Four-year landmark survival analysis of low-dose nivolumab added to metronomic chemotherapy in advanced head and neck squamous cell carcinoma: A phase III randomized trial.

6054 Background: In advanced head and neck squamous cell carcinoma (HNSCC), the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC-I) previously demonstrated an overall survival (OS) benefit versus triple metronomic chemotherapy (TMC) alone. We report extended follow-up with a 4-year landmark survival analysis to assess the durability of benefit. Methods: This was an open-label, randomised, phase III superiority trial enrolling 151 adult patients (≥18 years) with relapsed–recurrent or newly diagnosed advanced HNSCC with ECOG performance status 0–1, and adequate organ function. Patients were randomized 1:1 to receive oral TMC comprising of Methotrexate 9 mg/m² weekly, Celecoxib 200 mg twice daily and Erlotinib 150 mg daily, with (TMC-I) or without (TMC) nivolumab 20 mg intravenously every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was OS. Survival outcomes were analyzed using Kaplan–Meier methods, log-rank tests, and Cox proportional hazards models. A 4-year landmark analysis was performed. Results: At a median follow-up of 55.6 months (95% CI, 45.0–66.2), the median OS was 6.60 months (95% CI, 5.74–7.47) in the TMC arm and 9.33 months (95% CI, 8.00–10.66) in the TMC-I arm (p = 0.045). Treatment with TMC-I was associated with a 29% reduction in the risk of death [hazard ratio (HR), 0.709; 95% CI, 0.506–0.994; p = 0.046]. At 3 years, OS was 5.1% (95% CI, 1.7–12.3) with TMC versus 13.6% (95% CI, 9.7–26.3) with TMC-I [HR 0.686; 95% CI, 0.485–0.971; p = 0.033]. On 4-year landmark analysis, overall survival curve separation was maintained, with OS remaining superior in the TMC-I arm. The median PFS was 4.50 months (95% CI, 3.89–5.12) with TMC and 6.47 months (95% CI, 4.02–8.93) with TMC-I (p = 0.007). The OS benefit with TMC-I was consistent across pre-specified subgroups including age, gender, ECOG performance status, disease site, prior platinum exposure, and tumour programmed death ligand (PD-L1) expression. Conclusions: With extended follow-up exceeding 4.5 years, the addition of low dose nivolumab to triple metronomic chemotherapy demonstrates a clinically meaningful, durable and statistically significant survival advantage at a 4-year landmark in a predominantly relapsed/refractory advanced HNSCC population compared with TMC alone, confirming the long-term clinical benefit of this strategy in the palliative setting. Clinical trial information: CTRI/2020/11/028953.