Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Abstract

Purpose: A phase II multi-institutional clinical trial was conducted to determine overall survival (OS) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with a combination of cetuximab and nivolumab.

Patients and methods: Patients with R/M HNSCC were treated with cetuximab 500 mg/m2 i.v. on day 14 as a lead-in followed by cetuximab 500 mg/m2 i.v. and nivolumab 240 mg i.v. on day 1 and day 15 of each 28-day cycle. Expression of p16 and programmed cell death-ligand 1 (PD-L1) in archived tumors were determined. Tumor-tissue-modified human papillomavirus (TTMV) DNA was quantified in plasma.

Results: Ninety-five patients were enrolled, and 88 patients were evaluable for OS with a median follow-up of 15.9 months. Median OS in the 45 patients who had prior therapy for R/M HNSCC (cohort A) was 11.4 months, with a 1 year OS 50% [90% confidence interval (CI), 0.43-0.57]. Median OS in the 43 patients who had no prior therapy (cohort B) was 20.2 months, with a 1-year OS 66% (90% CI, 0.59-0.71). In the combined cohorts, the p16-negative immunostaining was associated with higher response rate (RR; P = 0.02) but did not impact survival while higher PD-L1 combined positive score was associated with higher RR (P = 0.03) and longer OS (log-rank P = 0.04). In the p16-positive patients, lower median (1,230 copies/mL) TTMV DNA counts were associated with higher RR (P = 0.01) and longer OS compared with higher median (log-rank P = 0.05).

Conclusions: The combination of cetuximab and nivolumab is effective in patients with both previously treated and untreated R/M HNSCC and warrants further evaluation.

Figure 1.

Consort diagram of the clinical trial

Figure 2.

A) One-year overall survival (OS) of 50% with a 90% confidence interval (CI, 0.59-0.71), assuming an exponential distribution in patients with prior treatment for incurable RM HNSCC and persistent or platinum-refractory R/M HNSCC (Cohort A). The red dotted line represents 1-year OS assumption of 36%, estimated based on the historical data from programmed cell death 1 (PD-1) inhibitor monotherapy. The cyan line represents the 90% lower bound. The red solid line represents the 1 year time point. B) One-year OS of 66% with a 90% confidence interval (CI, 0.59-0.71), assuming an exponential distribution in patients with no prior treatment for incurable RM HNSCC (Cohort B). The red dotted line represents 1-year OS assumption of 46%, estimated based on the historical data from PD-1 inhibitor monotherapy. The cyan line represents the 90% lower bound. The red solid line represents the 1 year time point. C) Spider plot to illustrate the best response by percent changes in tumor measures over time (Cohort B): CR - complete response, PR - partial response, SD – stable disease, and PD – progressive disease. D) Waterfall plot to illustrate the best response by percent changes in tumor measurement in each patient (Cohort B): “+” - p16-positive HNSCC. “−“ - p16-negative HNSCC. Top 7 patients with the deeper responses are p16-negative HNSCC. E) Spider plot to illustrate the baseline and subsequent changes in the tumor-tissue-modified human papillomavirus (TTMV) DNA levels in p16-positive patients (Cohort A and B): N=105 plasma samples from 36 p16-positive patients. F) Spider plot to illustrate percent changes in TTMV DNA levels in 34 p16-positive patients with available baseline TTMV DNA measurement (Cohort A and B). The best response was determined by the RECIST criteria.

Figure 3.

Survival analyses of patients in both Cohort A and B based on biomarkers. A) Progression-free survival (PFS) and B) Overall survival (OS) comparison between p16-positive and p16-negative patients (N=88). C) PFS and D) OS comparison between patients with programed cell death ligand 1 (PD-L1) combined positive score (CPS) <1, 1-19, and ≥20 (N=79). E) PFS and F) OS comparison between >median and <median 1,230 copies/mL of TTMV DNA in p16-positive patients (N=36).