. The data, while impressive, came from just 14 patients, and half of them were followed for less than a year. The trial intends to enroll 30 patients altogether in this cohort.

To support a future application, GSK also proposes a similar but larger—yet still single-arm—global phase 2 trial of 100 patients with dMMR locally advanced rectal cancer. The British pharma plans to use 12-month complete response rates from both trials to seek an accelerated approval, according to a briefing document from GSK.

Indications doled out under the accelerated approval pathway are required to provide further evidence to confirm the drug’s clinical benefit, and the FDA’s oncology department has recently made clear that it wants a confirmatory trial to be underway at the time of the review of an accelerated approval.

For GSK, the company plans to include longer follow-up of patients in the Memorial Sloan Kettering and GSK studies for the confirmatory package. In addition, “to augment our knowledge,” GSK said it will also start a randomized, global phase 3 trial to compare Jemperli with standard chemotherapy in colon cancer (not rectal cancer).

The FDA is now asking its oncologic advisory committee to discuss whether complete response data from single-arm trials would be adequate to support a future application.

For its part, GSK argues that 12-month complete response data are “reasonability likely to predict clinical benefit based on the published literature in the chemotherapy and immuno-oncology settings” and therefore could back an accelerated approval.

The agency also has questions about the study population, arguing whether more representation of a high-risk subgroup may be needed. Besides, GSK proposed the phase 3 trial as “supportive evidence,” and the FDA is wondering exactly what role those data should play in the confirmatory package.

The current standard of care for locally advanced rectal cancer involves chemotherapy, chemoradiotherapy and surgery. While the regimen may cure the disease, it’s linked to various toxicities. GSK hopes Jemperli could provide a nonoperative alternative that comes with the curative power but without the harmful side effects.