#VisualAbstract: Lenvatinib plus pembrolizumab improves overall survival and progression free survival for advanced renal cell carcinoma treatment

1. Lenvatinib plus pembrolizumab was superior to sunitinib in overall survival for patients with advanced renal cell carcinoma.

2. Lenvatinib plus pembrolizumab demonstrated longer progression-free survival compared to sunitinib.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The standard treatment of advanced renal cell carcinoma (RCC) has been antagonism of vascular endothelial growth factor (VEGF) with tyrosine kinase inhibitors such as sunitinib. Lenvatinib, an antiangiogenic agent, and pembrolizumab, an anti-programmed cell death 1 monoclonal antibody, have been explored in previous studies as monotherapies for RCC. As such, this study reported the efficacy and safety of lenvatinib plus pembrolizumab treatment compared to sunitinib in patients with advanced RCC. The study determined pembrolizumab plus lenvatinib treated patients had superior progression-free survival and overall survival compared to sunitinib. The most common adverse event was diarrhea, which was greater in the combination therapy group. There was more drug discontinuation in the lenvatinib and pembrolizumab group compared to the lenvatinib and everolimus group or the sunitinib group. One limitation is that patients and investigators were aware of the treatment assignments. Overall, this trial demonstrated that lenvatinib and immune-checkpoint inhibition with pembrolizumab showed superior survival compared to sunitinib alone.

Click here to read the study in the NEJM

Relevant Reading: Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma

In-Depth [randomized controlled trial]: This was a multicenter, randomized, open-label trial of 1,069 patients from 200 sites in 20 countries. Patients 18 years of age or older with advanced renal carcinoma, and no prior systemic therapy were included in the study. Patients were excluded from the study if there was not adequate blood pressures control or organ function. Patients were randomized in a 1:1:1 ratio into lenvatinib and pembrolizumab, lenvatinib and everolimus, or sunitinib, respectively. Everolimus and lenvatinib treatment (median, 14.7 months) had significantly longer progression-free survival compared to sunitinib (median, 9.2 months) (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.53 to 0.80; P < 0.001). However, the overall survival between both groups was not significant (HR, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Pembrolizumab and lenvatinib was superior in both progression-free survival (treatment median, 23.9 months; control median, 9.2 months; HR, 0.39; 95% CI, 0.32 to 0.49; P < 0.001) and overall survival (HR, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) when compared to sunitinib. Grade 3 or higher adverse events was observed in 82.4% of the lenvatinib plus pembrolizumab group, 83.1% of the lenvatinib plus everolimus group, and 71.8% of the patients who received sunitinib. In general, this trial demonstrated the use of an immune checkpoint inhibitor is an important treatment component for advanced RCC in combination with standard VEGF inhibition.

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