GSK's Jemperli prolongs life in endometrial cancer trial. Will FDA label expansion come next?

After a quick FDA approval in a subgroup of endometrial cancer patients, GSK is trumpeting a win for its Jemperli that might help the PD-1 inhibitor expand to a broader population.

Adding Jemperli to chemotherapy significantly extended the life spans of patients with primary advanced or first recurrent endometrial cancer in the phase 3 RUBY trial, GSK said Monday.

Jemperli’s improvement on overall survival was “statistically significant and clinically meaningful,” Hesham Abdullah, M.D., GSK’s head of oncology clinical development, told Fierce Pharma. As Abdullah noted, this marks the first time that a PD-1/L1 inhibitor has demonstrated an overall survival benefit in first-line endometrial cancer.

Overall survival is one co-primary endpoint of the RUBY trial. Previously, at an interim analysis, the combination of Jemperli and chemotherapy showed it could significantly reduce the risk of tumor progression or death over chemo alone. At that time, the GSK combo showed a trend toward 36% improvement on overall survival, which didn’t reach statistical significance.

After that, GSK in July won FDA approval for Jemperli, used alongside chemo, as a first-line therapy for a subgroup of endometrial cancer patients whose tumors are mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H).

For that filing, GSK said it targeted an indication where Jemperli demonstrated the strongest treatment effect to enable an accelerated submission.

Now that the trial has met its overall survival (OS) goal in the entire trial population, Abdullah said Jemperli’s benefit was “clinically meaningful” in both the dMMR/MSI-H and MMR-proficient (pMMR)/microsatellite-stable subgroups.

The exact OS data in the pMMR population will be crucial for GSK’s bid to potentially get Jemperli a wider first-line endometrial cancer approval. During the previous interim analysis, Jemperli showed a preliminary 27% death risk reduction in pMMR patients.

Abdullah declined to offer any further characterization of the new OS data but said that GSK is “extremely excited.” The British pharma plans to share the full results at an upcoming medical meeting and with the FDA, he said.

The Jemperli-chemo regimen is only one of the experimental arms in RUBY. The trial is also testing adding the PARP inhibitor Zejula to Jemperli during the maintenance phase of treatment, and that readout is expected in the first half of 2024, Abdullah said.

GSK faces potential competition from fellow PD-1/L1 developers on both the chemo combo and the PARP triplet regimen.

Around the same time of GSK’s prior progression-free survival readout, Merck’s PD-1 king Keytruda posted a similar win alongside chemo in first-line endometrial cancer in the phase 3 NRG-GY018 trial. What’s more, by cross-trial comparison, Keytruda’s performance appeared better than Jemperli’s in the pMMR population, albeit from a much shorter follow-up time.

At the recent European Society for Medical Oncology annual meeting, AstraZeneca also shared detailed results for its PD-L1 inhibitor Imfinzi and chemotherapy with or without the PARP inhibitor Lynparza in first-line endometrial cancer. In that trial, coded DUO-E, Lynparza appeared to offer the most benefit when added in the pMMR population, while the PARP drug didn’t seem to improve tumor progression in the dMMR subgroup.

Besides the OS and disease progression data, biomarker-defined subgroup analysis and tolerability profiles will be important when evaluating the different regimens, Abdullah said.

By GSK’s estimate, about 14,300 patients in the U.S. and 9,100 in the largest European countries will be diagnosed with first-line advanced or recurrent endometrial cancer in 2023, making them eligible for systemic therapies. It’s also estimated that about two-thirds of endometrial cancer cases are pMMR.