Lenvatinib plus pembrolizumab increased survival for advanced endometrial cancer patients when compared to chemotherapy

1. The median progression-free survival and overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy.

2. Clinically important adverse events in the combination group included hypertension, thyroid dysfunction, colitis and diarrhea

Evidence Rating Level: 1 (Excellent)

Study Rundown: Advanced endometrial cancer after platinum treatment remains difficult to treat and fiver-year survival remains poor. This study explored lenvatinib (a vascular endothelial growth factor receptors tyrosine kinase inhibitor) plus pembrolizumab (programmed cell death 1 inhibitor) as a therapy regimen for patients with advanced endometrial cancer who had progressed on platinum-based chemotherapy regimen. These patients were randomly assigned to either lenvatinib plus pembrolizumab or chemotherapy of the treating physician’s choice (either doxorubicin or paclitaxel). The two primary endpoints were progression-free survival and overall survival. Efficacy was also compared based on mismatch repair status (mismatch repair-proficient (pMMR) vs. mismatch repair-deficient (dMMR). The median progression-free survival and overall survival were significantly longer with lenvatinib plus pembrolizumab than with chemotherapy. Superiority was preserved across pMMR and dMMR subgroups. Adverse events of grade 3 or higher occurred similarly between both groups but with different side effect profiles. In the combination group, hypertension, urinary tract infections and diarrhea were commonly observed. At 12 weeks, the quality-of-life scores were not substantially different. Limitations to this study included variability in each physician’s choice of chemotherapy and a short follow-up period. The strength of this study was that it had limited bias and showed a strong signal of improved survival in the combination group. Overall, the study demonstrated that lenvatinib plus pembrolizumab when compared to later lines of chemotherapy is a viable treatment option.

Click to read the study in NEJM

Relevant Reading: Treatment for advanced and recurrent endometrial carcinoma: combined modalities

In-Depth [randomized control trial]: This phase III international randomized control trial included 827 patients with advanced endometrial cancer who previously progressed on platinum-based chemotherapy regimen; 697 patients had pMMR disease and 130 had dMMR disease. These patients were randomly assigned in a 1:1 ratio to receive lenvatinib plus pembrolizumab or chemotherapy of the treating physician’s choice (either doxorubicin or paclitaxel). The median progression-free survival for patients receiving lenvatinib plus pembrolizumab was 7.2 months and was 3.8 months for the chemotherapy group (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.47 to 0.66; P<0.001). The median overall survival for patients receiving lenvatinib plus pembrolizumab was 18.3 months and was 11.4 months for the chemotherapy group (HR 0.62; 95% CI, 0.51 to 0.75; P<0.001). Superiority was maintained across pMMR and dMMR subgroups. Adverse events of grade 3 or higher occurred in 88.9% of patients in the lenvatinib plus pembrolizumab treatment group and 72.7% in the chemotherapy treatment group. Common adverse events in the combination group include hypertension, urinary tract infections and diarrhea. Immune-related adverse events most commonly included thyroid dysfunction, colitis and dermatological reactions. Overall, lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival for patients with advanced endometrial cancer compared to chemotherapy.

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