Over the past 5 years, several new immunotherapy treatments have been tested for metastatic renal cell carcinoma (mRCC). Clinical trials assessing combinations of different immunotherapies, or of an immunotherapy with a tyrosine kinase inhibitor (TKI), have reported improved clinical outcomes compared with the standard of care — that is, treatments using TKIs alone. However, to understand the holistic impact of new treatments on patients, physicians must also consider effects on health-related quality of life (HRQoL). As patient-reported outcome measures (PROMs) on HRQoL are often treated as a secondary outcome in clinical trials, their collection and reporting are non-standardized and, therefore, difficult to compare and interpret. However, results from six clinical trials indicate that two immunotherapy treatments overwhelmingly outperform sunitinib in HRQoL measurements: nivolumab plus cabozantinib (CheckMate 9ER) and atezolizumab plus bevacizumab (IMmotion151). An additional two treatments generally outperform sunitinib: nivolumab plus ipilimumab (CheckMate 214) and lenvatinib plus pembrolizumab (CLEAR). Of three studies that reported no difference from sunitinib, two suffered design flaws that might have obscured HRQoL benefits (JAVELIN Renal 101 and KEYNOTE-426). To ensure future HRQoL data are of the highest quality and comparable across trials, future studies should adopt best practices for the design, analysis and reporting of PROMs.
Emerging immunotherapies for the management of advanced renal cell carcinoma (RCC) have raised questions of how to evaluate and compare treatments. We review six relevant clinical trials.
For clinical outcomes, including overall survival rates, progression-free survival and adverse events, immunotherapies generally outperform sunitinib monotherapy in these trials.
In addition to clinical outcomes, the trials measure patient health-related quality of life (HRQoL) using patient-reported outcome measures (PROMs) such as the EQ-5D, FACT-G and FKSI.
HRQoL results are affected by the types of PROM administered, administration schedules and analyses conducted on longitudinal data.
To maximize the sensitivity, validity and interpretability of PROMs in future clinical trials, researchers should use the most up-to-date version of each PROM, account for symptom burden in PROM schedules and conduct specific, recommended longitudinal analyses using defined clinically important differences.
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D.C. is the President of FACIT.org, which owns and distributes two of the patient-reported outcome measures discussed in the article (FACT-G and FKSI). D.C. has received consulting honoraria from Bristol-Myers Squibb, Ipsen, Pfizer, Merck and Novartis, and has received research funding to his institution from Bristol-Myers Squibb, Pfizer and Merck; these companies sponsored or collaborated on the following clinical trials discussed in the article: CheckMate 214, JAVELIN Renal 101, CLEAR, KEYNOTE-426 and CheckMate 9ER. The other authors declare no competing interests.
Peer review information
Nature Reviews Urology thanks Tim Eisen, Rana McKay and Grant Stewart for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors began by searching ClinicalTrial.gov for Phase III metastatic renal cell carcinoma trials with reports available. This list was cross-referenced with FDA-approved treatments for metastatic renal cell carcinoma and the National Comprehensive Cancer Network treatment guidelines.
European Organisation for Research and Treatment of Cancer 30-item Quality of Life Questionnaire: https://qol.eortc.org/questionnaire/eortc-qlq-c30/
EuroQoL FiveDimensions: http://www.euroqol.org/
Functional Assessment of Cancer Therapy — General: https://www.facit.org/measures/FACT-G
Functional Assessment of Cancer Therapy — Kidney Symptom Index: https://www.facit.org/measures/NFKSI-19
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Nolla, K., Benjamin, D.J. & Cella, D. Patient-reported outcomes in metastatic renal cell carcinoma trials using combinations versus sunitinib as first-line treatment. Nat Rev Urol 20, 420–433 (2023). https://doi.org/10.1038/s41585-023-00747-w
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