The FDA recently approved two new immunotherapy-chemotherapy options for patients with primary advanced or recurrent endometrial cancer. The first option is the PD-1-directed immune checkpoint inhibitor pembrolizumab (Keytruda), which is approved in combination with carboplatin and paclitaxel for patients with either mismatch repair (MMR)-deficient or MMR-proficient disease. The approval was based on the promising results of the KEYNOTE-868/NRG-GY018 trial. The second option is the PD-L1 inhibitor durvalumab (Imfinzi) in combination with the same chemotherapy regimen for women with MMR-deficient disease only, based on the results of the DUO-E trial. Both phase III trials demonstrated improvements in progression-free survival (PFS) with the addition of immunotherapy.
The KEYNOTE-868/NRG-GY018 trial included two separate cohorts, with patients randomized to standard chemotherapy plus either pembrolizumab or placebo. In the MMR-deficient cohort, the addition of pembrolizumab showed significant improvement in median PFS compared to the placebo group. Similarly, in the MMR-proficient cohort, median PFS was longer with the addition of pembrolizumab. Overall survival (OS) data was not fully mature at the time of analysis, but early results showed a trend favoring the pembrolizumab arms in both cohorts. However, it is important to note that adverse events (AEs) increased with the addition of pembrolizumab, with more grade 3 or higher toxicities observed compared to the placebo group.
The DUO-E trial tested two investigational combinations, with the addition of durvalumab to standard carboplatin-paclitaxel chemotherapy showing improvements in PFS regardless of MMR status. However, the exploratory analysis suggested that the MMR-deficient group benefited the most from the addition of durvalumab. Common adverse events with durvalumab included peripheral neuropathy, musculoskeletal pain, nausea, and rash. Serious AEs occurred in a significant percentage of patients, with rash and constipation being the most common. Overall, AEs leading to discontinuation of durvalumab were observed in 11% of patients in the trial.
The recent FDA approvals of pembrolizumab and durvalumab in combination with chemotherapy represent significant advancements in the treatment of primary advanced or recurrent endometrial cancer. These immunotherapy options provide new hope for patients with both MMR-deficient and MMR-proficient disease, demonstrating improved PFS compared to standard chemotherapy alone. While the addition of immunotherapy has shown promising results, it is crucial to closely monitor and manage the increased risk of adverse events associated with these treatments. Further research and long-term data are needed to fully understand the impact of these new treatment options on overall survival and quality of life for patients with endometrial cancer.
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