Health-related quality of life with belzutifan versus everolimus for advanced renal cell carcinoma (LITESPARK-005): patient-reported outcomes from a randomised, open-label, phase 3 trial
- PMID: 40112850
- DOI: 10.1016/S1470-2045(25)00032-4
Health-related quality of life with belzutifan versus everolimus for advanced renal cell carcinoma (LITESPARK-005): patient-reported outcomes from a randomised, open-label, phase 3 trial
Abstract
Background: The first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is approved for patients with advanced renal cell carcinoma previously treated with immune checkpoint and anti-angiogenic therapy based on results of the phase 3 LITESPARK-005 trial. We present patient-reported outcomes (PROs) from LITESPARK-005.
Methods: LITESPARK-005 was an open-label, multicentre, randomised, active-controlled phase 3 trial conducted at 147 hospitals and cancer centres in six regions. Eligible participants were 18 years or older with advanced clear cell renal cell carcinoma, had a Karnofsky Performance Status score of 70% or higher, had measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, had disease progression on or after treatment with anti-PD-1 or anti-PD-L1 immunotherapy and a VEGF tyrosine kinase inhibitor (in sequence or in combination), and had received no more than three previous systemic lines of therapy. Eligible participants were randomly assigned (1:1) centrally using interactive voice-response and web-response systems to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily. Randomisation was stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and number of previous VEGF-targeted or VEGF receptor-targeted therapies. The dual primary outcomes were progression-free survival and overall survival, results of which have been reported previously. In this study, prespecified secondary patient-reported outcomes (PROs) from LITESPARK-005 were assessed using the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO analysis population included all participants who received at least one dose of study therapy and completed at least one PRO assessment. Least-squares mean change from baseline in PROs at week 17 was assessed using a constrained longitudinal data analysis model. Time to deterioration in physical functioning (prespecified) and role functioning (post hoc), as assessed by the EORTC QLQ-C30, were also evaluated in the PRO analysis population. This trial is ongoing, closed to recruitment, and registered with ClinicalTrials.gov, NCT04195750.
Findings: Between March 10, 2020, and Jan 19, 2022, 996 participants were screened for eligibility and 746 participants were randomly assigned to belzutifan (n=374) or everolimus (n=372). The PRO full analysis set population included 366 participants in the belzutifan group and 354 in the everolimus group. Median time from randomisation to the database cutoff date (June 13, 2023) was 25·7 months (IQR 21·7-30·4). Completion rates for FKSI-DRS and QLQ-C30 were higher than 94% at baseline and higher than 55% at week 17 in each group. Change from baseline to week 17 in FKSI-DRS score (difference in least-squares mean between groups 1·5 [95% CI 0·7 to 2·2]) and QLQ-C30 global health status-quality of life (QOL) score (6·4 [3·2 to 9·6]) suggested stability with belzutifan versus worsening with everolimus. Change from baseline to week 17 was similar between groups for QLQ-C30 physical functioning (difference in least-squares mean 2·5 [95% CI -0·6 to 5·5]) and QLQ-C30 role functioning (4·2 [0·1 to 8·4]) subscale scores. Time to deterioration was similar between the belzutifan and everolimus groups for EORTC physical functioning (median 19·3 months [95% CI 11·1 to not reached] in the belzutifan group vs 13·8 months [10·6 to not reached] in the everolimus group; hazard ratio 0·93 [95% CI 0·72 to 1·20]) and role functioning (median 12·0 months [9·2 to not reached] vs 10·2 months [4·7 to 14·4]; 0·88 [0·69 to 1·11]).
Interpretation: Belzutifan for advanced renal cell carcinoma was associated with improved disease-specific symptoms and QOL compared with everolimus. Taken together with the efficacy and safety data from LITESPARK-005, belzutifan could offer a clinical benefit without compromising the QOL of patients in this setting.
Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
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Conflict of interest statement
Declaration of interests TP reports grants or contracts from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; consulting fees and honoraria from AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, Mashup, and Gilead; support for attending meetings or travel, or both, from Roche, Pfizer, MSD, AstraZeneca, Ipsen, Gilead, Astellas, and MSD; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; and other financial interests from Novartis, Pfizer, AstraZeneca, Roche/Genentech, Eisai, and Merck. TKC has received research funding from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH Life Sciences, Clinical Care Options, and others) outside the submitted work; reports funding related to clinical trials from AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; personal consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH Life Sciences, Clinical Care Options, and others) outside the submitted work; reports honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH Life Sciences, Clinical Care Options, and others) outside the submitted work; reports travel support in relation to meetings, lectures, and advisory boards; reports patents related to circulating tumour DNA and biomarkers of response to immune checkpoint inhibitors; has participated in advisory boards for Aravive; has a leadership role in KidneyCan (unpaid); has had roles on committees for the American Society of Clinical Oncology, European Society of Medical Oncology, and National Comprehensive Cancer Network; is on the steering committee for the National Cancer Institute; owns stock or stock options with Curesponse, Immdura, Osel, Pionyr, Precede Bio, Primium (for being an advisor), and Tempest; and is supported in part by Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. LA has received consulting fees (to the institution) from Astellas Pharma, BMS, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, EISAI, and Roche and has received travel support from BMS, Ipsen, MSD, and Pfizer. KP has received research funding (to the institution) from MSD; consulting fees from BMS, Ipsen, MSD, and Roche; honoraria from Bayer, BMS, Ipsen, MSD, Roche, and Novartis; payment for expert testimony from Ipsen; and support for attending meetings and/or travel from Ipsen. KP has participated in advisory boards for Orion Pharma and owns stock or stock options from Faron Pharmaceuticals. GdV has received personal fees from AstraZeneca, Bristol Myers Squibb, Eisai, F Hoffman-La Roche, Ipsen Pharma SAS, Merck KGaA, Merck Sharp & Dohme, Novartis, and Pfizer. MB has received honoraria from AstraZeneca, BMS, and MSD and has participated on advisory boards for BMS, MSD, and Roche. CS has received grants from Ipsen and consulting fees and honoraria from Astellas, Bayer, Bristol Myers Squibb (to the institution), Ipsen, MSD, Pfizer, Roche, and Sanofi. PG has received honoraria from OncLive. RI has received consulting fees, honoraria, and support for attending meetings or travel, or both, from MSD and has participated on advisory boards for MSD. ETL has received research funding (to the institution) from Merck & Co, Arrowhead, Astellas, Bristol Myers Squibb, Exelixis, Forma, Hibercell, Roche, Pfizer, and Promontory (phosplatin) and consulting fees from Pathos. EV has received honoraria from AstraZeneca, BMS, Eisai, Astellas, Janssen, MSD, and Pfizer and has participated on advisory boards from Ipsen, Janssen, MSD, and Pfizer. MG has received honoraria (to the institution) from Amgen, AstraZeneca, Astellas, MSD, Novartis, Pfizer, and Roche and has received support (to the institution) for attending meetings or travel, or both, from Bayer, Novartis, and Roche. WMS has received research funding (to the institution) from Abbvie, Amgen, Astellas, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Calithera, Corvus, Eisai, Exelixis, Genentech (Roche), Johnson & Johnson, Merck, Novartis, Pfizer, Seattle Genetics, X4Phramaceuticals, and Xencor; consulting fees from AstraZeneca, Caremark/CVS, and Xencor; and payment for expert testimony from Sandoz. WMS has participated on a data safety monitoring board for AstraZeneca, Merck, Pfizer, and Treadwell Therapeutics; is part of a scientific advisory committee (unpaid) from Kidney Cancer Association; and owns stock or stock option from Fortress Biotech. CK has received consulting fees and honoraria from Eisai, Ipsen, BMS, Merck, and Pfizer, and travel support from Ipsen. BM has received honoraria from Astellas, AstraZeneca, BMS, Eisai, Eli Lilly and Company, Merck Serono, MSD, Novartis, Pierre Fabre, Pfizer, Roche, and Servier, and travel support from AstraZeneca, BMS, Merck Serono, and MSD. BV has received honoraria from Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, and Merck Sharp & Dohme UK; has received support for attending meetings or travel, or both, from Ipsen and Merck Sharp & Dohme UK; and has participated on advisory boards for Ipsen and Merck Sharp & Dohme UK. MG-G has received honoraria from Astellas, BMS, Eisai, Ipsen, Merck, MSD, and Pfizer; payment for expert testimony for Astellas, BMS, and MSD; and support for attending meetings or travel, or both from Amgen, BMS, Janssen, MSD, and Pfizer. AP has received consulting fees from Astellas and Merck; honoraria from BMS, Merck, Astellas, Hanssen, Ipsen, Merck, MSD, Novartis, Roche, and Zentiva; and support for attending meetings or travel, or both, from BMS, Ipsen, Merck, and MSD. AP has participated on advisory boards for BMS, Ipsen, Merck, and MSD. MR has participated on advisory boards of MSD, Merck Serono, AstraZeneca, Bristol Myers Squibb, Eisai, and Gilead; has received payment for expert testimony from MSD; and has received support for attending meetings or travel, or both, from Merck Serono, Ipsen, and Johnson & Johnson. RS, TLS, and RFP are employees of, and own stock in, Merck Sharp & Dohme, a subsidiary of Merck & Co. LH and DV are employees of Merch Sharp & Dohme, a subsidiary of Merck & Co. BR has received research funding (to the institution) from ADC Therapeutics, Adela, Arcus, Arrowhead Pharmaceuticals, AstraZeneca, AVEO, BMS, Daiichi Sankyo, Dracen Pharmaceuticals, Dragonfly Therapeutics, Exelixis, Genentech, Gilead, HiberCell, Incyte, Janssen, Merck, Pfizer, Pionyr, POINT Biopharma, Stata Oncology, Surface Oncology, and Tempus; has received consulting fees from Alkermes, Aravive, Arrowhead, Athenex, Aveo, BMS, Corvus, Debiopharm, Eisai, EUSA, Exelixis, Genentech /Roche, HiberCell, Merck, Nikang Therapeutics, Pfizer, and Surface Oncology; and has participated in advisory boards for AstraZeneca.
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