In an Indian single-center phase III trial reported in the Journal of Clinical Oncology, Vijay Patil, MBBS, MD, DM, and colleagues found that the addition of low-dose nivolumab to triple metronomic chemotherapy significantly improved overall survival in patients with newly diagnosed or recurrent advanced head and neck squamous cell carcinoma.

As stated by the investigators, “The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1% to 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.”

The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1% to 3% of patients in low- and middle-income countries because of their cost...To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved overall survival and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.

— Vijay Patil, MBBS, MD, DM, and colleagues

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Study Details

The trial enrolled 151 patients at Tata Memorial Hospital, Mumbai, between January 2021 and September 2021. They were randomly assigned to treatment in the palliative setting with nivolumab at a flat dose of 20 mg every 3 weeks plus triple metronomic chemotherapy with oral methotrexate at 9 mg/m² once per week, celecoxib at 200 mg twice daily, and erlotinib at 150 mg once daily (n = 76) or triple metronomic chemotherapy alone (n = 75); treatment continued until disease progression or unacceptable toxicity. A total of 61% of patients in the nivolumab/triple metronomic chemotherapy group and 53% in the triple metronomic chemotherapy group had prior exposure to chemotherapy. Among patients with known PD-L1 status, 62 of 70 in the nivolumab/triple metronomic chemotherapy group and 54 of 66 in the triple metronomic chemotherapy group had PD-L1–positive disease. The primary endpoint was 1-year overall survival.

Overall Survival

Median follow-up was 10.9 months (95% confidence interval [CI] = 10.6–12.2 months). Overall survival at 1 year was 43.4% (95% CI = 30.8%–55.3%) in the nivolumab/triple metronomic chemotherapy group vs 16.3% (95% CI = 8.0%–27.4%) in the triple metronomic chemotherapy group (hazard ratio [HR] = 0.545, 95% CI = 0.362–0.820, P = .0036). Median overall survival was 10.1 months (95% CI = 7.4–12.6 months) vs 6.7 months (95% CI = 5.8–8.1 months, P = .0052).

Median progression-free survival was 6.6 months (95% CI = 4.4–8.9 months) in the nivolumab/triple metronomic chemotherapy group vs 4.6 months (95% CI = 4.2–5.3 months) in the triple metronomic chemotherapy group (HR = 0.564, 95% CI = 0.389–0.816, P = .002).

Adverse Events

Among 76 vs 74 patients in the safety analysis, grade ≥ 3 adverse events occurred in 46.1% of the nivolumab/triple metronomic chemotherapy group vs 50.0% of the triple metronomic chemotherapy group (P = .744). The most common adverse events in both groups were hyponatremia (30.3% vs 27.0%), anemia (17.1% vs 10.8%), fatigue (9.2% vs 6.8%), and rash (9.2% vs 12.2%). Adverse events led to death in two patients in the nivolumab/triple metronomic chemotherapy group, due to aspiration pneumonia and hepatorenal syndrome resulting from hepatitis B virus reactivation.

The investigators concluded, “To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved overall survival and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.”

Kumar Prabhash, MBBS, MD, DM, of Tata Memorial Hospital, Mumbai, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Motivation for Excellence, Mumbai Oncology Association, NATCO Pharma Limited, and INTAS Pharmaceuticals Limited. For full disclosures of the study authors, visit ascopubs.org.