Pembrolizumab Continues to Boost Overall Survival in Patients with Head and Neck Cancer at 4-Year Follow-Up


The overall survival benefit associated with pembrolizumab for patients with head and neck cancer continued to be observed at a 4-year follow-up of the KEYNOTE-048 trial.

Pembrolizumab (Keytruda) continued to outperform cetuximab in extending overall survival (OS) among patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to a follow-up of the 3-arm, phase 3 KEYNOTE-048 trial (NCT02358031). At 4-years follow-up, the benefit was observed both alone and in combination with chemotherapy.

Investigators randomly assigned 882 patients to pembrolizumab monotherapy (n = 301), pembrolizumab-chemotherapy (n = 281) or cetuximab-chemotherapy (n = 278). Investigators evaluated efficacy in PD-L1 combined positive score (CPS) greater than or equal to 20, CPS greater than or equal to 1, and total populations, with no multiplicity or alpha adjustment.

At a median follow-up of 45.0 months (interquartile range, 41.0-49.2), pembrolizumab improved OS in the PD-L1 CPS greater than or equal to 20 (HR, 0.61; 95% CI, 0.46-0.81) and CPS greater than or equal to 1 subgroups (HR, 0.74; 95% CI 0.61-0.89). The PD-1 inhibitor was noninferior in the total population (HR, 0.81; 95% CI, 0.68-0.97).

The pembrolizumab-chemotherapy combination improved OS in the PD-L1 CPS greater than or equal to 20 (HR, 0.62; 95% CI, 0.46-0.84) and CPS greater than or equal to 1 subgroups (HR, 0.64; 95% CI, 0.53-0.78). The combination also improved OS in the total population (HR, 0.71; 95% CI, 0.59-0.85).

These updated findings are in keeping with prior data from KEYNOTE-048, which showed that pembrolizumab alone significantly improved OS compared with cetuximab plus chemotherapy in the subsets of patients with a PD-L1 CPS greater than or equal to 20 and 1 or higher, and noninferior OS in the total population. Pembrolizumab plus chemotherapy also improved OS vs the control arm in the entire study population.

In June 2019, the FDA approved pembrolizumab alone or with chemotherapy for frontline treatment of patients with HNSCC based on these results.2

Results from the phase 1b KEYNOTE-012 trial (NCT01848834) previously demonstrated that pembrolizumab alone produced a higher overall response rate (21% vs 6%; P = .023) and a longer median OS (10 months vs 5 months; P = .008) in those with PD-L1 CPS greater than or equal to 1 vs a CPS of less than 1.3

Patients enrolled to KEYNOTE-048 had recurrent and/or metastatic squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx who had an ECOG performance status of 0 or 1 with tissue available for PD-L1 testing, and who had not received prior chemotherapy or systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, p16 status, and performance status.

Patients were randomly assigned to 200 mg of pembrolizumab alone every 3 weeks for 2 years, 200 mg of pembrolizumab plus platinum-based chemotherapy and 5-fluorouracil (5-FU), or the EXTREME regimen of cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2, plus cisplatin at 100 mg/m2 or carboplatin at area under the curve 5 given every 3 weeks, plus 5-FU at a daily dose of 1000 mg/m2 on days 1 through 4 of each 3-week cycle for a maximum of 6 cycles.

The objective response rate (ORR) on second course pembrolizumab was 27.3%. Investigators found that pembrolizumab-chemotherapy resulted in a numerically higher ORR compared with cetuximab-chemotherapy in the PD-L1 CPS greater than or equal to 20 population and similar ORRs in the CPS greater than or equal to 1 and total populations.

The ORR was 43.7% for pembrolizumab-chemotherapy vs 38.2% for cetuximab-chemotherapy in the PD-L1 CPS greater than or equal to 20 population. In the CPS greater than or equal to 1 group, the ORR was 37.2% for the chemoimmunotherapy combination vs 35.7% for cetuximab-chemotherapy and 36.3% vs 36.3% in the total population.

Median duration of response was numerically longer with pembrolizumab-chemotherapy in all populations.

Progression-free survival on next-line therapy (PFS2) improved with pembrolizumab in the PD-L1 CPS greater than or equal to 20 (HR, 0.64; 95% CI, 0.48-0.84) and CPS greater than or equal to 1 (HR, 0.79; 95% CI, 0.66-0.95) populations. Pembrolizumab-chemotherapy also improved PFS2 in the PD-L1 CPS greater than or equal to 20 (HR, 0.64; 95% CI 0.48-0.86), CPS greater than or equal to 1 (HR 0.66; 95% CI, 0.55-0.81), and total (HR, 0.73; 95% CI, 0.61-0.88) populations.

Investigators found that PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes. In contrast, PFS2 was shorter following pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes.

Seventeen percent of patients in the monotherapy group experienced grade 3 or higher treatment-related adverse effects (TRAEs) compared with 71.7% in the pembrolizumab-chemotherapy group, and 69.3% in the cetuximab-chemotherapy group.


  1. 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 III KEYNOTE-048 study. J Clin Oncol. Published online October 11, 2022. doi:10.1200/JCO.21.02508
  2. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA. June 10, 2019. Accessed October 14, 2022.
  3. Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer. 2018;119(2):153-159. doi:10.1038/s41416-018-0131-9

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