Patient-reported outcomes in LITESPARK-005: a timely step toward patient-centered metrics in advanced renal cell carcinoma

In recent years, the paradigm in oncology has shifted from focusing solely on traditional clinical endpoints such as progression-free survival (PFS) and overall survival (OS) toward incorporating patient-centered outcomes that better capture the lived experiences of patients with cancer (1). Patient-reported outcomes (PROs) offer direct insights into how patients perceive their symptoms, daily functioning, and overall quality of life (QOL) during and after treatment (2). This focus aligns with a broader movement in drug development and regulatory science that values the quality of survival (3). However, in the landscape of advanced renal cell carcinoma (aRCC) in second- and third-line settings, few randomized trials have incorporated PROs with sufficient methodological rigor (4).

LITESPARK-005 is a randomized, open label, phase III trial that compared belzutifan to everolimus in patients with aRCC that had progressed after prior treatment with programmed cell death 1/ligand 1 (PD-1/L1) and vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor therapies (5). Belzutifan is a small molecule inhibitor of the hypoxia-inducible factor 2 alpha (HIF-2α) (6,7). Patients were randomized in a 1:1 ratio to receive either belzutifan 120 mg orally once daily (n=374) or everolimus 10 mg orally once daily (n=372). The co-primary endpoints were PFS, per RECIST v1.1, and OS. The key secondary endpoints were objective response rate (ORR), duration of response, safety profile, and PROs. Belzutifan demonstrated improved PFS and ORR compared to everolimus, which supported its U.S. Food and Drug Administration (FDA) approval in December 2023, despite no significant improvement in the second primary outcome of OS (5-7). However, in this third line setting after failure of immunotherapy and angiogenic therapy, no agent has been shown to increase OS compared to everolimus.

Recently, Powles et al. have published the PRO paper from the primary LITESPARK-005 publication (8). PROs were collected throughout the study and analyzed for mean change over time (up to week 137). The least-squares mean difference was assessed at week 17 between groups, with survey completion rates and compliance rates of 60% and 80%, respectively. Time to symptom deterioration in role functioning was also assessed post-hoc. Baseline Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) (9) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (9) scores were similar between groups. The decline in health-related quality of life (HRQOL) observed in the PRO questionnaire analysis was primarily attributed to adverse medication effects or tumor progression, rather than to confounding factors such as comorbidities or aging (8). As the authors did in LITESPARK-005, the reporting of adjustment for other factors should be included in all future renal cell carcinoma (RCC) trials that include PROs in order to enhance interpretability and ability for regulatory agencies to conclude that HRQOL was truly improved with an agent.

At week 17, the belzutifan group had a least-squares mean difference of +1.5 points in the FKSI-DRS and +6.4 points in the EORTC QLQ-C30 Global Health Status domain. Scores were statistically similar in EORTC-QLQ-C30 physical and role functioning categories. Apart from the cognitive functioning subscale, the rest of the symptoms and functioning subscales showed greater worsening in the everolimus group. Notably, belzutifan had smaller baseline changes in fatigue and dyspnea symptom scores. This smaller baseline change may indicate a balance between the mechanistic action of belzutifan and the improvement of RCC related symptoms, that include fatigue and dyspnea. The authors did not fully explore this relationship, and future trials should be designed with attention to overlapping therapeutic toxicity and disease state.

Empirical mean changes throughout the study (up to week 137) in FKSI-DRS scores showed greater stability for those receiving belzutifan compared to those receiving everolimus. In contrast, changes were generally stable in both groups for EORTC QLQ-C30 GHS-QOL related measures. A higher proportion of participants in the belzutifan group (25% vs. 18%) experienced overall improvement in the FKSI-DRS score. This finding was also observed for EORTC QLQ-C30 GHS QOL score (57% vs. 18%) and physical functioning (18% vs. 12%). Role functioning scores had a similar proportion of improvement in both groups (21% vs. 19%) and median time to deterioration in both EORTC QLQ-C30 physical functioning and role functioning subscales were not statistically different. In all, the PROs reported show that HRQOL was ultimately better for patients on belzutifan and is reasonable to consider over everolimus in advanced RCC with multiple failed lines of treatment.

