Follicular lymphoma (FL) outcomes are heavily influenced by host immune activity with immune anti-tumor activity mitigated by PD-1/PD-L1 pathway engagement. Combination CD20-directed therapy plus PD-1 inhibition (PD-1i) increases T-cell tumor killing and NK-cell antibody-dependent cell cytotoxicity (ADCC). Mounting evidence supports immune-priming using PD-1i before cancer-directed agents. Our multicentre, open-label, phase II 1st FLOR study (NCT03245021) enrolled 39 previously-untreated advanced-stage FL patients to receive 4 cycles of nivolumab (240mg) then 4 cycles of 2-weekly nivolumab plus rituximab 375mg/m2 (induction) then 1 year of monthly nivolumab (480mg) plus 2 years of 2-monthly rituximab maintenance. Participants with complete response (CR) after nivolumab priming continued nivolumab monotherapy. The primary endpoint was toxicity during induction. Adverse events (AEs) ≥ grade 3 during induction occurred in 33% (n=13); most commonly elevated amylase/lipase (15%), liver enzyme derangement (11%) and infection (10%). Three patients discontinued nivolumab secondary to toxicity; two pancreatitis, one acute kidney injury. Overall response rate (ORR) was 92% (CR 59%). Median follow-up was 51 months. Median and 4-year progression-free survival (PFS) were 61 months (95%CI 2-72) and 58% (95%CI 34-97); 70% of responders remained in CR. 4-year overall survival was 95%. High baseline total metabolic tumor volume and total lesion glycolysis conferred inferior PFS (p=0.04 and p=0.02). Additionally, high baseline tumor CD8A gene expression was associated with improved PFS (p=0.03). Nivolumab priming followed by nivolumab-rituximab in treatment-naive FL is associated with favorable toxicity and high response rates potentially providing an alternative to chemotherapy. TMTV and high tumor CD8A expression are promising immunotherapy biomarkers for FL.
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