Findings from the phase 3 KEYNOTE-048 study indicated that long-lasting improved survival benefit can be achieved with pembrolizumab plus chemotherapy compared with cetuximab and chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma.
First-line pembrolizumab (Keytruda) plus chemotherapy continued to demonstrate improved overall survival (OS) benefit compared with cetuximab (Erbitux) plus chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinomas, according to results from the phase 3 KEYNOTE-048 study (NCT02358031).
At a median follow-up of 45.0 months, pembrolizumab demonstrated OS improvements in patients whose PD-L1 combined positive scores (CPS) were 20 or more and 1 or more. The median OS for those receiving pembrolizumab was 14.9 months (95% CI, 11.5-20.6) vs 10.8 months (95% CI, 8.8-12.8) for those receiving cetuximab/chemotherapy who had a CPS score of 20 or more (HR, 0.61; 95% CI, 0.46-0.81; P = .00034). Among patients with a CPS 1 or more, pembrolizumab alone produced a median OS of 12.3 months (95% CI, 10.8-14.8) compared with 10.4 months (95% CI, 9.0-11.7) among those in the cetuximab arm (HR, 0.74; 95% CI, 0.61-0.8p; P = .00080). Additionally, in the overall population, the median OS was 11.5 months (95% CI, 10.3-13.5) vs 10.7 (95% CI, 9.3-12.1), respectively (HR, 0.81; 95% CI, 0.68-0.97; P = .00994).
Additionally, the median OS among those with a CPS of 20 or more who were treated with pembrolizumab/chemotherapy was 14.7 months (95% CI, 10.3-19.3) compared with 11.1 months (95% CI, 9.2-13.0) in the cetuximab arm (HR, 0.62; 95% CI, 0.46-0.84; P = .00082). In the cohort of patients with a CPS of 1 or more, the median OS was 13.6 months (95% CI, 10.7-15.5) vs 10.6 months (95% CI, 9.1-11.7) in each respective arm (HR, 0.64; 95% CI, 0.53-0.78; P = .00001). In the overall population, the median OS was 13.0 months (95% CI, 10.9-14.7) compared with 10.7 months (95% CI, 9.3-11.7), respectively (HR, 0.71; 95% CI, 0.59-0.85; P = .00008).
The KEYNOTE-048 study randomly assigned a total of 882 patients to receive either the pembrolizumab alone (n = 301), pembrolizumab plus chemotherapy (n = 281), or the cetuximab regimen (n = 300). Patients received 200 mg of intravenous pembrolizumab once every 3 weeks, with or without chemotherapy consisting of 100 mg/m2 of cisplatin every 3 weeks or carboplatin and fluorouracil at 1000 mg/m2 every 3 weeks; or a 400 mg/m2 loading dose of cetuximab followed by 250 mg/m2 per week along with the same chemotherapy backbone. Patients continued treatment until disease progression, unacceptable toxicity, or withdrawal.
Patients 18 years and older with previously untreated recurrent or metastatic squamous cell carcinoma of the oropharynx with a known p16 expression, oral cavity, hypopharynx, or larynx that could not be cured with local therapy were eligible to enroll on the study.
The primary end points of the study were progression-free survival and OS. Secondary end points included objective response rate (ORR), and safety. The exploratory end point was duration of response (DOR).
Baseline patient characteristics were comparable across treatment groups and PD-L1 populations. Patient subgroup analyses based on patient characteristics generally favored the efficacy of pembrolizumab with or without chemotherapy compared with cetuximab plus chemotherapy. The only exception was observed among patients with recurrent-only disease, where cetuximab/chemotherapy was favored against pembrolizumab alone (HR, 1.05; 95% CI, 0.77-1.43).
Pembrolizumab alone did not improve ORR in any patient population compared with cetuximab/chemotherapy, with investigators reporting an ORR of 16.9% and 36.0%, respectively, in the total population. Additionally, in the CPS of 20 or more cohort, the ORR was 23.3% vs 36.1% with pembrolizumab alone and the cetuximab regimen, respectively. The ORR for the CPS of 1 or more cohort was 16.9% vs 36.0%, respectively. However, pembrolizumab and chemotherapy achieved an ORR of 43.7% vs 38.2% among patients receiving cetuximab/chemotherapy in the CPS of 20 or more population. Additionally, among those with a CPS of 1 or more, the ORR was 37.2% compared with 35.7% in the pembrolizumab/chemotherapy and cetuximab arms, respectively. In the overall population, investigators reported an ORR of 36.3% in both respective arms.
Median DOR was longer with pembrolizumab with or without chemotherapy in all patient populations. The median DOR for the total population was 23.4 months (95% CI, 5.7-35.9) for patients receiving pembrolizumab alone and 4.5 months (95% CI, 2.9-7.2) for those receiving cetuximab-chemotherapy. Additionally, the median DOR among those in the CPS 20 or more and 1 or more cohorts were 23.4 months (95% CI, 6.9-38.7) vs 4.2 months (95% CI, 2.8-6.4) and 24.8 months (95% CI, 6.9-35.9) vs 4.5 months (95% CI, 2.9-6.0), respectively.
The safety profiles of pembrolizumab with or without chemotherapy and cetuximab plus chemotherapy were consistent with those reported previously. The study reported no new safety signals.
Harrington KJ, Burtness B, Greil R, et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase 3 KEYNOTE-048 study. J Clin Oncol. Published online October 11, 2022. doi:10.1200/JCO.21.02508