Phase I trial of cetuximab, radiation therapy, and ipilimumab in locally advanced head and neck cancer
Mené entre 2013 et 2016 sur 18 patients atteints d'un carcinome épidermoïde de la tête et du cou de stade III-IVb, cet essai de phase I évalue la toxicité de l'ajout de l'anticorps anti-CTLA-4 ipilimumab au traitement combinant cétuximab et radiothérapie
Background: Concurrent radiation therapy (RT) with cetuximab, an anti-EGFR monoclonal antibody (mAb), is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). CTLA-4+ T regulatory cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added anti-CTLA-4 mAb ipilimumab to cetuximab-RT. Methods: A [3 + 3] design established the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, q3-week doses to fixed, standard cetuximab-RT. Eligible subjects had stage III‐IVb, high-risk (HPV-) or intermediate-risk (HPV+) HNSCC. Dose limiting toxicity (DLT) was defined as grade 4 adverse event (AE) except in‐field radiation dermatitis or immune‐related (ir) AE requiring {greater than or equal to} 2 weeks of systemic steroids. Tumor and blood were collected for correlatives. Results: From July 2013‐May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering de-escalation 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 (OS) were 72% (90% CI: 57-92%) and 72% (90% CI: 56-92%). High expression of co-inhibitory receptors PD1/LAG3/CD39 on tumor-infiltrating Treg associated with worse DFS (HR=5.6, 95% CI: 0.83-37.8, p=0.08). Conclusions: The RP2D for ipilimumab plus cetuximab‐RT is 1mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy. Clinical trial information: NCT01935921