Nivolumab and Ipilimumab Combined with Definitive Radiation Therapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: In-field Toxicity Analysis of a Phase I Clinical Trial

Abstract

Cisplatin added to radiation therapy (RT) for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is associated with a modest improvement in survival at the cost of increased toxicity, highlighting the need for newer agents. Immune checkpoint inhibitors (ICI) have a favorable safety profile and are the standard of care in recurrent/metastatic SCCHN, but their role in the definitive setting with RT remains to be determined. We conducted a single institution clinical trial assessing the safety of combined nivolumab (Nivo), a PD-1 inhibitor, and ipilimumab (Ipi), a CTLA-4 inhibitor, with concurrent RT in patients with high risk LA-SCCHN. Newly diagnosed, chemotherapy eligible patients (pts) with stage IVA-IVB p16(-) SCC of the oral cavity, oropharynx, larynx, and hypopharynx, or T4, N2c, or N3 p16(+) SCC of the oropharynx (AJCC 7th edition) were enrolled. Nivo (3 mg/kg Q2 weeks IV x17 doses) and Ipi (1 mg/kg Q6 weeks IV x6 doses) were administered 2 weeks prior to the start of RT. RT (70 Gy in 2 Gy daily fractions) was delivered to the primary tumor using VMAT and daily cone-beam CT IGRT. The primary objective was safety of combined ICI and RT. Between July 2017 and July 2019, 24 pts were enrolled with a median follow-up of 15 months (range 7-31); median age 60 (range 48-77); 20 male; 16 oropharynx (14 HPV+), 6 larynx, and 2 hypopharynx. All pts completed RT with no treatment delays. Seventeen out of twenty-four pts (71%) experienced grade 3 acute in-field adverse events (AE) consisting of mucositis (9), dysphagia (6), dermatitis (5), odynophagia (4), and dysphonia (1) during concurrent ICI-RT; there were no grade 4/5 AEs during ICI-RT. Five pts (22%) developed soft tissue ulcers (STU) at the primary tumor site during the ICI maintenance phase, one of which was not treated and led to a fatal carotid rupture. All STUs developed at a median of 91 (range 50-107) days post RT and were negative for viable tumor. Four primary site STUs were managed with either hyperbaric oxygen (HBO) (2), lingual artery embolization (1), or surgical debridement (1). One pt treated with HBO healed after 189 days while the pt who underwent debridement healed after 285 days. Two additional pts developed areas of necrosis at adjacent sites not involved by tumor, underwent surgical debridement, and healed after an average of 18.5 days. Two other pts experienced osteoradionecrosis (ORN) at sites of prior teeth extractions and were treated with HBO. Two pts experienced persistent inflammation without ulceration (PI). Six out of eleven pts (55%) with STU, necrosis, ORN, or PI discontinued maintenance ICI. Locoregional PFS is 100%. Combined PD-1 and CTLA-4 blockade with concurrent RT is associated with excellent locoregional control in high risk LA-SCCHN, albeit at the cost of in-field complications. Patients treated with such an approach should be closely monitored for soft tissue ulceration.