After a quick FDA approval in a subset of endometrial cancer, GSK is back with more data for two Jemperli regimens in hopes of reaching a broader patient population. And AstraZeneca, utilizing a similar immunotherapy strategy, has also come up with a rivaling update as it awaits an FDA decision.
For GSK, Jemperli plus chemotherapy showed a “clinically meaningful trend” in reducing the risk of death by 21% among patients with advanced endometrial cancer that’s mismatch repair proficient (pMMR) or microsatellite stable (MSS). Patients on the Jemperli regimen lived a median 34 months, compared with 27 months for those on chemo alone.
The data, from an exploratory analysis of the first part of the phase 3 RUBY trial, were shared at the Society of Gynecologic Oncology (SGO) annual meeting. They come as part of a statistically significant overall survival win for the Jemperli-chemo combo in the overall trial group as it cut the risk of death by 31% in a broader endometrial cancer population that also includes patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors.
With the updated analysis from RUBY Part 1, GSK said it expects the FDA will accept its submission to expand the PD-1 inhibitor Jemperli to the overall front-line endometrial cancer population in the first half of this year. The Jemperli-chemo combo was already greenlighted in July just for dMMR/MSI-H patients, who account for about 15% to 20% of new advanced endometrial cancer diagnoses in the U.S.
Simultaneously, Part 2 of the RUBY trial found that a cocktail of Jemperli, chemo and GSK’s PARP inhibitor Zejula reduced the risk of progression or death by 37% in pMMR/MSS patients, according to data shared at SGO 2024. For the overall population, which also includes dMMR/MSI-H patients, the risk reduction was 40%.
The Part 2 findings are particularly meaningful for patients with pMMR/MSS tumors as they further improved on the benefit observed for the Jemperli-chemo regimen in Part 1, Mansoor Raza Mirza, M.D., from the Copenhagen University Hospital and RUBY principal investigator, said in a statement Saturday. Previously, Jemperli and chemo cut the risk of progression or death by 24% versus chemo in the pMMR subgroup.
However, the Part 2 data also raised the question of whether the further addition of Zejula is necessary for dMMR/MSI-H patients. Among that subset of patients, the Zejula-Jemperli-chemo combo showed a 52% advantage in progression-free survival over chemo alone, which was even smaller than the impressive 72% risk reduction Jemperli-chemo had posted without the PARP drug.
Zejula appears to have brought extra toxicity. In Part 1, grade 3 or higher treatment-emergent adverse events were about 12% higher for Jemperli and chemo compared with control. In Part 2, the Zejula-containing regimen tripled that difference to about 36%.
The potential longer-term detriment from PARP inhibitors have lately drawn attention at the FDA, leading to market withdrawal, restricted new approval or delayed application.
A GSK spokesperson said the company was unable to provide additional details about its regulatory plans at this time.
Meanwhile, AstraZeneca could face the same question of patient selection for its PD-L1 inhibitor Imfinzi and Merck-shared PARP drug Lynparza in first-line endometrial cancer.
In an interim analysis of AZ’s phase 3 DUO-E trial shared at SGO 2024, a combination of Imfinzi, Lynparza and chemo cut the risk of death in dMMR/MSI-H endometrial cancer patients by 72% over chemo, a slight improvement from the 66% posted by the Imfinzi-chemo pairing. None of these numbers were mature or statistically significant. Previously, the trial found that the Lynparza-containing regimen reduced the risk of progression or death by 59% over chemo alone, whereas Imfinzi and chemo could already cut that risk by 58%, according to results announced in October.
In the overall trial population that also includes pMMR patients, the Imfinzi-chemo pairing so far cut the risk of death by 23%, whereas the Lynparza-containing regimen delivered a 41% showing. Again, the data were immature as only 28% of deaths had happened across the three trial arms before a final overall survival analysis.
The overall survival data are promising at this early stage of maturity, Andrea Mugan, AstraZeneca’s global franchise head of gynecological and genitourinary cancers, said in an interview with Fierce Pharma.
As PARP inhibitor’s contribution in dMMR tumors comes into question, AZ also faces the question of whether Imfinzi could handle pMMR disease without Lynparza.
During the current interim analysis, Imfinzi plus chemo only pared down the risk of death by 9% in pMMR patients, while adding Lynparza widened that to 31%. Imfinzi-chemo showed a progression-free survival benefit of 23% in this subgroup, versus 43% for the Lynparza regimen, according to data first released in October.
“We do believe in the data we’re showing for the benefit of both regimens in the first-line endometrial cancer population,” Mugan said. But she acknowledged that Imfinzi showed the biggest benefit in the dMMR population, and that the “incremental benefit” for Lynparza was more pronounced in the pMMR subgroup.
AZ’s filings for DUO-E have been accepted by the FDA, the European Medicines Agency and regulators in Japan, the company said. It’s not clear whether AZ is gunning for approvals for both regimens for both dMMR and pMMR cancers.