The European Commission has approved pembrolizumab as a monotherapy or in combination with platinum and 5-FU chemotherapy for the frontline treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma and PD-L1 expression (composite positive score ≥1) on their tumors.
Kevin Harrington, BSc, MBBS, MRCP, PhD
The European Commission has approved pembrolizumab (Keytruda) as a monotherapy or in combination with platinum and 5-FU chemotherapy for the frontline treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) and PD-L1 expression (composite positive score [CPS] ≥1) on their tumors.1
The approval is based on results from the phase III KEYNOTE-048 trial, in which single-agent pembrolizumab demonstrated a statistically significant improvement in overall survival (OS) compared with the standard EXTREME regimen, which comprises cetuximab (Erbitux) with carboplatin or cisplatin plus 5-FU, in patients with PD-L1—positive tumors (HR, 0.74; 95% CI, 0.61-0.90; P = .00133).2
When used in combination with chemotherapy, the PD-1 inhibitor led to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.53-0.80; P = .00002). Both OS improvements were observed in patients whose tumors have PD-L1 expression (CPS ≥1).
“This disease is especially debilitating since it can be highly visible and affect a patient’s appearance and their daily functions, such as eating and speaking,” study investigator Kevin Harrington, BSc, MBBS, MRCP, PhD, professor of biological cancer therapies at The Institute of Cancer Research, London, and consultant clinical oncologist at The Royal Marsden NHS Foundation Trust, stated in a press release. “Considering the great need for new treatment options, we are encouraged by today’s Keytruda approval in Europe, which will allow certain patients to be treated with immunotherapy earlier in the course of their treatment.”
With the European approval, pembrolizumab as a single agent and in combination for this indication will be available for use in all 28 EU member states plus Iceland, Lichtenstein, and Norway.
In the open-label, randomized, phase III KEYNOTE-048 study, investigators evaluated whether pembrolizumab could prolong survival and slow disease progression versus the EXTREME regimen—platinum-based chemotherapy with cisplatin or carboplatin, 5-FU, and cetuximab—in the recurrent or metastatic setting. A total 882 patients were randomized in a 1:1:1 ratio to either standard EXTREME treatment (cetuximab at 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus cisplatin at 100 mg/m2 or carboplatin AUC 5 every 3 weeks, plus 5-FU at 1000 mg/m2 daily on day 1 through 4 of each 3-week cycle for a maximum of 6 cycles; n = 300); single-agent pembrolizumab at 200 mg every 3 weeks for 2 years (n = 301); or a combination of pembrolizumab and platinum-based chemotherapy with 5-FU (n = 281). Treatment was administered until unacceptable toxicity or progressive disease.
Patients enrolled on the study had squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; had not received prior chemotherapy or systemic therapy for their recurrent or metastatic disease; and had good ECOG performance status with tissue available for PD-L1 testing. Patients were stratified by PD-L1 expression, p16 status, and ECOG performance status.
The primary endpoints were progression-free survival (PFS) and OS in patients with a PD-L1 CPS ≥20, ≥1, and in all patients enrolled.
For single-agent pembrolizumab, results in those with PD-L1 CPS ≥1 showed that the median OS was 12.3 months for patients with who received pembrolizumab (n = 257) compared with 10.3 months for those who received standard therapy (n = 255), leading to a 26% reduction in the risk of death. However, the median PFS was 3.2 months and 5.0 months, respectively (HR, 1.13; 95% CI, 0.94-1.36; P = .89580).
Also with the monotherapy regimen, the ORR was lower with pembrolizumab at 19.1% compared with 35% with the EXTREME regimen; the complete response (CR) and partial response (PR) rates were 5% and 14% with pembrolizumab and 3% and 32% with standard therapy (P = 1.0000). The duration of response (DOR) with pembrolizumab was 23.4 months and was 4.5 months with the EXTREME regimen; 81% of patients on pembrolizumab had a DOR lasting ≥6 months compared with 36% of those on standard treatment.
Findings with the pembrolizumab/chemotherapy combination demonstrated a median OS of 13.6 months and 10.4 months with the pembrolizumab regimen (n = 242) and standard treatment (n = 235), respectively, which led to a 35% reduction in the risk of death. The median PFS was similar, at 5.1 months with pembrolizumab/chemotherapy and 5.0 months with EXTREME (HR, 0.84; 95% CI, 0.69-1.02; P = .03697). The ORR was 36% in both arms; in the pembrolizumab arm, there was a 7% CR rate and a 30% PR rate. The CR rate and PR rate with EXTREME was 3% and 33%. Additionally, the median DOR was 6.7 months and 4.3 months with pembrolizumab/chemotherapy and EXTREME, respectively. Fifty-four percent of patients on pembrolizumab had a DOR ≥6 months compared with 34% of those who received EXTREME.
“Keytruda is now the first anti—PD-1 treatment option in the first-line setting for metastatic or unresectable recurrent head and neck cancer, a disease that has been treated the same way in the [European Union] for more than a decade,” Jonathan Cheng, MD, vice president, clinical research, Merck (MSD) Research Laboratories. “The European Commission approval underscores our commitment to transforming the way cancer is treated around the world.”
In June 2019, the FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma as monotherapy in patients whose tumors express PD-L1 (CPS ≥1) or in combination with platinum and FU for this patient population, but irrespective of PD-L1 expression.