CA017-078 analysis finds no EFS difference with nivolumab in MIBC

Adding perioperative nivolumab (Opdivo) to neoadjuvant gemcitabine/cisplatin (GC) did not significantly improve pathologic complete response (pCR) or event-free survival (EFS) in muscle-invasive bladder cancer (MIBC). These are the final results of the phase 3 CA017-078 trial (NCT03661320).¹ Andrea Necchi, MD, presented the findings at the European Society for Medical Oncology (ESMO) Congress 2026.¹ The median follow-up was 54.5 months. The pCR rate was numerically higher with the nivolumab regimen, but neither co-primary end point met its prespecified significance threshold.¹

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy has been a standard approach for eligible patients. Even so, approximately 50% of patients experience recurrence within 3 years, according to the presentation.¹ In CheckMate 274, adjuvant nivolumab improved disease-free survival in high-risk muscle-invasive urothelial carcinoma. In NIAGARA, perioperative durvalumab added to neoadjuvant GC improved both EFS and overall survival (OS).^2,3 Perioperative enfortumab vedotin plus pembrolizumab has also shown EFS, OS, and pCR benefits in the KEYNOTE-B15/EV-304 and KEYNOTE-905/EV-303 trials.¹

CA017-078, also called ENERGIZE, enrolled patients with previously untreated cT2-T4aN0M0 MIBC with a pure or predominant urothelial component. Patients also needed a glomerular filtration rate (GFR) of at least 50 mL/min and an ECOG performance status of 0 or 1.¹ Between September 2019 and November 2022, investigators randomly assigned 653 patients 1:1 to 1 of 2 arms:¹

• Neoadjuvant nivolumab 360 mg plus GC every 3 weeks for 4 cycles, then radical cystectomy and adjuvant nivolumab 480 mg every 4 weeks for nine cycles (n = 325)
• Neoadjuvant GC alone for 4 cycles, then surgery and observation (n = 328)

Randomization was stratified by clinical stage (T2 vs T3/T4a), GFR (50 to less than 60 mL/min vs 60 mL/min or higher), and PD-L1 status (1% or higher vs less than 1% or indeterminate).¹ A third arm adding linrodostat to nivolumab was terminated in December 2021 on an independent data monitoring committee recommendation. It was excluded from formal testing.¹

The pCR analysis included all randomized patients, so patients who did not undergo cystectomy counted as nonresponders.¹ At the prespecified pCR final analysis, the pCR rate was 39.1% with nivolumab plus GC vs 29.6% with GC alone (odds ratio, 1.54; 99.91% CI, 0.88-2.69). This did not cross the recalculated significance threshold (P < .000873).¹ A descriptive update at the EFS final analysis showed an absolute difference of 9.5% (95% CI, 2.3%-16.7%; 99.91% CI, -2.6% to 21.6%).¹

EFS by blinded independent central review did not differ between arms (HR, 0.94; 95.74% CI, 0.71-1.25; P = .6697).¹ Events occurred in 104 of 325 patients (32.0%) in the nivolumab arm and 104 of 328 (31.7%) in the GC arm. Median EFS was not reached vs 67.6 months (95% CI, 63.0 months to not estimable).¹ EFS rates by arm were:¹

• 12 months: 82.6% vs 78.6%
• 24 months: 72.3% vs 71.6%
• 36 months: 68.1% vs 68.5%

Overall survival, subgroup outcomes, and subsequent therapy in CA017-078

OS, a secondary end point, was analyzed descriptively because the EFS testing condition was not met.¹ At the EFS final analysis, 71 of 325 patients (21.8%) in the nivolumab arm and 81 of 328 (24.7%) in the GC arm had died (HR, 0.88; 95% CI, 0.64-1.21). Median OS was not reached in either arm.¹ The OS data remain immature. The analysis included 152 deaths, and a second interim OS analysis is planned at 174 deaths.¹

Descriptive pCR rates were higher with nivolumab plus GC across prespecified strata:¹

• PD-L1 expression of 1% or higher: 46.4% vs 35.5%
• PD-L1 expression below 1%: 33.3% vs 24.3%
• cT2 disease: 40.6% vs 31.5%
• cT3/cT4a disease: 35.1% vs 23.9%

The combined response rate, defined as ypT1N0 or less, was 51.7% vs 41.8% (difference, 9.9%; 95% CI, 2.3%-17.5%).¹

Descriptive EFS and OS subgroup analyses showed no clear difference between arms by PD-L1 status, clinical stage, or calculated creatinine clearance.¹ For PD-L1 expression of 1% or higher, the unstratified EFS HR was 0.69 (95% CI, 0.45-1.04). For PD-L1 expression below 1%, it was 1.17 (95% CI, 0.81-1.70).¹

Treatment delivery and subsequent therapy also differed between arms:¹

• Radical cystectomy was performed in 85.8% of the nivolumab arm and 86.9% of the GC arm.
• Of 318 treated patients in the nivolumab arm, 239 (75.2%) started adjuvant nivolumab and 175 (55.0%) completed it.
• Subsequent anticancer therapy was more common in the GC arm (23.8% vs 15.7%), particularly subsequent checkpoint inhibitor therapy (14.9% vs 3.4%).
• No patients in the GC arm received adjuvant anti-PD-1 or anti-PD-L1 therapy. Checkpoint inhibitors in this arm were given at disease progression, Necchi noted.

