KEY TAKEAWAYS
- The NEXT phase 2 trial aimed to investigate the efficacy of adjuvant nivo in combination with definitive CRT for nmUC patients.
- The primary endpoint was FFS.
- Researchers noticed a promising efficacy of adjuvant nivo with manageable adverse events, highlighting its potential in high-risk nmUC patients.
Definitive chemoradiation (CRT) is the cornerstone for preserving bladder function in non-metastatic urothelial cancer (nmUC). However, therapeutic advancements are continually sought to improve outcomes.
With the NEXT trial, Gliceida Galarza Fortuna and her team aimed to evaluate the efficacy of adjuvant nivo in conjunction with definitive CRT in patients with nmUC.
They performed an inclusive analysis in this multicenter study, enrolling patients with nmUC who received standard-of-care (SOC) CRT. Nivolumab, administered at a dosage of 480 mg every 4 weeks for up to 12 doses, served as the investigational adjuvant therapy. The primary endpoint was the assessment of failure-free survival (FFS) at 2 years, with safety as a secondary endpoint.
This analysis represents the first evaluation of efficacy and safety following enrollment completion, alongside correlation studies of disease risk features and changes in plasma cell-free DNA (cfDNA) with clinical outcomes. Shallow whole-genome sequencing of plasma cfDNA was conducted and mapped to the human reference genome (HG19), with a derived Copy Number Instability (CNI) Score (Oncocyte) from statistically significant altered regions.
About 28 patients were enrolled in the study from August 3, 2017, to January 25, 2023. The median age of the participants was 72 years (range 54-86 years), with 10 patients (36%) having ≥ T3 and/or N+ disease. As of the data cut-off on September 14, 2023, the median number of nivolumab cycles administered was 8.5 (range 1-12), and the median follow-up duration was 11 months (range 6-45 months).
The FFS rate at 2 years for (n=24) patients was 38.7% (95% CI 23%-65.2%). Disease relapse occurred in 16 patients, with 9 experiencing local recurrences. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 10.7% of patients, including elevated transaminases, diarrhea, and polymyalgia rheumatica. Additionally, in the Grade 3 radiation therapy oncology group (RTOG), adverse events occurred in 2 patients.
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 patients (79%), and in a Cox proportional hazards model, the number of high-risk features significantly predicted progression (P = 0.006), with each additional high-risk feature associated with a hazard ratio for progression of 1.77 (95% CI 1.17-2.67). Median Copy Number Instability (mCNI) at the start of nivolumab treatment was higher in relapsed patients compared to those with ongoing response 31 (range 3-232) vs. 24 (range 3-109), and the mCNI on C4D1 for patients who progressed was 15.5 (range 6-371) vs. 9 (range 3-65) in patients with ongoing response. Oncogenic gene copy number changes and the associated pathways associated with progression.
The study concluded that adjuvant nivolumab and CRT therapy for nmUC demonstrate promising efficacy and manageable adverse events, particularly in patients with high-risk disease. Disease relapse appears to correlate with high-risk clinical features and Copy Number Instability (CNI) in plasma cfDNA. Moreover, oncogenic copy number changes in genes associated with DNA repair, RTK-RAS-PI3K, WNT, and cell cycle pathways suggest potential molecular mechanisms underlying disease progression.
The study was sponsored by the University of Utah
Source:https://meetings.asco.org/abstracts-presentations/229760
Clinical Trial: https://clinicaltrials.gov/study/NCT03171025
Fortuna G G, Grass G D, Maughan B L, et al. (2024). “NEXT: A phase 2 study of nivolumab adjuvant to chemoradiation in patients (pts) with localized urothelial carcinoma.” Presented at ASCO GU 2024 (Abstract 612).
