ESMO: AstraZeneca proposes adding Lynparza to Imfinzi as endometrial cancer race heats up

After two immunotherapies demonstrated their power against endometrial cancer, AstraZeneca now suggests that adding Merck-partnered Lynparza to its Imfinzi may offer another option.

The addition of Imfinzi and Lynparza on top of chemotherapy reduced the risk of disease progression or death by 45% in patients with newly diagnosed advanced or recurrent endometrial cancer. Adding just Imfinzi to chemo cut that same risk by 29%.

The results, from the phase 3 DUO-E trial, were presented at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid. They followed positive readouts from two PD-1 inhibitors—GSK’s Jemperli and Merck’s Keytruda—also in first-line endometrial cancer.

The DUO-E study is positive in the overall trial population, meeting its primary endpoint for both the doublet and triplet regimens, Cristian Massacesi, M.D., chief medical officer and oncology chief development officer at AstraZeneca, said in an interview with Fierce Pharma. But some patients appeared to have benefited more than others.

First, PD-1/L1 inhibitors are known to work very well against tumors with genetic abnormalities known as mismatch repair deficiency (dMMR). In these patients, just putting Imfinzi on top of chemo pared down the risk of progression or death by 58%. But the further addition of Lynparza didn’t appear to offer any extra benefit as the triplet reduced the same risk by 59% over chemo alone.

What’s more, the Imfinzi-chemo combo’s 58% progression-free survival (PFS) benefit in the dMMR population was notably smaller than the 70%-plus showing Jemperli and Keytruda have put up with chemo in their separate first-line endometrial cancer trials.

Massacesi acknowledged that the benefit from the addition of Lynparza on the doublet is numerically less in dMMR and that the approach’s real potential was in the MMR-proficient population, where immunotherapies have less power.

In the pMMR subgroup, the Imfinzi-chemo combo reduced the risk of progression or death by 23% compared with chemo alone, whereas the Lynparza-containing triplet improved that to 43%.

The AZ doublet’s risk reduction in the pMMR group was similar to what GSK’s Jemperli showed in the RUBY trial. But the Imfinzi-chemo regimen merely improved the median PFS over chemo alone by 0.2 months. Massacesi argued that the median doesn’t accurately reflect Imfinzi’s benefit, which often happens later in treatment.

Massacesi would not comment on AZ’s regulatory plan nor on whether the British pharma will seek FDA approval for both the doublet and triplet for all patients, dMMR and pMMR alike. Based on the RUBY data, GSK in July won a fast FDA nod for Jemperli in first-line dMMR endometrial cancer while waiting for more mature data to decide on the pMMR population.

By comparison, Keytruda has shown a 46% PFS improvement in the pMMR population in the NRG-GY018 trial, although the number was drawn from a very short follow-up time. Merck has yet to disclose its plan with the FDA regarding a first-line endometrial cancer indication.

The FDA has recently increased its scrutiny around PARP inhibitors like Lynparza. Some clinical data in the late-stage treatment settings have suggested that these drugs might cause long-term harm to patient survival, especially in tumors without homologous recombination repair mutations, despite an initial disease progression benefit.

While the data remained immature, the Imfinzi-chemo arm showed a 23% reduction in the risk of death over chemo, and the Imfinzi-Lynparza-chemo regimen a 41% reduction.

When presenting the DUO-E data at ESMO 2023, investigator Shannon Westin, M.D., from the MD Anderson Cancer Center noted that Asian patients, who make up about a third of the DUO-E population, didn’t seem to have benefited at all from the Imfinzi-chemo doublet. Researchers are still trying to understand the reason, she said. 

Then there’s the question of whether Imfinzi is the best immunotherapy partner for Lynparza in an endometrial cancer population. At least for now, Massacesi said, Imfinzi is the only one that has such data.