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Two-Stage Estimation of Overall Survival in the Phase 3 CheckMate 9ER Trial, Adjusting for the Impact of Subsequent

Marc-Oliver Grimm¹, Emma Karim², Venediktos Kapetanakis³

¹Department of Urology, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany. Marc-Oliver.Grimm@med.uni-jena.de.

Oncology and Therapy

|November 14, 2025

Abstract

Introduction:

The CheckMate 9ER (CM9ER) trial demonstrated the superiority of cabozantinib plus nivolumab (CaboNivo) over sunitinib (SUN) in patients with untreated advanced renal cell carcinoma (aRCC). We conducted a post hoc analysis using CM9ER data (median follow-up 67.6 months) and two-stage estimation (TSE) to assess the efficacy of CaboNivo versus SUN, adjusting for the impact of subsequent treatment.

Methods:

Patients in the intention-to-treat (ITT) CM9ER population who discontinued their randomized study therapy were included in step 1 of the TSE, which used accelerated failure time modeling to estimate the extent that subsequent therapy extended survival in each treatment arm. Step 2 adjusted the CM9ER ITT population overall survival (OS) estimates to account for this impact; an adjusted hazard ratio (HR) for OS was then calculated to evaluate the relative impact of CaboNivo versus SUN without the effects of subsequent treatment.

Results:

In total, 540 patients from CM9ER (CaboNivo, n = 264; SUN, n = 276) discontinued treatment and were included in the analysis, of whom 297 (CaboNivo, n = 129; SUN, n = 168) initiated subsequent systemic therapy. Patient characteristics were balanced between ITT and TSE populations. Median (interquartile range) time from randomization to treatment discontinuation was 22.2 (9.92-31.51) months for CaboNivo and 9.6 (3.48-18.62) months for SUN. The TSE-adjusted median (95% confidence interval [CI]) OS was 42.7 (38.4-49.1) months for CaboNivo and 21.3 (18.1-24.9) months for SUN (HR [95% CI] 0.53 [0.43-0.65; p < 0.001]), compared with unadjusted estimates of 46.5 (40.6-53.7) months and 35.5 (29.2-42.8) months, respectively (HR [95% CI] 0.79 [0.65-0.96; p = 0.0196]).

Conclusions:

Removing the effect of subsequent therapy strengthened the relative OS benefit of CaboNivo versus SUN in CM9ER. Consistent with clinical practice, these results further support first-line CaboNivo as a standard of care for aRCC. Graphical abstract available for this article.

Trial Registration:

NCT03141177.

Keywords:

Advanced renal cell carcinoma (aRCC)Cabozantinib plus nivolumab (CaboNivo)CheckMate 9ER (CM9ER)Overall survival (OS)Subsequent therapy Sunitinib (SUN)Two-stage estimation (TSE)

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