ATHENA: A multicenter phase II of atezolizumab (A) and bevacizumab (B) in patients (pts) with recurrent or metastatic squamous-cell carcinoma of the head and neck (R/M HNSCC) - The HPV-negative cohort

The standard therapy for R/M HNSCC includes anti-PD1. The combination A + B could be synergistic according to encouraging antitumor activity and safety in various tumor types and approval for hepatocellular carcinoma. This imCORE network investigator-initiated, multi-center, single arm, phase 2 trial evaluated the combination of A (1200 mg) + B (15 mg/kg), given intravenously every 3 weeks, after progression on platinum-based chemotherapy in R/M HNSCC pts naïve for anti-PD1. The primary endpoint was objective response rate as per RECIST V1.1 after 18 weeks of treatment (ORR18W). The trial used an adaptive Simon 2-stage design. In the HPV-negative cohort, we hypothesized that excluding an ORR18W ≤15% (null hypothesis) while targeting an ORR18W ≥30% (relevant hypothesis, power 80%) or ≥35% (high hypothesis, power 90%) would be an optimal approach. At the end of the stage I, if less than 5 objective response were reported in the first 27 evaluable patients, the study will be closed for futility. Secondary endpoints included: disease control rate as per RECIST V1.1 after 18 weeks (DCR18W), progression free survival (PFS), overall survival (OS) and adverse events (AE). A total of 30 pts (24 male, median age: 64.0 years [range:39.0-77.0]) were enrolled in the HPV-negative cohort. Among the 28 pts evaluable for primary endpoint, the ORR18W was 3.6% (1 /28, unilateral 95% lower confidence limit: 0.2%). The DCR-18W was 17.9% (95%CI: 6.1-36.9). With a median follow-up of 75.1 weeks (range: 2.9-100.9), the median PFS and OS were 6.2 (95%CI: 5.7 - 12.7) and 41.1 weeks (95%CI: 28.4 - 80.4), respectively. Main AE (≥ 10%, all grades) related to A were thyroid disorders, diarrhea, fatigue, transaminase increased, arthralgia and pruritus. Main AE (≥ 10%, all grades) related to B were fatigue, proteinuria and hypertension. Eleven pts (weeks 36.7 %) experienced at least one Grade ≥3 related AE and 13.3% at least one SAE related to study drugs including one sudden death. Based on the first stage of this study, the efficacy of A+B is limited in HPV-negative RM-HNSCC and does not warrant further investigation.