As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)

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Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. Patients and methods: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with 25% of tumour cells expressing PD-L1 [TC 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: Among evaluable patients (n Z 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9e24.4); 29.4% (95% CI, 15.1e47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5e21.3) for HPV-negative patients. Median PFS and OS for treated patients (n Z 112) was 2.1 months (95% CI, 1.9e3.7) and 7.1 months (95% CI, 4.9e9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5e22.1) and 33.6% (95% CI, 24.8e42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade 3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. Conclusion: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in firstand second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.

IMPORTANCE Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES Safety and tolerability and efficacy measured by objective response rate. RESULTS Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02319044