Low-dose immunotherapy in head and neck cancer: a randomised study (Tata Memorial)
Giving about one-twentieth of the standard dose of nivolumab alongside cheap oral chemotherapy nearly tripled one-year survival in advanced head and neck cancer, showing that immunotherapy can be made affordable without losing its effect.
Overview
Open-label phase 3 randomising 151 patients with advanced head and neck squamous cell carcinoma being treated with palliative intent to triple oral metronomic chemotherapy with or without nivolumab 20 mg flat every 3 weeks. One-year overall survival was 43.4% (95% CI 30.8-55.3) with nivolumab versus 16.3% (8.0-27.4) without; median overall survival 10.1 versus 6.7 months (hazard ratio 0.545; 95% CI 0.362-0.820; P=0.0036); grade 3 or worse adverse events 46.1% versus 50%.
The dose is roughly 6% of the approved flat dose and the drug cost correspondingly small. The trial has become the reference case for dose-optimisation in immuno-oncology and for pragmatic trials in low- and middle-income countries.
- One-year overall survival 43.4% with low-dose nivolumab versus 16.3% without.
- Median overall survival 10.1 versus 6.7 months; hazard ratio 0.545 (95% CI 0.362-0.820).
- No increase in grade 3 or worse adverse events (46.1% versus 50%).
- Nivolumab dose was a flat 20 mg every 3 weeks, a small fraction of the licensed dose.
For the majority of the world's head and neck cancer patients who cannot afford full-dose checkpoint inhibitors, a low dose added to oral metronomic chemotherapy is a tested alternative that improves survival. It also challenges the assumption that approved doses are the necessary doses: pharmacology had long suggested receptor saturation at far lower exposures.
- Single-centre and open-label; the comparator was metronomic chemotherapy rather than the standard-dose immunotherapy used in high-income settings.
- Whether low-dose nivolumab matches full-dose nivolumab head to head is untested.
- Patients were mostly tobacco-related, HPV-negative oral cancers, so applicability to oropharyngeal HPV-positive disease is unknown.
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