Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer

Robert L. Ferris, Jessica Moskovitz, Sheryl Kunning, Ayana T. Ruffin, Carly Reeder, James Ohr, William E. Gooding, Seungwon Kim, Brian J. Karlovits, Dario A.A. Vignali, Umamaheswar Duvvuri, Jonas T. Johnson, Daniel Petro, Dwight E. Heron, David A. Clump, Tullia C. Bruno, Julie E. Bauman

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Purpose: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4–positive (CTLA-4þ) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti–CTLA-4 mAb, to cetuximab-radiotherapy. Patients and Methods: A (3 þ 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus–negative (HPV-)] or intermediate-risk HPV-positive (HPVþ)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. Results: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation 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 were 72% [90% confidence interval (CI), 57–92] and 72% (90% CI, 56–92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83–37.8; P = 0.08). Conclusions: The RP2D for ipilimumab plus standard cetuximab–radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

Original languageEnglish (US)
Pages (from-to)1335-1344
Number of pages10
JournalClinical Cancer Research
Issue number7
StatePublished - Apr 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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