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A 62-year-old man with a history of smoking and excess alcohol use presented with a two-month history of hoarseness and dysphagia and was diagnosed with laryngeal squamous cell carcinoma. Five months after completing concurrent cisplatin and radiation therapy, he returns to his oncologist with lung metastases. He asks about additional therapeutic options for his cancer diagnosis. How would you advise him?
This patient is one of 52,000 people in the United States diagnosed every year with squamous-cell carcinoma of the head and neck (SCCHN). SCCHN is a worldwide condition that arises from squamous cells lining mucosal surfaces of the head and neck. It is associated with alcohol and tobacco use, poor oral hygiene, consuming certain preserved foods, chewing betel nuts, and infection with human papillomavirus or Epstein-Barr virus. Recurrent SCCHN is thought to be driven by immune evasion via tumor expression of ligands (PD-L1) for the immune-checkpoint receptor programmed death-1 (PD-1). Therefore, nivolumab — an anti–PD-1 monoclonal antibody — represents a potential therapeutic candidate. Nivolumab has been approved for treatment of metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma.
In this week’s issue of NEJM, Ferris and colleagues compared the efficacy of nivolumab to single-agent systemic chemotherapy in a phase 3 randomized, controlled, open-label study in 361 patients with recurrent SCCHN whose disease had progressed within six months after platinum-based chemotherapy. Patients in the nivolumab group received intravenous nivolumab (3 mg/kg) every two weeks. Patients in the single-agent chemotherapy group received a weekly dose of intravenous methotrexate (40–60 mg/m2), docetaxel (30–40 mg/m2), or cetuximab (250 mg/m2) after a loading dose of 400 mg/m2. The primary endpoint was overall survival, defined as the time from randomization to date of death from any cause. Secondary endpoints were progression-free survival, objective tumor response based on imaging, safety, and quality of life.
Among the 240 patients who received nivolumab and the 121 patients who received single-agent chemotherapy, median overall survival was significantly longer in the nivolumab group (7.5 vs. 5.1 months; hazard ratio, 0.70; 97.73% CI: 0.51 to 0.96; P=0.010). Progression-free survival did not differ significantly between the two groups. The authors performed an exploratory biomarker analysis to compare the treatment effect in patients based on their tumor PD-L1 expression status and p16 status. Median overall survival was longer with nivolumab, regardless of tumor PD-L1 expression or p16 status.
Nivolumab was associated with fewer severe adverse events than single-agent chemotherapy (13.1% vs. 35.1%). The most frequently reported adverse events with nivolumab were fatigue, rash, pruritus, nausea, and decreased appetite. Nivolumab was associated with more skin-related side effects and fewer gastrointestinal events than single-agent chemotherapy. Serious adverse events in the nivolumab group included one case of pneumonitis and one report of hypercalcemia. Patients in the nivolumab group reported better quality of life (including physical functioning, pain, sensory problems, and social contact problems) than patients in the single-agent chemotherapy group.
In this study, nivolumab led to improved overall survival, fewer severe adverse events, and better quality of life in patients with recurrent SCCHN refractory to platinum-based chemotherapy. Importantly, nivolumab not only extended overall survival but also contributed to better functioning for patients with this aggressive cancer that often affects vital areas of speech and swallowing.
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Jennifer Yeh is an eighth-year MD/PhD student at Harvard Medical School. She is originally from Los Angeles, CA, and graduated from the Massachusetts Institute of Technology in 2009. She completed her PhD in Biological & Biomedical Sciences in 2015 on molecular modulators of the oncogenic transcription factor STAT3 in the lab of Dr. David Frank.