Nivolumab adjuvant to chemo-radiation in localized muscle-invasive urothelial cancer: primary analysis of a multicenter, single-arm, phase II, investigator-initiated trial (NEXT)

Abstract

Background: Muscle-invasive urothelial cancer (UC) has a high risk of recurrence after definitive treatment. Nivolumab adjuvant to radical surgery improves disease-free survival in patients with UC with a high risk of recurrence; however, its role adjuvant to chemoradiation therapy (CRT) is unknown.

Methods: The NEXT trial is a single-arm, phase-2 study evaluating the efficacy and tolerability of nivolumab adjuvant to CRT in patients with localized or locoregional UC. The primary endpoint is failure-free survival (FFS) at 2 years. Secondary endpoints include patterns of recurrence, toxicity and quality of life (QoL). Plasma cell-free DNA (cfDNA) was subjected to shallow whole-genome sequencing to correlate with outcomes.

Results: 28 patients were enrolled and received 480 mg of nivolumab intravenously every 4 weeks for up to 12 cycles adjuvant to CRT. The FFS at 2 years was 33.2% (95% CI 18.5% to 59.6%). Nine (32%) patients had localized progression, and eight (29%) had distant progression. 25 (89%) had one or more high-risk features (ie, plasmacytoid differentiation, T4, N+, multiple tumors, tumors >5 cm, residual disease before CRT, carcinoma in situ, and hydronephrosis). Patients with ≤2 high-risk features had a median FFS of 45.2 months (95% CI 14.56 to not reached (NR)) compared with 8.2 months (95% CI 7.1 to NR) in those with three or more risk features (p=0.0024). Nivolumab-associated treatment-related adverse events occurred in 18 (64.3%) patients, only 3 had grade 3 TRAEs, with significant changes in QoL. Plasma cfDNA copy number instability (CNI) scores ≤25 before the first dose of adjuvant nivolumab and at cycle 4 were associated with better overall survival compared with CNI scores ≥26 (49.6 months vs 20.5 months, p=0.0024). Genome copy number changes indicated chromatin remodeling and tyrosine kinase pathways, among others, as oncogenic drivers implicated in progression.

Conclusion: Nivolumab adjuvant to CRT in localized or locally advanced UC is well tolerated. Stratification by risk factors and correlation with plasma cfDNA analyses generate hypotheses for potential patient selection and putative therapeutic targets for future study.

Trial registration number: NCT03171025.

Keywords: Bladder Cancer; Circulating tumor DNA - ctDNA; Immune Checkpoint Inhibitor.

Figure 1. (A) Study schema. (B) Consolidated Standards of Reporting Trials diagram. AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance status; SOC, standard of care.

Figure 2. Kaplan-Meier curves for (A) failure-free survival (FFS) at 2 years from start of chemoradiation for the overall population; (B) overall survival (OS) for the overall population; (C) FFS stratified by risk factors; (D) mOS stratified by risk factors; (E) mOS stratified by CNI on C1D1; (F) mOS stratified by CNI on C4D1. CNI, copy number instability; mFFS, median FFS; mOS, median OS; NR, not reached.