Pembrolizumab Receives Priority Review Designation from FDA for Frontline HNSCC

Based on data from the phase III KEYNOTE-048 trial, pembrolizumab has received a priority review designation from the FDA alone or in combination with platinum and 5-fluorouracil chemotherapy as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma.

Jonathan Cheng, MD

Based on data from the phase III KEYNOTE-048 trial, pembrolizumab (Keytruda) has received a priority review designation from the FDA alone or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).1

In results from KEYNOTE-048, treatment with pembrolizumab alone led to a significant improvement in overall survival (OS) compared with standard chemotherapy in patients whose tumors expressed PD-L1 with a combined positive score (CPS) ≥20 and CPS ≥1.2An OS improvement was also seen with the combination of pembrolizumab and chemotherapy in the overall patient population.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the application by June 10, 2019, Merck (MSD), the developer of the PD-1 inhibitor, reported in a press release.

“Head and neck cancer remains a challenging and devastating disease, and newly diagnosed patients are in need of improved treatment options,” said Jonathan Cheng, MD, vice president, clinical research, Merck Research Laboratories. “Merck continues to make meaningful advances in the treatment of head and neck cancer, and we look forward to working with the FDA to bring these important new options to patients in the first-line setting.”

Additionally, KEYNOTE-048 is the confirmatory trial for the phase Ib KEYNOTE-012 trial, which was the basis for the accelerated approval in August 2016 for single-agent pembrolizumab for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

The open-label, randomized, phase III KEYNOTE-048 study 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 (Erbitux)—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/m2loading dose followed by 250 mg/m2weekly, plus cisplatin at 100 mg/m2or carboplatin AUC 5 every 3 weeks, plus 5-FU at 1000 mg/m2daily 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. The data cutoff date was June 13, 2018, with a minimum follow-up of 17 months.

Results of the study, which were presented at the 2018 ESMO Congress, showed that in patients with PD-L1 CPS ≥20 (n = 255), the median OS was 14.9 months versus 10.7 months in those who received pembrolizumab alone versus EXTREME (HR, 0.61; 95% CI, 0.45-0.83;P= .0007), respectively, and the 2-year OS rate was 38% versus 22%. There was no difference in PFS between the 2 arms (HR, 0.99; 95% CI, 0.75-1.29; P= .5).

Moreover, the ORRs were 23.3% and 36.1% with pembrolizumab and standard therapy, respectively; however, the median DOR was longer with the PD-1 inhibitor at 20.9 months versus 4.5 months.

For patients with a PD-L1 CPS ≥1 (n = 512), the results were similar, in which the median OS for pembrolizumab monotherapy versus EXTREME was 12.3 months versus 10.3 months, respectively (HR, 0.78; 95% CI, 0.64-0.96;P= .0086); the 2-year OS rates were 30% versus 19%. The ORR was 19.1% with pembrolizumab and 34.9% with standard therapy, yet the median DOR was again longer with pembrolizumab at 20.9 months and 4.5 months, respectively. There was no difference in PFS between the 2 groups (HR, 1.16; 95% CI, 0.75-1.29).

In the overall population (N = 559), treatment with pembrolizumab added to chemotherapy (n = 281) versus the EXTREME regimen (n = 278) led to a median OS of 13.0 months versus 10.7 months, respectively (HR, 0.77; 95% CI, 0.63-0.93;P= .0034); the 2-year OS rates were 29% versus 19%, respectively. Additionally, the ORRs were 35.6% and 36.3% with pembrolizumab/chemotherapy versus EXTREME therapy, and the DOR was 6.7 months versus 4.3 months, respectively. There was no PFS difference between the 2 groups (HR, 0.92; 95% CI, 0.77-1.10; P= .2).

Additionally, the OS improvement with the combination of pembrolizumab/chemotherapy versus EXTREME in those with PD-L1 CPS ≥20 and CPS ≥1 was not statistically significant, Burtness explained.

Single-agent pembrolizumab was also examined against EXTREME treatment in the overall population. The ORR for pembrolizumab alone in this group was 17% versus 36% with EXTREME. The OS for single-agent pembrolizumab was noninferior to EXTREME in this population; superiority will be evaluated at the final analysis of the trial.

Regarding safety, pembrolizumab was well tolerated with a safety profile that was consistent with prior studies. The combination of pembrolizumab and chemotherapy had a comparable safety profile to EXTREME. The rates of grade 3 to 5 treatment-related adverse events (TRAEs) were 17% for those treated with pembrolizumab monotherapy and 69% for patients who received standard treatment. In the pembrolizumab/chemotherapy group, the rate of grade 3 to 5 TRAEs was 71%.


  1. FDA Grants Priority Review to Merck’s Supplemental Biologics License Application for KEYTRUDA® (pembrolizumab) for the First-Line Treatment of Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC). Merck. Published February 11, 2019. Accessed February 11, 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.