Safety profile of perioperative nivolumab plus gemcitabine/cisplatin

Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 50.0% of patients receiving nivolumab plus GC and 49.5% of those receiving GC alone.¹ Grade 3 or higher adverse events of any cause were reported in 73.0% vs 56.3%. Serious adverse events occurred in 45.9% vs 18.5%.¹ Necchi noted treatment exposure was longer in the nivolumab arm, with the adjuvant phase adding a median of about 8 months. Adverse events in the GC arm were tracked only through 100 days after the postsurgery visit.¹

The most common TRAEs were similar between arms:¹

• Nausea: 48.7% vs 48.9%
• Anemia: 30.8% vs 30.8%
• Neutropenia: 27.7% vs 30.8%
• Fatigue: 25.2% vs 26.2%

Increased blood creatinine was reported in 15.4% of the nivolumab arm and 8.3% of the GC arm.¹ Among 64 patients (20.1%) who discontinued adjuvant nivolumab, the most common reasons were study drug toxicity (n = 27) and disease progression (n = 15).¹ One treatment-related death (0.3%) from pneumonitis occurred in the nivolumab arm, with none in the GC arm. The investigators described the safety profile as consistent with the known profiles of the individual agents.¹

Circulating tumor DNA as a prognostic biomarker in MIBC

Exploratory analyses used the Signatera tumor-informed molecular residual disease assay (Natera). Of the 653 randomized patients, 346 (53.0%) had ctDNA results at both cycle 1 day 1 (C1D1) and cycle 4 day 1 (C4D1).¹ Biomarker results were descriptive, with no formal hypothesis testing. Among patients with detectable ctDNA at C1D1, clearance by C4D1 occurred in 81.3% (87/107) of the nivolumab arm vs 71.7% (66/92) of the GC arm (P = .130).¹

In both arms, patients who cleared ctDNA had higher pCR rates than those who did not:¹

• Cleared ctDNA: 43.7% (38/87) vs 33.3% (22/66) (P = .242)
• Did not clear ctDNA: 5.0% (1/20) vs 7.7% (2/26) (P > .99)

In pooled analyses across both arms, detectable pretreatment ctDNA was associated with shorter EFS and OS.¹ Patients who were ctDNA negative at both time points, or who cleared ctDNA by C4D1, had longer EFS and OS than patients who stayed ctDNA positive at C4D1.¹ However, nivolumab plus GC and GC alone showed no clear treatment difference within either ctDNA clearance group.¹

“We should be very cautious in interpreting the biomarker data here, but no clear disconnection between arms is appreciable,” Necchi said during the presentation.

Necchi and colleagues concluded the co-primary end points were not met. They described the mature randomized phase 3 data, including the exploratory ctDNA analyses, as practice-informing.¹ Necchi tied this partly to the future role of chemotherapy as a backbone for newer combination regimens.

“The combined analysis in the combined biomarker population corroborated the robustness of the ctDNA as a prognostic biomarker, either at baseline or after the neoadjuvant part,” Necchi said.

The trial was designed partly to guide future clinical or biomarker-based patient selection. Necchi reported no subgroup signal to support selecting patients for the nivolumab regimen.¹ The results add to a perioperative landscape in which the presentation cited positive phase 3 data for durvalumab plus GC and for enfortumab vedotin plus pembrolizumab.¹

REFERENCES

1. Necchi A, Gupta S, van der Heijden MS, et al. Results from a phase 3 trial of neoadjuvant (neoadj) chemotherapy alone vs in combination with nivolumab followed by postsurgical adjuvant nivolumab in patients (pts) with muscle-invasive bladder cancer (MIBC). Presented at: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. Abstract 4736O.

2. Galsky MD, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab in high-risk muscle-invasive urothelial carcinoma: Expanded efficacy from CheckMate 274. J Clin Oncol. 2025;43:15-21. doi:10.1200/JCO.24.00340

3. Powles T, Catto JWF, Galsky, MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391:1773-1786. doi:10.1056/NEJMoa2408154