GSK's unusual Jemperli expansion plan wins FDA panel backing—with a twist

During a heated discussion around a potential GSK application for Jemperli in a rare cancer type, a panel of the FDA's external advisers largely took the middle ground between the company and the regulatory agency.

In a win for GSK, experts on the FDA’s oncologic advisory committee Thursday voted 8 to 5 that data from single-arm trials would be enough to support a future application of Jemperli in patients with locally advanced rectal cancer that’s mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H).

However, in a unanimous recommendation, the experts said they want more adjustments to GSK’s proposed development plan, including a longer follow-up of the trial, to support an approval.

GSK plans to ask FDA for an accelerated approval of Jemperli as a neoadjuvant treatment for dMMR/MSI-H rectal cancer based on 12-month clinical complete response data from 130 patients across two single-arm trials. The company wants to then use longer follow-up data, and a separate randomized phase 3 study in colon cancer, to support a full approval. GSK aims to make the case that Jemperli could offer a new standard of care with the curative power—but without some of the devastating long-term harms as other treatments.

For its part, the FDA appears averse to the idea of using complete response data from single-arm trials to support an approval in early-stage rectal cancer, where the goal of treatment is to cure the disease. To the FDA, single-arm trials don’t allow sufficient evaluation of benefits and risks because they don’t weigh a treatment versus a comparator.

Typically, the FDA has more confidence in single-arm trials if the disease and existing treatment outcomes are well understood and could serve as external controls. But that is not the case in dMMR early-stage rectal cancer, FDA’s oncology chief Richard Pazdur, M.D., said during the discussion Thursday.

GSK and the experts it invited to the discussion noted that a randomized trial in this setting may simply be infeasible, partly because of the rare nature of dMMR rectal cancer. In 2023, an estimated 46,050 rectal cancer cases across all stages are expected in the U.S., according to an FDA presentation. The estimated prevalence of dMMR cases within rectal cancer ranges between 3% and 20%.

Besides, patients may be unwilling to be randomized to surgery when a nonoperative arm is available, the GSK team argued, especially after the high-profile media reports of Jemperli’s encouraging early results.

The advisory committee mostly agree that a randomized trial may be impractical in this case, but several experts questioned the adequacy of just 12 months of data.

“I don’t think that there’s a clear correlation [...] between complete clinical response and disease-free survival and distant metastasis,” Christopher Lieu, M.D., from the University of Colorado Cancer Center, said. Still, he voted in favor of GSK's plan to use single-arm trials.

In a popular opinion among the panelists, Lieu suggested that data on disease recurrence and patient survival at three years, a secondary endpoint of GSK’s proposed 100-patient trial, are “critically important.”

On using 12 months of complete response data, GSK argued that marker is a good indicator of longer-term outcomes based on existing literature. But the FDA pointed out that information on the connection of tumor clearance at one year and the risk of recurrence is still limited and is based on retrospective analyses, which can be unreliable.

A higher bar

The FDA has used tumor response data from single-arm trials to grant some cancer drugs accelerated approvals. But as FDA's Pazdur noted during the discussion, “the uncertainty is far more acceptable” when dealing with patients who have no other therapies available in late-stage metastatic disease, and the bar for an early-stage disease “has to be higher.”

For Jemperli's potential expansion, GSK mainly built its case around a preliminary analysis of a small group of a patients enrolled in a Memorial Sloan Kettering Cancer Center study. Among 14 patients who completed treatment with Jemperli, all saw no residual disease at an interim analysis. If that kind of deep response lasts, the cancer could be considered cured.  

The problem is, the FDA doesn’t think 12 months is long enough to capture the potential risk of a cancer rebound. In addition, staffers from the agency also questioned whether the results can be generalized to a broader population because Sloan Kettering is one of the best cancer care facilities with experience and resources to manage patients in a nonoperative setting.

As for the phase 3 randomized trial, GSK argues colon and rectal cancers are similar tumor types, including in the dMMR subpopulation. Immune checkpoint inhibitors like Jemperli are already approved in patients with dMMR metastatic colorectal cancer.

Thursday’s advisory committee meeting was quite unusual in that it’s not about an ongoing drug review but about a trial design and regulatory plan to potentially support a future submission.

“The committee’s positive vote in favor of our proposed clinical trial program … reinforces our plans to generate data in support of a future U.S. regulatory submission” in dMMR locally advanced rectal cancer, Hesham Abdullah, GSK's head of oncology development, said in a statement.

Also Thursday, the FDA converted an accelerated approval for Jemperli in recurrent or advanced dMMR endometrial cancer into a full one based on a longer follow-up of the single-arm GARNET trial.