PURPOSE The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS).METHODS This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS.RESULTS One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P =.0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively (P =.0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively (P =.744).CONCLUSION To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.</p
