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

Abstract

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-4+) 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 + 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 (HPV+)] 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 7 Pg. 1335-1344 (04 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35091445 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Ipilimumab
• Cetuximab

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cetuximab (adverse effects)
• Dermatitis (drug therapy, etiology)
• Head and Neck Neoplasms (drug therapy)
• Humans
• Ipilimumab (adverse effects)
• Papillomavirus Infections (drug therapy)
• Squamous Cell Carcinoma of Head and Neck (drug therapy, etiology)