Neoadjuvant nivolumab plus gemcitabine-cisplatin followed by postsurgical adjuvant nivolumab versus neoadjuvant gemcitabine-cisplatin in patients with muscle-invasive bladder cancer: final results from the phase III CA017-078 trial.

Adults with previously untreated cT2-T4aN0M0 MIBC eligible for radical cystectomy (RC) and cisplatin were randomized to neoadjuvant nivolumab plus GC followed by RC and adjuvant nivolumab (nivolumab plus GC arm), or neoadjuvant GC followed by RC alone (GC arm). Co-primary endpoints were pathological complete response (pCR; defined as ypT0N0) and event-free survival (EFS). Overall survival (OS) was a secondary endpoint within the prespecified hierarchical testing strategy, and formal testing was contingent on a statistically significant EFS result.

The addition of perioperative nivolumab to neoadjuvant GC did not improve outcomes and was associated with predictable toxicity. Exploratory analysis showed ctDNA was strongly prognostic.

At this final analysis with 54.5 months of median follow-up, 325 patients were randomized to the nivolumab plus GC arm, 328 to the GC arm. pCR rates were 39.1% and 29.6%, respectively (adjusted difference 9.5%, 99.91% CI -2.6-21.6). EFS was not improved in the nivolumab plus GC versus GC arm (104 events in each arm; HR 0.94, 95.74% CI 0.71-1.25; P=0.6697). OS was summarized descriptively because EFS did not meet the testing criterion (HR 0.88, 95% CI 0.64-1.21). Grade 3-4 treatment-related adverse events occurred in 50.0% versus 49.5%; one treatment-related death occurred with nivolumab plus GC. Pretreatment ctDNA was positive in 229/416 tested patients (55%) overall, 108/211 (51%) in the GC arm, and 121/205 (59%) in the nivolumab plus GC arm. Clearance by cycle 4 day 1 (C4D1) occurred in 153/199 patients (76.9%) overall, 87/107 (81.3%) with nivolumab plus GC, and 66/92 (71.7%) with GC. ctDNA detection at baseline and at C4D1 was associated with shorter EFS and OS.

Perioperative immune-checkpoint inhibition improves outcomes in muscle-invasive bladder cancer (MIBC). The phase III, randomized CA017-078 (ENERGIZE) trial evaluated perioperative nivolumab plus neoadjuvant gemcitabine-cisplatin (GC) versus neoadjuvant GC alone for previously untreated, resectable MIBC.