Phase I trial of cetuximab, radiation therapy, and ipilimumab in locally advanced head and neck cancer

Background: Concurrent radiation therapy (RT) with cetuximab, an anti-EGFR monoclonal antibody (mAb), is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). CTLA-4+ T regulatory cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added anti-CTLA-4 mAb ipilimumab to cetuximab-RT. Methods: A [3 + 3] design established the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, q3-week doses to fixed, standard cetuximab-RT. Eligible subjects had stage III‐IVb, high-risk (HPV-) or intermediate-risk (HPV+) HNSCC. Dose limiting toxicity (DLT) was defined as grade 4 adverse event (AE) except in‐field radiation dermatitis or immune‐related (ir) AE requiring {greater than or equal to} 2 weeks of systemic steroids. Tumor and blood were collected for correlatives. Results: From July 2013‐May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering de-escalation of ipilimumab to 1 mg/kg. Dose Level ‐1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival (OS) were 72% (90% CI: 57-92%) and 72% (90% CI: 56-92%). High expression of co-inhibitory receptors PD1/LAG3/CD39 on tumor-infiltrating Treg associated with worse DFS (HR=5.6, 95% CI: 0.83-37.8, p=0.08). Conclusions: The RP2D for ipilimumab plus cetuximab‐RT is 1mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy. Clinical trial information: NCT01935921