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

Background: Results from the phase 3 CLEAR study showed that lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell carcinoma. We aimed to assess the health-related quality-of-life (HRQOL) outcomes from the CLEAR study.
Methods: This open-label, randomised, phase 3 study was done across 200 hospitals and cancer centres in 20 countries. Patients were required to be 18 years or older, with advanced clear-cell renal cell carcinoma, and a Karnofsky performance status of 70% or higher. Patients who had received previous systemic anticancer therapy for renal cell carcinoma were not eligible. Patients were randomly assigned (1:1:1) to lenvatinib (oral 20 mg per day) plus pembrolizumab (intravenous 200 mg every 21 days), lenvatinib (oral 18 mg per day) plus everolimus (oral 5 mg per day) in 21-day cycles, or sunitinib (oral 50 mg per day, 4 weeks on followed by 2 weeks off). Patients were assigned to treatments with a computer-generated randomisation scheme and were stratified by geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint, previously reported, was progression-free survival, and HRQOL was a secondary endpoint. Most HRQOL analyses were done in patients who underwent randomisation, received at least one dose of study treatment, and had any HRQOL data. Completion and compliance analyses were done in the full analysis set. Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the EQ-5D-3 Level (EQ-5D-3L) preference questionnaire were administered at baseline and on day 1 of each subsequent 21-day cycle. This study is registered with ClinicalTrials.gov, NCT02811861, and is closed to new participants.
Findings: Between Oct 13, 2016, and July 24, 2019, 355 patients were randomly assigned to the lenvatinib plus pembrolizumab group, 357 to the lenvatinib plus everolimus group, and 357 to the sunitinib group. Median follow-up for HRQOL analyses was 12·9 months (IQR 5·6-22·3). Because of the promising efficacy and safety results of lenvatinib plus pembrolizumab in the first-line setting, we focus the HRQOL results in this report on that combination versus sunitinib. Mean change from baseline in the lenvatinib plus pembrolizumab group compared with the sunitinib group was -1·75 (SE 0·59) versus -2·19 (0·66) for FKSI-DRS, -5·93 (0·86) versus -6·73 (0·94) for EORTC QLQ-C30 global health status/quality of life (GHS/QOL), and -4·96 (0·85) versus -6·64 (0·94) for the EQ-5D visual analogue scale (VAS). Median time to first deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 9·14 weeks (95% CI 6·43-12·14) versus 12·14 weeks (9·14-15·29; HR 1·13 [95% CI 0·94-1·35], log-rank p=0·20) for FKSI-DRS, 12·00 weeks (7·29-15·14) versus 9·14 weeks (6·29-12·14; 0·88 [0·74-1·05], log-rank p=0·17) for EORTC QLQ-C30 GHS/QOL, and 9·43 weeks (6·43-12·29) versus 9·14 weeks (6·29-12·00; 0·83 [0·70-0·99], log-rank p=0·041) for the EQ-5D VAS. Median time to definitive deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 134·14 weeks (95% CI 120·00-not estimable) versus 117·43 weeks (90·14-131·29; HR 0·70 [95% CI 0·53-0·92], log-rank p=0·0081) for FKSI-DRS, 114·29 weeks (102·14-153·29) versus 75·14 weeks (57·29-105·14; 0·60 [0·47-0·77], log-rank p<0·0001) for EORTC QLQ-C30 GHS/QOL, and 124·86 weeks (94·71-134·57) versus 74·86 weeks (54·14-96·00; 0·67 [0·53-0·85], log-rank p=0·0012) for the EQ-5D VAS. No outcomes on any of the instruments significantly favoured sunitinib over lenvatinib plus pembrolizumab. Most HRQOL comparisons of lenvatinib plus everolimus versus sunitinib were similar or favoured sunitinib.
Interpretation: These HRQOL results demonstrate that patients given lenvatinib plus pembrolizumab treatment had similar or favourable scores compared with patients given sunitinib, particularly with respect to time to definitive deterioration. These results support the efficacy and safety profile of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma.
Funding: Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
Competing Interests: Declaration of interests RM reports research funding (institutional) from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer; and consulting fees from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, and Pfizer. CP reports consulting fees and honoraria from Angelini Farma, AstraZeneca, Bristol Myers Squibb, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, Merck Sharp & Dohme (MSD), Novartis, and Pfizer; expert testimony for EUSA Pharma and Pfizer; protocol steering committee membership for Bristol Myers Squibb, Eisai, EUSA Pharma, and MSD; and travel support from Roche. BA reports support for the present manuscript from Eisai; grants or contracts from Amgen, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; consulting fees and honoraria from Amgen, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; expert testimony for Amgen, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; travel support from AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, and Roche; and participation on a data safety monitoring board or advisory board for Astellas, Ipsen, and Janssen. SYR reports grants or contracts and honoraria from, and participation on a data safety monitoring board or advisory board for, Eisai. TKC reports support for the present manuscript from Eisai and Merck; research funding (institutional) from AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; patents filed, royalties, or other intellectual properties (no income as of current date) related to biomarkers of immune checkpoint blockers and circulating tumour DNA; consulting fees, honoraria, or advisory roles for Alexion, Analysis Group, Aravive, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Janssen Oncology, IQVIA, Lilly, Merck, NCCN, NiKang, Novartis, Nuscan, Peloton, Pfizer, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Up-to-Date, Continuing Medical Education-related events (eg, OncLive, PVI, and MJH Life Sciences), US National Cancer Institute Genitourinary Steering Committee, American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network; travel in relation to meetings, lectures, and advisory boards; stock ownership in Pionyr and Tempest. MJM-V reports consulting fees from Astellas Pharma, Bristol Myers Squibb, EUSA Pharma, Ipsen, EISAI, Janssen-Cilag, Novartis, Pfizer, Roche, and Sanofi; honoraria from Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Janssen-Cilag, Pfizer, and Roche; and support for attending meetings or travel from Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Pfizer, and Roche. AK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck, Bristol Myers Squibb, Ipsen, Eisai, Janssen, and AbbVie; leadership or fiduciary roles in other board, society, committee, or advocacy groups, paid or unpaid; being vice chair of Kidney Cancer Canada; and stock or stock options from Verity Pharma. JCG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, MSD Australia (Merck), Ipsen, and Bristol Myers Squibb; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb and Janssen (Johnson & Johnson); and stock or stock options from ICON Cancer Care, Australia. ME reports research funding from Kissei, Sanofi, Astellas, ONO, Takeda, and Bayer; and honoraria for lectures from MSD, ONO, Chugai, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Janssen, and Merck. LB and JW are employees of RTI Health Solutions, which was contracted by Eisai, to perform statistical analyses reported in this manuscript. JJP and CSH are full-time employees of Eisai. TLS is a paid employee of and shareholder in Merck & Co. RFP is an employee and a stock owner of Merck & Co. KM is an employee of Eisai. DC reports consulting fees (personal) from Eisai, Bristol Myers Squibb, Pfizer, Merck, Novartis, Ipsen, and Evidera, and is president of FACIT.org. S-HH declares no competing interests.
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