Concurrent Cetuximab and Nivolumab as a Second-Line or beyond Treatment of Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results of Phase I/II Study

SIMPLE SUMMARY: To improve overall survival (OS), we evaluated a combination of cetuximab and nivolumab for toxicity and efficacy in patients with incurable recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). In addition, electronic health record-derived real-world data were used to provide clinical context for our prospective findings and to explore sequential treatment effects of cetuximab and immune checkpoint inhibitors (CPI) including nivolumab and pembrolizumab. The cetuximab and nivolumab combination was very well tolerated. Although patients with no prior CPI showed a trend for more favorable progression-free survival relative to patients with prior CPI, the improvement in the 1-year OS did not reach the statistical threshold in this heavily treated patients. Optimal sequencing of cetuximab and CPI may have an impact in prognosis and requires further evaluation in management of patients with incurable HNSCC. ABSTRACT: We hypothesized the combination of cetuximab and nivolumab would improve survival in recurrent and/or metastatic (R/M) HNSCC by providing synergy in cancer control and evaluated toxicities and efficacy of the combination. Effects of sequential administration of cetuximab and anti-Programmed Cell Death-1 checkpoint inhibitors (CPI) were also explored. Patients who failed at least one line of palliative treatment for incurable HNSCC were treated with cetuximab 500 mg/m(2) IV on Day (D)-14 as a lead-in followed by cetuximab 500 mg/m(2) IV and nivolumab 240 mg/m(2) IV on D1 and D15 every 28-D cycle. Electronic health record-derived real-world data (RWD) were used to explore sequential treatment effects of CPI and cetuximab. A total of 45 evaluable patients were analyzed, and 31/45 (69%) patients had prior exposure to either CPI or cetuximab. The only grade 4 treatment-related adverse event was cetuximab infusion reaction in one patient. The 1-year progression-free survival (PFS) and overall survival (OS) rates were 19% and 44%, respectively. Although patients with no prior CPI (23/45, 51%) showed a trend for more favorable PFS relative to patients with prior CPI (22/45, 49%), the improvement in the 1-year OS did not reach the statistical threshold. For evaluation of sequential CPI and cetuximab treatment effects, we selected RWD-cetuximab cohort with 173 patients and RWD-CPI cohort with 658 patients from 6862 R/M HNSCC. Our result suggested patients treated with RWD-cetuximab after RWD-CPI had worse OS compared to no prior RWD-CPI (HR 1.81, 95% CI 1.02–3.16). Our data suggest the combination of cetuximab and nivolumab is well tolerated. Optimal sequencing of cetuximab and CPI may have an impact in prognosis and requires further evaluation.