On June 10, 2019, the FDA approved pembrolizumab (Keytruda; Merck) as monotherapy or in combination with platinum and fluorouracil for the treatment of newly diagnosed patients with metastatic or unresectable recurrent head and neck squamous-cell carcinoma (HNSCC) whose tumors express PD-L1 (combined positive score [CPS] ≥1), as determined by an FDA-approved test. The FDA reviewed the application for this new indication under its priority review program.
Pembrolizumab is the first anti–PD-1 treatment that can be used as first-line monotherapy for this patient population. Keytruda was previously approved as a single agent or in combination with other agents for many types of cancers. In 2016, Keytruda was initially approved for patients with recurrent or metastatic HNSCC whose disease progressed during or after platinum-containing chemotherapy based on data from the phase 1b KEYNOTE-012 clinical trial.
This latest approval was based on the results from the phase 3 KEYNOTE-048 trial of 882 patients with metastatic or unresectable recurrent HNSCC whose disease was deemed incurable by local therapies or who had not received previous systemic therapy for metastatic disease. The patients were randomized in a 1:1:1 ratio to pembrolizumab alone; pembrolizumab plus chemotherapy (cisplatin or carboplatin and fluorouracil); or cetuximab (Erbitux) plus chemotherapy (carboplatin or cisplatin and fluorouracil). PD-L1 expression (or CPS) was determined using the PD-L1 IHC 22C3 pharmDx kit.
The results from a prespecified interim analysis showed a significant improvement in overall survival (OS) in patients with a CPS ≥1 or ≥20 who received pembrolizumab monotherapy versus those who received cetuximab plus chemotherapy. In patients with CPS a ≥1, the median OS was 12.3 months with pembrolizumab and 10.3 months with cetuximab plus chemotherapy (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.96; P = .0171). In the patients with CPS ≥20, the median OS was 14.9 months with pembrolizumab and 10.7 months with cetuximab plus chemotherapy (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).
A significant OS improvement was also seen in the overall population of patients who received pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy (median OS, 13 months vs 10.7 months, respectively; HR, 0.77; 95% CI, 0.63-0.93; P = .0067).
However, pembrolizumab monotherapy was not superior to chemotherapy alone in the overall patient population, and no significant difference was seen in progression-free survival with pembrolizumab alone or pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy.
The most common (≥20%) adverse events associated with pembrolizumab monotherapy were fatigue, constipation, and rash. The most common adverse events associated with pembrolizumab plus chemotherapy were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.