The LITESPARK-005 trial stands out among second-line and beyond aRCC trials for its structured and timely integration of PROs as predefined secondary endpoints. It featured a priori statistical planning and transparent reporting of compliance and completion rates at analyzed time points. This contrasts with the broader genitourinary (GU) oncology landscape, where only 52% of GU trials that led to FDA approval defined PROs as secondary endpoints. The remaining 48% of trials treated them as either exploratory outcomes or failed to clearly categorize them (10). In line with the FDA and European Medicines Agency (EMA) statements, making PRO analysis a formal endpoint is imperative in reducing bias and improving interpretability (1,11). While only two-thirds of GU tumor trials that supported FDA approvals published PRO data, typically with an average 10 months between primary and PRO publications, LITESPARK-005 reported PROs 8 months after the primary results (10). LITESPARK-005 used validated instruments such as FKSI-DRS and EORTC QLQ-C30, included multiple assessment time points. It also reported compliance rates, addressing several shortcomings identified in prior trials.

In efforts to standardize and improve the consistency of PRO reporting in genitourinary cancer trials, Safa and colleagues developed a 24-point Patient-Reported Outcome Endpoints Analysis Score (PROEAS). It was created based on Standards in Analyzing PROs and Quality of Life (SISAQOL) recommendations (4). LITESPARK-005 was assessed using PROEAS and achieved a score of 13 points, exceeding the average score of 11.86 reported for RCC trials (10).

While LITESPARK-005 has a more rigorous PROs design than others, several gaps and limitations must be highlighted. First, although PROs endpoints were prespecified, no formal hypotheses or significance thresholds were defined. Moreover, meaningful clinical differences were defined for FKSI-DRS (≥3 points) and EORTC QLQ-C30 (≥10 points). Only the week 17 assessment was formally prespecified for statistical comparison. Subsequent timepoints were presented descriptively through empirical means without predefined endpoints or hypothesis testing, rendering the longitudinal findings exploratory. Second, the analysis was not multiplicity-controlled increasing the risk of a type I error for between-arm differences. Third, explicit definitions were not provided for missing PROs data. There is no statement about excluding post-death assessments from missing-data counts. Lastly, the original protocol for LITESPARK-005 details a broader array of secondary PROs outcomes and includes an additional questionnaire (EQ-5D-5L). These results were not reported and clarity on whether the compliance rate was low or the survey was not administered would help strengthen the analysis.

In contrast, some other second- and third-line RCC trials with PROs data had significant drawbacks compared to the LITESPARK-005 design. CheckMate 025 used FKSI-DRS and EQ-5D tools with appropriate reporting and transparency. However, unlike LITESPARK-005, PROs data was solely an exploratory analysis and not a formal endpoint. Similarly, the METEOR trial employed FKSI-19 and EQ-5D-5L also did not define the PROs analysis as a formal endpoint and thus, data was not subjected to hypothesis testing or power analysis. Without being sufficiently powered or having a-priori definitions, the statistical analysis is prone to bias and interpretability is reduced. While, LITESPARK-005 may not have explicit hypothesis statements as we noted, it is likely that is a reporting issue rather than methodological. The AXIS trial utilized FKSI-15 and EQ-5D tools, had prespecified endpoints, and the overall methodology/reporting for PROs data was excellent. However, their conclusions that axitinib delays worsening of symptoms for longer than sorafenib is not fully rooted in their PROs analysis. Their analysis showed no difference while on therapy and both groups had worse scores at end of therapy. They used efficacy results showing that axitinib increased PFS and it can be used to delay decline in HRQOL since they were generally on therapy for longer. Yet, since patients were not followed extensively after coming off therapy, it is unknown if those results persist after the study. LITESPARK-005 was able to use PROs data to directly draw their conclusions in QOL measures. Overall, many of the previous advanced line RCC trials had PROs data, but it was not as key of a part in the studies as they were for LITESPARK-005.

