New lenvatinib and pembrolizumab combination for metastatic renal cell carcinoma in 1^st line drug treatment: comparative effectiveness and safety

Currently, combination immunotarget therapy is the treatment standard for patients with disseminated carcinoma of the renal parenchyma. Simultaneous inhibition of immune checkpoints of programmed cell death 1 (PD-1)/PD-L1 and VEGF/VEGFR signal transduction showed synergistic antitumor effect both in preclinical models and clinical practice.

The article presents the results of phase III CLEAR (NCT02811861) trial.

In the phase III CLEAR (NCT02811861) trial, 1069 patients with renal cell carcinoma with clear-cell component who previously did not receive systemic antitumor therapy were randomized 1:1:1 in groups of lenvatinib (20 mg/day per os) + pembrolizumab (200 mg intravenously once in 21 days), combination lenvatinib (18 mg/day per os) + everolimus (5 mg/day per os), and sunitinib (50 mg/day per os for 4 weeks with 2-week interval). The groups included 355, 357, and 357 patients respectively. Primary endpoint was progression-free survival (PFS) controlled by expertise of an independent central committee per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). Additionally, patient overall survival (OS) and drug therapy tolerability were evaluated.

Median PFS for lenvatinib with pembrolizumab was significantly higher than for sunitinib (23.9 months vs. 9.2 months; progression hazard ratio (HR) 0.39; 95 % confidence interval (CI) 0.32–0.49; p <0.001). Similar advantage in PFS was observed for lenvatinib with everolimus compared to sunitinib (median PFS 14.7 months vs. 9.2 months; HR 0.65; 95 % CI 0.53–0.8; p <0.001). OS also was higher for lenvatinib and pembrolizumab combination compared to sunitinib (death HR 0.66; 95 % CI 0.49–0.88; p = 0.005). No advantages in OS of lenvatinib and everolimus compared to sunitinib were detected (death HR 1.15; 95 % CI 0.88–1.5; p = 0.3). Frequency of grade III and higher adverse events among patients receiving lenvatinib + pembrolizumab, lenvatinib + everolimus, and sunitinib were 82.4, 83.1, and 71.8 %, respectively.

Pembrolizumab + lenvatinib combination showed high effectiveness in 1st line treatment of renal cell carcinoma compared to sunitinib per PFS and OS values.

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