Merely a month into an FDA approval for a broad first-line endometrial cancer population, Merck’s Keytruda has some company.
On Thursday, the FDA expanded the endometrial cancer use for GSK’s Jemperli, used in combination with chemotherapy, to include patients with mismatch repair proficient (pMMR) or microsatellite-stable (MSS) tumors.
The new go-ahead rounds out the PD-1 inhibitor’s first-in-class nod a year ago, which was limited to a relatively small subgroup of patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MIS-H) tumors. It also leveled the playing field for Jemperli in endometrial cancer against Keytruda, which in July earned a broad label regardless of the patient’s biomarker status.
GSK sought the original nod quickly to make sure that it “moved with pace” in a competitive checkpoint inhibitor market, GSK’s head of oncology R&D, Hesham Abdullah, M.D., said in an interview with Fierce Pharma ahead of Thursday’s FDA decision.
When competing with the omnipresent Keytruda, being first in an indication comes with a valuable edge. But the question is whether Jemperli has fully capitalized on that one-year head start and can maintain its momentum against the PD-1 leader. To Abdullah, there’s one more card Jemperli can play.
“One of the things that we really wanted to do was make sure that we characterized the effect that [Jemperli], in combination with chemotherapy, was having on overall survival,” Abdullah said.
PD-1 inhibitors are known to work well in dMMR tumors. In first-line endometrial cancer, both Jemperli and Keytruda have produced exceptional tumor progression-free survival benefits against chemo alone in the 70% range in dMMR patients in separate phase 3 trials.
But by the time GSK sought the original nod, Jemperli’s use alongside chemo only led to a mild 24% reduction in the risk of progression or death versus chemo alone. By comparison, Keytruda got its broad label with a 40% progression-free survival showing in the pMMR group. More than 70% of endometrial cancers are pMMR.
This time around, GSK armed Jemperli with data showing it could extend patients’ lives. Jemperli and chemo significantly cut the risk of death by 31% compared with chemo in part 1 of the phase 3 RUBY trial regardless of the patient’s biomarker status. In the pMMR subgroup specifically, the death risk reduction was 21% in favor of the combo, although the number doesn’t bear statistical significance.
In contrast, Keytruda can’t claim an overall survival benefit yet. During an interim analysis of Keytruda’s phase 3 NRG-GY018 trial, only 12% deaths had happened in the dMMR cohort and 17% in the pMMR group.
Abdullah argued that overall survival, as the gold standard for measuring oncology drug efficacy and safety, is important and gives Jemperli, a relatively newer product, additional credence. He also pointed to diverging results among PD-1 inhibitors in past clinical trials in other tumor types to show that one PD-1 inhibitor’s success is not necessarily a guarantee for another’s. But how that advantage can translate into uptake remains to be seen given doctors’ overall familiarity with Keytruda.
During GSK’s first-quarter earnings call in May, Chief Commercial Officer Luke Miels acknowledged Keytruda’s leading position and as an “easier choice” in the PD-1 class. But he said GSK was seeing “quite a striking shift in terms of physicians’ assessment of Jemperli and willingness to try it.” He also pointed to potential guideline changes as another driver of growth given the weight of overall survival in those assessments.
In the first quarter, Jemperli’s new patient share in first-line dMMR endometrial cancer nearly doubled to 33% compared with the end of 2023.
There’s potential for GSK to further enhance Jemperli with the addition of the PARP inhibitor Zejula, especially in the pMMR population. That idea is being tested in part 2 of the RUBY trial, and it has shown stronger progression-free survival results in pMMR patients compared with Jemperli. GSK is still following that arm for long-term overall survival results. PAPR inhibitors have previously been linked to potential detriments to certain ovarian cancer patients over the long term.
Keytruda’s NRG-GY018 trial doesn’t have a separate PARP arm. But Merck’s partner AstraZeneca is exploring the same idea for its PD-L1 inhibitor Imfinzi and the PARP drug Lynparza in the phase 3 DUO-E trial. Last month, Imfinzi and chemo—without Lynparza—also received a dMMR-only nod from the FDA based on that study.
For Jemperli overall, GSK expects its PD-1 latecomer could reach more than £2 billion peak sales. The British pharma is exploring various combinations, including with TIGIT and its newly licensed B7-H3 and B7-H4 antibody-drug conjugates. Among them, Abdullah noted the B7-H4 candidate holds promise in endometrial and ovarian cancers.