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.

Recent findings on the impact of ErbB receptors status on prognosis and therapy of head and neck squamous cell carcinoma

“…To mention a few of the ongoing studies, the triple combination of ICIs, Cetuximab and radiotherapy for patients with advanced HNSCC is being investigated in clinical trials employing the anti-PD-L1 antibodies Avelumab and Durvalumab and the anti-CTLA-4 antibody Ipilimumab ( Table 2 ; 157 ). As regards the Cetuximab/Ipilimumab/radiotherapy combination, preliminary results indicate that the efficacy of this regimen is comparable to that of the standard cisplatin/radiotherapy combination in terms of progression-free and overall survival but offers the advantage of avoiding the administration of the heavily cytotoxic cisplatin ( 125 ). The combination of Cetuximab and ICIs such as Pembrolizumab or Avelumab is also investigated in patients with recurrent/metastatic HNSCC ( Table 2 ), and promising clinical activity has been reported for the Cetuximab/Pembrolizumab combination ( 126 ).…”

Combination therapy with oncolytic viruses and immune checkpoint inhibitors in head and neck squamous cell carcinomas: an approach of complementary advantages

“…This was the first ICI to receive FDA approval for commercial use, ushering in a new era of tumor immunotherapy. A phase I clinical trial (NCT01935921) of cetuximab, radiotherapy, and ipilimumab to treat locally advanced head and neck cancer showed that the RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg [ 78 ]. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.…”

Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

“…While ICIs inhibit existing cells, in a way that is complementary to the congenital adaptive immune system, they also interact with a variety of immune cells, thus enhancing the synergistic effect [47]. Ferris et al conducted a phase I trial (NCT01935921) of cetuximab plus radiotherapy combined with ipilimumab (CTLA-4 mab) for LAHNSCC [48]. It was the first time that radiotherapy plus double target immunotherapy (cetuximab plus ipilimumab) was tested in LAHNSCC patients, who received conventional cetuximab plus radiotherapy, with an additional dose of ipilimumab (1 mg/kg) at 5, 8, 11 and 14 weeks of treatment [48].…”