BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti–programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. METHODS In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. RESULTS The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P = 0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P = 0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. CONCLUSIONS Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636.)

Nivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up. OS benefit was observed with nivolumab irrespective of PD-L1 expression and HPV status. (Clinicaltrials.gov: NCT02105636).

Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%-17%), and median overall survival was 11.9 months (95% CI, 9.5-14.3 months). This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit. .

Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.