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

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.