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Pembrolizumab Nears European Approval for HNSCC

Jason M. Broderick @jasoncology
Published: Monday, Jul 30, 2018

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of pembrolizumab (Keytruda) for the treatment of adult patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who progressed following platinum-based chemotherapy and have a PD-L1 tumor proportion score (TPS) ≥50%.

Randomization was stratified by ECOG performance status (0 vs 1), known p16 status for cancer of the oropharynx, and PD-L1 TPS (≥50% vs <50%).The results were also analyzed according to combined positive score (CPS).

Treatment continued until confirmed disease progression or intolerable toxicity. The primary endpoint was overall survival (OS) in the intent-to-treat population. The one-sided prespecified efficacy boundary was an alpha of 0.0175, corresponding to a hazard ratio of 0.80.

After a median follow-up of 7.3 months, 22 patients in the pembrolizumab arm continue on pembrolizumab and 2 continue on standard of care therapy. About one-fourth of the population in each treatment arm were p16-positive, one-fourth in each arm had PD-L1 TPS ≥50%, and close to 80% in each arm had PD-L1 CPS ≥1.

There were 179 deaths in the pembrolizumab arm and 201 in the standard of care arm, for a hazard ratio (HR) of 0.81 (95% CI, 0.66-0.99) favoring pembrolizumab (P = .0204). Median OS was 8.4 months and 7.1 months, respectively.

In the population with PD-L1 CPS ≥1, the 1-year survival was 40.1% in the pembrolizumab arm versus 26.7% in the control arm (HR, 0.75; P = .0078). Median progression-free survival (PFS) was 8.7 months and 7.1 months, respectively.

In the population with PD-L1 TPS ≥50%, 1-year survival was again significantly improved from 25.8% in the control arm to 46.6% in the pembrolizumab arm (HR, 0.54; P = .0017). Median OS was 11.6 months in patients pembrolizumab and 7.9 months for those assigned to standard of care.

The objective response rate (ORR) was also higher in pembrolizumab-treated patients. ORR was 14.6% with pembrolizumab compared with 10.1% with standard of care, respectively were (P = .0610) in the ITT analysis. Similarly, ORR favored pembrolizumab in both the PD-L1 CPS ≥1 subgroup (17.3% vs 9.9%; P = .0171), and the PD-L1 TPS ≥50% subgroup (26.6% vs 9.2; P = .0009).

Median PFS was not significantly different between the 2 treatment groups in the ITT analysis and in the subgroup with PD-L1 CPS ≥1, but in the subset with PD-L1 TPS ≥50%, median PFS was significantly superior at 3.5 months in the pembrolizumab group compared with 2.2 months in the standard of care arm (HR, 0.58; P = .0034).

Best overall response followed a similar pattern, with 4 complete responses versus 1 in the pembrolizumab and standard of care arms, respectively.

Merck (MSD), the manufacturer of pembrolizumab, announced in July 2018 that the PD-1 inhibitor significantly improved OS compared with the standard frontline regimen of cetuximab (Erbitux) plus platinum chemotherapy and 5-FU in patients with recurrent or metastatic HNSCC and a PD-L1 expression level ≥20%, according to findings from the phase III KEYNOTE-048 trial.2

The coprimary endpoint of PFS in patients with PD-L1 expression ≥20% had not been reached. The trial is continuing, including evaluation of the third study arm examining pembrolizumab combined with platinum chemotherapy and 5-FU. No specific data have been made available, with Merck planning to present the results at a future medical conference and share them with regulatory agencies.

The open-label phase III KEYNOTE-048 trial randomized 825 patients to 1 of 3 arms: single-agent pembrolizumab at 200 mg IV on day 1 of each week in 3-week cycles for up to 24 months; the same pembrolizumab regimen plus investigator's choice of cisplatin at 100 mg/m2 IV or carboplatin at AUC 5 IV on day 1 of each week in 3-week cycles (maximum, 6 cycles) plus 5-FU at 1000 mg/m2/day IV continuous from day 1 to day 4 of each 3-week cycle (maximum, 6 cycles); or cetuximab on day 1 at a dose of 400 mg/m2 IV, and then 250 mg/m2 IV on day 1 of each week plus cisplatin/carboplatin and 5-FU at the same dosages as in the pembrolizumab combination arm.

PD-L1 expression was measured by CPS, which includes levels on both tumor and inflammatory cells. Beyond the coprimary endpoints of OS and PFS, secondary outcome measures included response and quality of life. Merck noted in its press release that there were no new safety signals in KEYNOTE-048 compared with previous trials evaluating pembrolizumab in patients with HNSCC.

In the United States, the FDA granted an accelerated approval to pembrolizumab in August 2016 for single-agent use as a treatment for patients with recurrent or metastatic HNSCC following progression on a platinum-based chemotherapy.


  1. Cohen EEW, Harrington KJ, Le Tourneau C, et al. Pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 KEYNOTE-040 trial. Presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA45_PR.
  2. KEYTRUDA® (pembrolizumab) Monotherapy Met a Primary Endpoint in the Phase 3 KEYNOTE-048 Trial, Significantly Improving OS as First-Line Therapy in Head and Neck Squamous Cell Carcinoma Patients Whose Tumors Expressed PD-L1 (CPS ≥20). Posted July 25, 2018. Accessed July 25, 2018.

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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
Medical Crossfire®: How Can We Optimize Outcomes in Head and Neck Cancers with Immunotherapeutic Strategies?Oct 31, 20191.5
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