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. Experimental Design: Patients with R/M HNSCC were treated with cetuximab 500 mg/m2 IV Day (D) -14 as a lead-in followed by cetuximab 500 mg/m2 IV and nivolumab 240 mg IV on D1 and D15 of each 28-D 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% 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, median (log-rank p=0.05). Conclusion: The combination of cetuximab and nivolumab is effective in patients with both previously treated and untreated R/M HNSCC and warrants further evaluation.

Head and neck squamous cell carcinoma (HNSCC) has one of the most hypoxic and immunosuppressive tumor microenvironments (TME) among solid tumors. However, there is no proven therapeutic strategy to remodel the TME to be less hypoxic and proinflammatory. In this study, we classified tumors according to a Hypoxia-Immune signature, characterized the immune cells in each subgroup, and analyzed the signaling pathways to identify a potential therapeutic target that can remodel the TME. We confirmed that hypoxic tumors had significantly higher numbers of immunosuppressive cells, as evidenced by a lower ratio of CD8+ T-cells to FOXP3+ regulatory T-cells, compared to non-hypoxic tumors. Patients with hypoxic tumors had worse outcomes after treatment with pembrolizumab or nivolumab, anti-Programmed Cell Death-1 inhibitors. Our expression analysis also indicated that hypoxic tumors predominantly increased the expression of the epidermal growth factor receptor (EGFR) and transforming growth factor-β pathway genes. Cetuximab, an anti-EGFR inhibitor, decreased the expression of hypoxia signature genes, suggesting that it may alleviate the effects of hypoxia and remodel the TME to become more proinflammatory. Our study provides a rationale for treatment strategies combining EGFR-targeted agents and immunotherapy in the management of hypoxic HNSCC.

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The current paradigm of clinical trials treating patients until disease progression using maximum tolerated dose does not account for the dynamic tumor-host-drug interactions that result in acquired resistance. Here, we present the concept of an Evolutionary Tumor Board (ETB) and report interim results from a prospective, non-interventional pilot study in which novel therapeutic strategies based on evolutionary principles were developed under the ETB framework. The ETB approach relies on an interdisciplinary team that integrates clinical, preclinical, and theoretical knowledge and the application of mathematical modeling to predict patient responses to different therapies, including novel approaches derived from eco-evolutionary first principles. We have previously proposed several evolutionary therapies that aim to enhance the efficacy of an overall treatment regimen, using existing agents for a given disease. Key among these evolutionary therapies is the idea of first-strike second-strike, where different agents are administered in sequence, and new strikes are applied as soon as the efficacy of the previous strike is nearing a minimum, as opposed to waiting until progression is identified on periodic imaging. This approach requires careful analysis of longitudinal patient data coupled with predictive dynamics generated by mathematical models. Here we describe the ETB process and the interim results from 15 patients enrolled in the feasibility trial. In addition, we describe the challenges faced as well as the solutions that can be implemented via improved modeling approaches, better patient data collection, and a reassessment of how we understand tumor dynamics in the light of evolutionary principles.

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