Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomized, phase 3 study

Introduction. Results from the phase III CLEAR trial showed that the combination of lenvatinib and pembrolizumab increased progression-free survival and overall survival compared with sunitinib alone in patients with advanced renal cell carcinoma. The purpose of the study is to evaluate indicators of health-related quality-of-life (HRQOL) according to the CLEAR study. Materials and methods. An open randomized phase III clinical trial was conducted on the basis of 200 medical institutions and cancer centers in 20 countries around the world. Inclusion criteria for patients: age over 18 years, advanced clear cell renal cell carcinoma, general somatic status on the Karnofsky scale of 70% or higher. Patients who had previously received antitumor drug therapy for renal cell carcinoma were not included in the study. All patients were randomized (1:1:1) into 3 groups: combination of lenvatinib (20 mg/day, orally) with pembrolizumab (200 mg, intravenously, every 21 days), combination of lenvatinib (18 mg/day, orally) with everolimus (5 mg/day, orally) 21-day cycle and sunitinib monotherapy (50 mg/day, orally, 4/2 regimen: 28 days of treatment followed by a break of 14 days, 42-day treatment cycle). Patients were assigned to treatment groups using a computerized randomization scheme and stratified by geographic region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint of the study was progression-free survival and the secondary endpoint was HRQOL score. HRQOL was assessed in randomized patients who received at least 1 dose of study drug and completed HRQOL data. Analysis of completion and compliance rates (compliance) was performed with the full set of study instruments. Questionnaire using the Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) index of symptoms of kidney cancer therapy and symptoms associated with the disease, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the European Foundation for Research on Quality of Life Questionnaire (EQ-5D-3L) were performed at baseline and on day 1 of each subsequent 21-day treatment cycle. This study is registered with ClinicalTrials.gov, NCT02811861 and is currently closed to new participants. Results.Between October 13, 2016 and July 24, 2019, 355 patients were randomized to lenvatinib plus pembrolizumab, 357 to lenvatinib plus everolimus, and 357 to sunitinib monotherapy. The median follow-up time for HRQOL analysis was 12.9 months (interquartile range 5.6-22.3 months). Due to the proven high efficacy and safety profile of the combination of lenvatinib and pembrolizumab in the 1st line antitumor treatment of advanced renal cell carcinoma, the main part of the present analysis of the HRQOL assessment is devoted to the comparative study of this combination and sunitinib monotherapy. The mean change from baseline in HRQOL in the lenvatinib plus pembrolizumab group compared to the sunitinib monotherapy group was -1.75 (standard error (SD) 0, 59) vs -2.19 (SD 0.66) on the FKSI-DRS questionnaire, -5.93 (SD 0.86) vs -6.73 (SD 0.94) on the EORTC QLQ-C30 GHS/QOL questionnaire (general health/quality of life scale) and -4.96 (SD 0.85) versus -6.64 (SD 0.94) on the EQ-5D-3L visual analog scale. The median time to first deterioration in HRQOL in the lenvatinib plus pembrolizumab group compared to the sunitinib monotherapy group was 9.14 weeks (95% confidence interval (CI) 6.43-12.14) versus 12.14 weeks (95% CI 9. 14-15.29, hazard ratio (RR) 1.13 (95% CI 0.94-1. 35), log-rank p =0.20, FKSI-DRS, 12.00 weeks (95% CI 7.29-15.14) vs. 9.14 weeks (95% CI 6.29-12.14; RR 0.88 (95% CI 0.74-1.05); log-rank p =0.17) on the EORTC QLQ-C30 GHS/QOL questionnaire and 9.43 weeks (95% CI 6.43-12.29) vs. 9.14 weeks (95% CI 6.29-12.00) RR 0.83 (95% CI 0.70-0.99), log-rank p -0, 041) on the EQ-5D-3L visual analog scale. The median time to definitive deterioration in HRQOL in the lenvatinib plus pembrolizumab combination group compared to the sunitinib monotherapy group was 134.14 weeks (95% CI 120.00-failed) versus 117.43 weeks (95% CI 90.14-131.29 ; RR 0.70 (95% CI 0.53-0.92); log-rank p =0.0081) according to the FKSI-DRS questionnaire, 114.29 weeks (95% CI 102.14-153.29) vs. 75.14 weeks (95% CI 57.29-105.14; RR 0.60 (95% CI 0.47-0.77); log-rank p<0.0001) on the EORTC QLQ-C30 GHS/QOL and 124.86 weeks (95% CI 94.71-134.57) vs. 74.86 weeks (95% CI 54.14-96.00; RR 0.67 (95% CI 0.53-0.85); log-rank p =0.0012) according to the visual analogue scale EQ-5D-3L. None of the HRQOL assessment tools showed a significant benefit of sunitinib over the combination of lenvatinib and pembrolizumab. Conclusion. The results of the analysis of the HRQOL score showed that patients treated with the combination of lenvatinib and pembrolizumab have similar or more favorable measures of health-related quality of life compared to patients receiving sunitinib monotherapy, especially with respect to time to final worsening. The results of this study confirm the efficacy and safety of the combination of lenvatinib and pembrolizumab as a first-line anticancer therapy in patients with advanced renal cell carcinoma.