Merck's Keytruda Gains 40th US Approval, Surpasses GSK with Endometrial Cancer Indication

Merck & Co.'s blockbuster drug Keytruda has achieved another milestone with its latest FDA approval for treating first-line endometrial cancer, marking its 40th indication in the United States. Keytruda, already the world's best-selling medicine, will now be used in combination with chemotherapy and subsequently as a monotherapy in patients with primary advanced or recurrent endometrial cancer. This approval, announced on Monday, sets a precedent in the cancer immunotherapy arena.

This new approval allows Keytruda to surpass GSK's rival PD-1 inhibitor Jemperli, which had received FDA approval for first-line endometrial cancer in July 2023. However, Keytruda sets itself apart by covering tumors irrespective of their mismatch repair status, a genomic biomarker. Currently, Jemperli's approval is restricted to a smaller group of patients with mismatch repair-deficient (dMMR) cancer.

Keytruda's latest FDA approval was primarily based on the successful results from the phase 3 NRG-GY018 trial, also known as Keynote-868. In this trial, the combination of Keytruda and chemotherapy reduced the risk of disease progression or death by 70% in dMMR patients and by 40% in patients with mismatch repair proficient (pMMR) tumors, compared to chemotherapy alone. When the study results were first published last year, the data showed slight variations.

For patients in the dMMR cohort, those in the control group experienced a median progression-free survival of 6.5 months, while the median was not reached for those treated with Keytruda. Among the pMMR group, the median progression-free survival was 8.5 months for the control arm and 11.1 months for the Keytruda arm. At the time of interim analysis, overall survival data were still immature, with 12% deaths in the dMMR cohort and 17% in the pMMR cohort. Although the precise overall survival data are not yet clear, the FDA's approval likely reflects no evident harm to patients' life expectancy.

Despite Keytruda's pioneering achievement in addressing a broad first-line endometrial cancer population, Jemperli's expansion beyond the dMMR subgroup might be imminent. GSK's application to broaden Jemperli's approval to include pMMR patients has been accepted by the FDA under priority review, with a target decision date of August 23 this year. In the phase 3 RUBY trial, the combination of Jemperli and chemotherapy significantly reduced the risk of death by 31% in endometrial cancer patients, regardless of their tumor's mismatch repair status. This made Jemperli the first PD-1/L1 inhibitor to achieve a statistically significant overall survival benefit in first-line endometrial cancer in a general population.

In the pMMR subgroup specifically, the Jemperli-chemo combination exhibited a "clinically meaningful trend" by reducing the risk of death by 21% compared to chemotherapy alone, according to data released in March.

On the same day as Keytruda's latest approval, AstraZeneca announced that its PD-L1 inhibitor Imfinzi also received FDA approval for first-line dMMR endometrial cancer when used in combination with chemotherapy. An AstraZeneca spokesperson confirmed that the company would continue evaluating overall survival data to potentially extend Imfinzi's reach to more patients.

Additionally, both GSK and AstraZeneca are exploring the integration of a PARP inhibitor with their respective immunotherapies, showing promising results so far. However, neither company has yet made regulatory strides with these PARP-containing combinations.