Pembrolizumab +/- Chemotherapy Continues to Show OS Benefit in HNSCC

Long-term follow-up of KEYNOTE-048 shows improvements in overall survival with pembrolizumab monotherapy and in combination for patients with recurrent or metastatic head and neck squamous cell carcinoma.

A 4-year follow-up of the KEYNOTE-048 study (NCT02358031) showed that first-line pembrolizumab (Keytruda) alone and combined with chemotherapy continues to have an overall survival (OS) benefit vs cetuximab and chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).1

At a median follow-up of 45.0 months, OS was improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46-0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61-0.89). Findings were also non-inferior in the total population (HR, 0.81; 95% CI, 0.68-0.97). There was an OS improvement with pembrolizumab plus chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46-0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53-0.78), and total (HR, 0.71; 95% CI, 0.59-0.85) populations.

These updated findings are similar to prior data from KEYNOTE-048 which found pembrolizumab monotherapy to significantly improve OS vs cetuximab plus chemotherapy in patients with a PD-L1 CPS greater than or equal to 20 and 1 or higher, and noninferior OS in the total population.

“With long-term follow-up of KEYNOTE-048, first-line pembrolizumab alone and pembrolizumab-chemotherapy showed enduring survival benefits compared with cetuximab-chemotherapy in reccurent or metastatic HNSCC. Consistent with earlier analysis, pembrolizumab alone continued to prolong OS compared with cetuximab-chemotherapy in the PD-L1 CPS ≥ 20 and CPS ≥ 1 populations and pembrolizumab-chemotherapy continued to prolong OS compared with cetuximab-chemotherapy in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total populations,” wrote the study authors led by Kevin Harrington, BSc, MBBS, PhD, MRCP, FRCP, FRCR, professor of biological cancer therapies, Institute of Cancer Research, joint head, Division of Radiotherapy and Imaging, consultant clinical oncologist, The Royal Marsden NHS Foundation Trust, in the published findings.

The phase 3 KEYNOTE-048 trial enrolled and randomly assigned 882 patients 1:1:1 to receive pembrolizumab alone (n = 301), pembrolizumab plus chemotherapy (n = 281), or cetuximab plus chemotherapy (n = 278). Efficacy was evaluated in PD-L1 combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment.2

Enrollment was open to patients with histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx. Patients must also have had an ECOG performance status of 0 or 1, tissue available for PD-L1 testing, adequate organ function, 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 receive 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 cetuximab at a dose of 400 mg/m2 then 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, plus5-Fluorouracil at 1000 mg/m2 a day on days 1 through 4 of each 3-week cycle for a maximum of 6 cycles.

Between treatment groups and across PD-L1 populations, baseline characteristics were similar. The median time from random assignment to data cutoff was 45.0 months, and the median chemotherapy cycles received were 6 (range, 1-11) for pembrolizumab-chemotherapy and 6 (range, 1-9) for cetuximab-chemotherapy.

Primary end points included progression-free survival (PFS) and OS with secondary end points including percentage of patients with PFS at 6 months and 12 months per RECIST, objective response rate (ORR), quality of life, number of patients experiencing adverse events (AEs), and number of patients who discontinued treatment due to an AE.

Updated findings of the trial revealed that the ORR on second course pembrolizumab was 27.3%. Investigators noted that PFS on next-line therapy (PFS2) also was 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.

The combination of pembrolizumab and 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.

Further, PFS2 was similar after pembrolizumab and longer after pembrolizumab plus chemotherapy on next line taxanes. However, PFS2 was shorter after pembrolizumab and was similar after pembrolizumab plus chemotherapy on next-line non-taxanes.

The ORR was 43.7% in the pembrolizumab plus chemotherapy vs 38.2% for cetuximab plus chemotherapy in the PD-L1 CPS ≥ 20 population, 37.2% vs 35.7% in the CPS ≥ 1 population, and 36.3% vs 36.3% in the total population. The median duration of response was numerically longer with pembrolizumab combined with chemotherapy in all populations.

Regarding safety, any-grade treatment-related AEs were observed in 58.3% (n = 175) of patients in the pembrolizumab monotherapy group, 95.7% (n = 264) in the pembrolizumab plus chemotherapy group, and 96.9% (n = 278) in the cetuximab plus chemotherapy group. In the monotherapy group, 17% of patients (n =51) had a grade 3 or higher treatment-related AE compared with 71.7% (n = 198) in the pembrolizumab plus chemotherapy group, and 69.3% (n = 199) in the cetuximab plus chemotherapy group.

References:
  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 [published online ahead of print, 2022 Oct 11]. J Clin Oncol. 2022;JCO2102508. doi:10.1200/JCO.21.02508
  2. A study of pembrolizumab (MK-3475) for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck (MK-3475-048/KEYNOTE-048). ClinicalTrials.gov. Updated August 19, 2022. Accessed October 18, 2022. https://clinicaltrials.gov/ct2/show/NCT02358031