NEXT: A phase 2 study of nivolumab adjuvant to chemoradiation in patients (pts) with localized urothelial carcinoma.
Authors: Galarza Fortuna Gliceida , Grass G. Daniel , Maughan Benjamin L. , Jain Rohit K. , Dechet Christopher B. , Beck Julia , Schuetz Ekkehard , Sanchez Alejandro , ONeil Brock , Poch Michael Adam , Li Roger , Lloyd Shane , Tward Jonathan David , Phunrab Tenzin Kunsang , Hawks Josiah , Swami Umang , Boucher Kenneth M. , Agarwal Neeraj , Gupta Sumati 
Published: January 2024

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Background: Definitive chemoradiation (CRT) is the preferred bladder preservation treatment for non-metastatic urothelial cancer (nmUC). The NEXT trial (NCT03171025) evaluated the efficacy of adjuvant nivolumab to definitive CRT in pts with nmUC. Methods: This multicenter study enrolled nmUC pts who received standard-of-care CRT. Nivolumab 480 mg was administered every 4 weeks for up to 12 doses. Primary endpoint: failure-free survival (FFS) at 2 years (yrs). Secondary endpoint: safety. This is the first efficacy and safety analysis after completion of enrollment, and correlation of disease risk features, and changes in plasma cell-free DNA (cfDNA) with outcomes. Shallow whole genome sequenced data from plasma cfDNA was mapped to the human reference genome (HG19), and copy number instability (CNI) Score (Oncocyte) was derived from statistically significant altered regions. Results: From 8/03/2017 to 1/25/2023, 28 pts were enrolled. The median age was 72 yrs (range 54-86 yrs). Ten patients (36%) had ≥ T3 and/or N+ disease. At time of data cut-off (9/14/23), median nivolumab cycles were 8.5 (range 1-12), and median follow-up was 11 months (range 6 - 45). FFS at 2 yrs (n=24) was 38.7 % (95% CI 23%-65.2%). Disease relapse occurred in 16 pts, of which 9 had local recurrences. Grade ≥3 treatment-related adverse events (AEs) occurred at a frequency of 10.7%. These were elevated transaminases, diarrhea, and polymyalgia rheumatica. Grade 3 radiation therapy oncology group (RTOG) AEs occurred in 2 pts. One or more high-risk disease features (ie. plasmacytoid differentiation, T4, N+, multiple tumors, tumors > 5 cm, residual disease before CRT, CIS, and hydronephrosis) were present in 22 pts (79%). In a Cox proportional hazards model, the number of high-risk features was a significant predictor of progression (p = 0.006). Each additional high-risk feature was associated with a hazard ratio for progression of 1.77 (95% CI 1.17-2.67). Median CNI (mCNI) on C1D1 of nivolumab in relapsed pts was 31 (range 3-232) vs. 24 (range 3-109) in pts with ongoing response. The mCNI on C4D1 for pts who progressed was 15.5 (range 6-371) vs. 9 (range 3-65) in pts with ongoing response. Oncogenic gene copy number changes and the associated pathways associated with progression are listed in the table. Conclusions: Adjuvant nivolumab to CRT for nmUC has promising efficacy with tolerable AEs, even in pts with high-risk disease. Disease relapse correlates with high-risk clinical features and CNI in plasma cfDNA. Oncogenic copy number changes in genes involved in DNA repair, RTK-RAS-PI3K, WNT, and cell cycle pathways are present in cfDNA of those who progressed (Table). Clinical trial information: NCT03171025 . [Table: see text]