CheckMate 025 also used FKSI-DRS and EQ-5D tools to evaluate QOL, but less emphasis was placed on prespecifying clinically meaningful thresholds or within-group change metrics (12). The AXIS trial, which also used the FKSI and EQ-5D tools, was limited by less frequent assessments and a narrower focus on global health and symptom control (13). The METEOR trial employed the FKSI-19 and EQ-5D-5L, with robust completion rates, but its PROs reporting primarily described between-group differences without predefined thresholds for meaningful clinical change (14). Overall, compared to other trials leading to FDA approval, LITESPARK-005 demonstrated a more methodologically comprehensive approach to PROs reporting.

Alongside methodological rigor, improvements in PROs instruments specific for advanced RCC therapy are necessary. The use of standardized PROs instruments may overlook mechanism-specific toxicities and the distinction between treatment-related and disease-related differences in HRQOL. For example, belzutifan’s HIF-2α inhibition carries toxicities of anemia and hypoxia-induced fatigue that overlap with disease-related symptoms but may have distinct temporal patterns (15). Another challenge specific to second- and third-line RCC populations is that the FKSI-DRS and EORTC QLQ-C30 have been validated in locally advanced RCC populations, but not in heavily pretreated, third-line RCC patients, which reduces their sensitivity and specificity (14,16).

Fortunately, progress is being made in capturing informative and clinically relevant PROs data for the RCC population. A newly introduced instrument, the FKSI-23, may better address differentiating between disease-related symptoms and side effects of treatment (17). Developed through input from patients, advocates, and clinicians, the FKSI-23 expands upon the FKSI-DRS by incorporating physical, emotional, and treatment side-effect domains within a single metric, offering a more holistic assessment of symptom burden and tolerability (17). Furthermore, continuous monitoring with wearable devices could help identify hypoxia-related fatigue specifically and enable proactive dose reduction (18).

Future studies should also consider incorporating Patient-Reported Outcomes Measurement Information System (PROMIS) tools as potential supplements to existing PROs instruments, as these items have been successfully integrated in multiple cancer centers into routine oncological visits (19).

PROs guide doctors in choosing the proper treatment for a patient and help a patient contribute to the decision-making process. The inclusion of robust, statistically interpretable PROs data in LITESPARK-005 marks a milestone for advanced RCC trials, which should help shift the trend toward more PRO-based outcomes. Belzutifan was shown to offer meaningful disease control compared to everolimus, while stabilizing HRQOL. However, current tools may underestimate mechanism-specific toxicities and determining whether adverse effects on QOL are from therapy or disease remains a challenge. As we refine our approach to treating advanced RCC and the sequencing of therapies beyond the first-line treatments, we must continue to account for the patient experience beyond traditional endpoints. This sentiment is in line with the FDA guidance affirming the importance of PROs and supporting the inclusion of PROs as formal endpoints. However, they note that the utilization of PROs data in regulatory decisions remains difficult due to heterogeneity of methodology, instrument validation, and ambiguous result reporting. Thus, for regulatory bodies to integrate these findings, RCC trial design must pay attention to clearly defined, hypothesis-driven, and statistically powered PROs endpoints with verified instruments with minimal clinically important change.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-97/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-97/coif). J.C. has received advisory board or consultancy fees during his lifetime from Merck, Pfizer, Exelixis, Aveo, Eisai, and Mycaregorythm; was an editor for PDQ NCI; received honorarium for non-branded educational programs supported by DAVA Oncology and MJH Life Sciences; has received research funding during his lifetime (to J.C.’s institution) from Allogene, Astellas, Bristol Meyers, Eisai, Eli Lilly, Exelixis, Genentech, Merck, and Pfizer; and is the co-founder of AI-OS LLC. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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