Frontline Pembrolizumab Regimens Receive Japanese Approval in Head and Neck Cancer

Japan's Pharmaceuticals and Medical Devices Agency has granted approval to frontline pembrolizumab as monotherapy and in combination with chemotherapy for the treatment of patients with recurrent or distant metastatic head and neck cancer.

Jannie Oosthuizen

Japan’s Pharmaceuticals and Medical Devices Agency has granted approval to frontline pembrolizumab as monotherapy and in combination with chemotherapy for the treatment of patients with recurrent or distant metastatic head and neck cancer.1

The approval for pembrolizumab in both indications is based on findings from the phase III KEYNOTE-048 trial, which evaluated the PD-1 inhibitor alone and in combination with platinum-based therapy and 5-fluorouracil (5-FU) compared with standard cetuximab (Erbitux) with platinum-based therapy plus 5-FU in patients with recurrent or metastatic head and neck squamous cell carcinoma.

The combination of pembrolizumab plus chemotherapy demonstrated a 23% reduction in the risk of death versus standard therapy (HR, 0.77; 95% CI, 0.63-0.93; P = .00335).2 Moreover, single-agent pembrolizumab demonstrated noninferiority compared with the standard regimen (HR, 0.85; 95% CI, 0.71-1.03; P = .00014), and it also demonstrated a statistically significant improvement in OS in patients with PD-L1—positive (combined positive score [CPS] ≥1) tumors versus standard therapy.

“Last year, an estimated 850,000 new cancer diagnoses were made in Japan alone, underscoring the critical need for innovative research and development to identify additional treatment options,” Jannie Oosthuizen, managing director of MSD (Merck) in Japan, stated in a press release. “The new approvals of Keytruda in advanced renal cell carcinoma and head and neck cancer build on previous approvals in melanoma, advanced non-small cell lung cancer and advanced MSI-H cancers, allowing us to bring Keytruda to even more patients in Japan.”

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 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. 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.

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 5-FU for this patient population, but irrespective of PD-L1 expression. The European Commission approved the same regimens, also based on the KEYNOTE-048 data, in November 2019.


  1. Merck’s Keytruda (pembrolizumab) approved in Japan for three new first-line indications across advanced renal cell carcinoma (RCC) and recurrent or distant metastatic head and neck cancer [news release]. Published December 20, 2019. Accessed December 20, 2019.
  2. Burtness B, Harrington KJ, Greil R, et al. KEYNOTE-048: Phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA8_PR.