Based on improved survival and favorable toxicity profiles, immunotherapy with anti-PD-1 agents (pembrolizumab, nivolumab) has become the standard of care in recurrent/metastatic squamous cell head and neck cancer (R/M SCCHN) in the first- and second-line settings. Nevertheless, in low- and middle-income countries, only 1 – 3% of patients with R/M SCCHN have access to immunotherapy, as recommended by the international guidelines. In countries like India, patients often receive palliative treatment with metronomic chemotherapy regimens, based on results from regional trials that showed improved patient outcomes. Retrospective analyses across different cancer types, including SCCHN, indicate that nivolumab may be effective at doses as low as 0.3 mg/kg once every 3 weeks.

These data led Indian investigators to conduct a randomized phase III study to evaluate whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improves overall survival (OS) compared with TMC alone in patients with R/M SCCHN. Patients with platinum-refractory and platinum-nonrefractory R/M SCCHN (n= 151) were randomized to the all-oral TMC regimen (methotrexate 9 mg/m² once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily) or TMC plus low-dose intravenous nivolumab (20 mg flat dose once every 3 weeks). The primary endpoint was 1-year OS. The addition of low-dose nivolumab to TMC improved the 1-year OS compared with TMC alone (43.4% vs. 16.3%; hazard ratio, 0.545; P = 0.0036). At a median follow up of 10.9 months, median OS was 10.1 months in the immunotherapy arm vs. 6.7 months in the TMC arm (P = 0.0052) and median progression-free survival (mPFS) was 6.6 months vs. 4.6 months, respectively (P = 0.002). The survival benefit with low-dose nivolumab was seen across all subgroups regardless of PD-L1 status. Response rates with low-dose nivolumab were not significantly higher compared with metronomic therapy alone (59.2% vs. 45.3%; P = 0.104); however, the median duration of response was around 5 months longer in the immunotherapy arm (8.7 months vs. 3.3 months; P = 0.003). Importantly, the addition of low-dose nivolumab to metronomic chemotherapy did not increase adverse events, and quality-of-life scores were relatively better than for patients in the TMC alone arm.

According to the investigators’ conclusions, these results support the use of low-dose nivolumab plus metronomic chemotherapy as an alternative standard of care for patients who cannot access full-dose immune checkpoint inhibitors. The authors of an accompanying editorial highlighted that the findings of the study are “most notable not for the magnitude of clinical benefits but for the dose of nivolumab used to achieve them,” which is only about 6% of the doses approved by regulatory agencies in the US or Europe. They emphasized that the savings from this alternative nivolumab dosing schedule may allow low- and middle-income countries to increase patients’ access to immunotherapy. Based on significant reductions in healthcare costs with ultra-low-dose immunotherapy, the authors comment that there is “an urgent need for near-equivalence studies to further investigate the clinical outcomes associated with dose de-escalation.”

References:
Patil VM, et al. J Clin Oncol. 2022, October 20 [Online ahead of print].
Mitchel AP and Goldstein DA. J Clin Oncol. 2022, October 20 [Online ahead of print].