Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma (PULA HNSCC)

Abstract

Background: Concurrent IMRT with cetuximab (C), an EGFR-specific antibody for PULA HNSCC is suboptimal for intermediate-risk (IR) or high risk (HR) HNSCC. CTLA-4+Tregs dampen cellular immunity and correlate negatively with clinical outcomes. Thus, we conducted a phase I study adding ipilimumab (ipi), an anti-CTLA- 4Ab to standard C-IMRT in patients (pts) with intermediate or high risk PULA HNSCC. Methods: Key eligibility: stage III-IVb PULA HNSCC [pharynx, larynx]; highrisk [HPV-] or intermediate risk [HPV+and either: ≥ 10 pack-year tobacco and ≥N2 disease; or T4 or N3 disease]. A phase I [3+3] dose escalation design was used to establish a recommended phase II dose [RP2D). Dose limiting toxicity [DLT] was defined as any grade 4 adverse event [AE] except in-field radiation dermatitis or any immune-related [ir] AE requiring ≥ 2 weeks of systemic steroids. Results: From July 2013-May 2016, 18 pts enrolled: 5 larynx, 3 hypopharynx, 3 HPVoropharynx, 7 HPV+ oropharynx; 14 smokers; 2 stage III, 13 stage IVa, 3 stage IVb. Two of 6 pts incohort 1 experienced grade 3 dermatologic DLT's: perforating folliculitis and autoimmune dermatitis. Cohort -1 was expanded to N=12 without DLT's. irAE included: grade 1, 2, and 3 dermatitis [2, 1, and 3 cases], grade 4 colitis [1], and grade 1 hyperthyroidism [1]. Four pts recurred, 3 of whom died. Five patients remain diseasefree for >2 years. Median follow up for disease-free patients was 14 months [range 5 - 37 months]. The probability of 2-year overall survival was 71% [95% CI: 49% - 100%]. The two-year probability of progression- free survival was 77% [95% CI: 59% - 100%]. Immune biomarkers demonstrated modulation of suppressive regulatory T cell [Treg] subsets. Conclusions: Ipi plus C-IMRT is tolerable and yields acceptable survival without cytotoxic chemotherapy for IR and HR patients. The RP2D for ipi plus C-IMRT is 1mg/kg weeks 5, 8, 11, and 14. Treg biomarkers are modulated by this type of immunotherapy.