From trial results to bedside decisions: a time-resolved view of CheckMate-9ER

First-line systemic therapy for metastatic clear cell renal cell carcinoma (mccRCC) has evolved rapidly, and immune checkpoint inhibitor (ICI)-based combinations now constitute the dominant standard of care (1,2). The practical challenge is no longer whether these regimens are effective in the average trial population, but how best to select among them for an individual patient in a real-world setting while balancing efficacy, toxicity, and patient preferences.

The final analysis of CheckMate-9ER, with a median follow-up of 5.6 years, provides mature evidence comparing nivolumab plus cabozantinib (Nivo/Cabo) with sunitinib (3). In the intention-to-treat population, Nivo/Cabo improved progression-free survival [PFS; hazard ratio (HR), 0.58; median, 16.4 vs. 8.3 months; 60-month PFS, 13.6% vs. 3.6%] and overall survival (OS; HR, 0.79; median, 46.5 vs. 35.5 months; 60-month OS, 40.9% vs. 35.4%), and yielded higher response rates (objective response rate, 55.7% vs. 27.4%; complete response rate, 13.9% vs. 4.6%). Long-term safety was consistent with prior reports, with grade 3–4 treatment-related adverse events occurring in 67.8% of patients treated with Nivo/Cabo and 55.0% treated with sunitinib. Importantly, International Metastatic RCC Database Consortium (IMDC) subgroup results suggested possible heterogeneity: in favorable-risk disease, PFS benefit persisted whereas OS benefit was not evident; in intermediate/poor-risk disease, both PFS and OS favored Nivo/Cabo.

HR-based reporting generally presumes proportional hazards (PH), whereby the risk ratio between arms is assumed to be stable throughout follow-up. In the ICI era, this assumption may be violated, in part because a subset of patients achieves durable long-term benefit, producing a “tail plateau” (4). When the PH assumption is violated, a single HR can be an incomplete summary that masks time-varying effects. This concern is not merely theoretical in mccRCC. In our recent restricted mean survival time (RMST)-based network meta-analysis (NMA) of first-line phase III trials, PH violations were frequent (approximately 60% for both OS and PFS comparisons), supporting the use of time-dependent measures (5). RMST provides a PH-free summary by translating survival differences into months gained by a clinically meaningful time horizon (τ). Notably, the RMST-NMA suggested that comparative performance can shift over time. ICI-tyrosine kinase inhibitor (TKI) combinations, including Nivo/Cabo, tended to dominate earlier horizons (12–48 months), whereas ipilimumab plus nivolumab emerged more prominently at later horizons (>48 months). This time-horizon dependence aligns with clinical intuition; some regimens may prioritize rapid disease control, while others may yield more durable long-term benefit in a subset of patients.

Against this background, we conducted a time-resolved reanalysis using reconstructed individual patient data (rIPD) derived from the published Kaplan-Meier curves in the CheckMate-9ER final analysis, estimating piecewise HRs for 0–24 versus 24–60 months and RMST differences at τ=24 and τ=60 months (Table 1; Figure 1). Details of the rIPD reconstruction, piecewise Cox regression, and RMST analyses are provided in the supplementary materials (Appendix 1, Tables S1, Figures S1,S2) (5,6). The aim of our reanalyses was to clarify whether the benefit of Nivo/Cabo is sustained across follow-up and whether its temporal pattern differs by IMDC risk group.

Figure 1 Time-dependent treatment effects estimated from reconstructed individual patient data based on published Kaplan-Meier curves from CheckMate-9ER. Piecewise HRs for nivolumab plus cabozantinib versus sunitinib are shown for 0–24 and 24–60 months, stratified by IMDC risk group and endpoint. HR, hazard ratio; IMDC, International Metastatic RCC Database Consortium; OS, overall survival; PFS, progression-free survival; r-IPD, reconstructed individual patient data.

In intermediate/poor-risk disease, the observed OS benefit was concentrated in the first 24 months, whereas the 24–60-month HR was close to 1.0 (Figure 1). The 60-month RMST gain remained positive, suggesting persistence of earlier absolute survival gains rather than clear ongoing late separation (Table 1). Taken together, these findings suggest that in intermediate/poor-risk disease, Nivo/Cabo may be best conceptualized as a regimen with front-loaded value, delivering early prevention of progression and death when baseline risk is highest. This perspective matters for counseling and planning, particularly as chronic TKI toxicity accumulates over time. It may be especially relevant for patients with symptomatic disease, high tumor burden, threatened organ function, or limited physiologic reserve, in whom early disease control can preserve performance status and maintain eligibility for subsequent therapies.

The apparent front-loaded benefit and strong early disease control also raise a practical consideration for selected patients with limited metastatic burden. In oligometastatic presentations, early tumor shrinkage may expand opportunities for consolidative local ablative strategies, including metastasectomy or stereotactic body radiotherapy, aimed at durable control in carefully selected patients. However, this concept remains speculative and should be tested prospectively using standardized eligibility criteria and prespecified endpoints. Similar “window-of-opportunity” considerations may apply to other high-response ICI-TKI regimens, such as pembrolizumab plus lenvatinib (7), supporting the broader view that time horizon and response depth are relevant when integrating systemic and local strategies. Although our discussion focuses on oligometastatic settings, the broader concept that ICI-TKI regimen-induced downsizing can improve the feasibility and planning of definitive local treatment has also been explored in locally advanced disease, including studies assessing radiographic response after preoperative systemic therapy (8).

In favorable-risk disease, OS estimates were imprecise and long-term PFS remained uncertain. However, early PFS estimates (0–24 months) still favored Nivo/Cabo (Table 1; Figure 1), indicating uncertainty about the durability and magnitude of long-term benefit rather than an absence of activity. Shared decision-making should therefore foreground uncertainty, patient priorities, and tolerance for chronic therapy. When OS benefit cannot be reliably quantified, treatment selection may hinge on the relative importance of early tumor shrinkage, symptom control, quality of life, and long-term treatment burden. In this context, Bayesian probability framing may help communicate uncertainty: rather than emphasizing “significant versus not significant”, clinicians can convey that the probability of a clinically meaningful OS gain appears low or uncertain in favorable-risk disease, while a PFS benefit remains plausible (9).

Our rIPD-based analysis has several limitations. rIPD reconstruction from published Kaplan-Meier curves is inherently approximate and may be affected by digitization error and incomplete recovery of censoring patterns. Moreover, reconstructed datasets cannot capture patient-level covariates or post-progression therapies from the original analyses. Thus, our time-resolved estimates should be considered as hypothesis-generating.

In summary, the CheckMate-9ER final analysis confirms durable efficacy of Nivo/Cabo compared with sunitinib and supports its continued role in first-line mccRCC. A time-resolved reanalysis suggests that the observed relative OS benefit in intermediate/poor-risk disease is greatest within the first 24 months, whereas in favorable-risk disease, long-term estimates remain imprecise. These exploratory findings support complementing conventional HR summaries with time-dependent and absolute-effect measures.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0254/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0254/coif). S.Y. received honoraria from Eisai Co., Ltd. Y.F. received consulting fees from Janssen and payment for expert testimony from Eisai Co., Ltd., Janssen, Merck & Co, Astellas Pharma Inc., NIPPON KAYAKU, ONO PHARMACEUTICAL CO, Bristol-Myers Squibb Company, and Takeda Pharmaceutical Company. The other author has 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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