The phase III KEYNOTE-048 trial is examining the efficacy of pembrolizumab alone, pembrolizumab/cisplatin or carboplatin/fluorouracil (5-FU), or cetuximab/cisplatin or carboplatin/5-FU as first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma. At the second interim study analysis, pembrolizumab significantly improved overall survival in the study populations with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of ≥ 20 and ≥ 1, and had noninferior overall survival in the total population with favorable safety. Pembrolizumab/chemotherapy significantly improved overall survival in the total population with comparable safety. At the 2019 ASCO Annual Meeting, Rischin et al presented the protocol-specified final results of the trial (Abstract 6000).
KEYNOTE-048 enrolled 882 patients with locally incurable recurrent or metastatic head and neck cancer who had no prior systemic therapy in the recurrent or metastatic setting. Patients were randomly assigned to receive one of the following regimens:
Patients also provided a tumor sample for PD-L1 testing.
Overall survival superiority was tested sequentially for pembrolizumab/chemotherapy vs cetuximab/chemotherapy in the PD-L1 CPS ≥ 20 population, then the CPS ≥ 1 population, and for pembrolizumab vs cetuximab/chemotherapy in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively).
The data cutoff was approximately 25 months after the last patient randomization.
Treatment with pembrolizumab/chemotherapy resulted in a median overall survival of 14.7 months vs 11.0 months with cetuximab/chemotherapy in the CPS ≥ 20 population (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.45–0.82, P = .0004). In the CPS ≥ 1 population, the median overall survival was 13.6 months with pembrolizumab/chemotherapy vs 10.4 months with cetuximab/chemotherapy (HR = 0.65, 95% CI = 0.53–0.80, P < .0001). The hazard ratio for progression-free survival was 0.76 (95% CI = 0.58–1.01) for CPS ≥ 20 and 0.84 (95% CI = 0.69–1.02) for CPS ≥ 1.
The overall response rate was 42.9% with pembrolizumab/chemotherapy vs 38.2% with cetuximab/chemotherapy in the CPS ≥ 20 population; and 36.4% vs 35.7% in the CPS ≥ 1 population. The median duration of response was 7.1 vs 4.2 months and 6.7 vs 4.3 months, respectively.
In the total study population, pembrolizumab did not significantly improve overall survival vs cetuximab/chemotherapy, with a median overall survival of 11.5 vs 10.7 months, respectively (HR = 0.83, 95% CI = 0.70–0.99, P = .0199). The hazard ratio for progression-free survival was 1.29 (95% CI = 1.09-1.53). The overall response rate for pembrolizumab vs cetuximab/chemotherapy was 16.9% vs 36.0%, and the median duration of response was 22.6 vs 4.5 months.
All-cause grade 3–5 adverse event rates were 54.7% for pembrolizumab alone, 85.1% for pembrolizumab/chemotherapy, and 83.3% for cetuximab/chemotherapy.
The study authors concluded, “Overall, KEYNOTE-048 showed that compared with cetuximab/chemotherapy, pembrolizumab/chemotherapy had superior overall survival in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total populations with comparable safety, and pembrolizumab [alone] had superior overall survival in the CPS ≥ 20 and ≥ 1 populations, noninferior overall survival in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab/platinum/5-FU as new first-line standards of care for recurrent or metastatic head and neck squamous cell carcinoma.”
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
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