The Food and Drug Administration approved pembrolizumab (Keytruda, Merck) for adults with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin after surgery, and then as a single agent.
This is the first approval for HNSCC in 6 years and the first overall perioperative approval for locally advanced HNSCC.
Efficacy and Safety;
Efficacy was evaluated in KEYNOTE-689 (NCT03765918), a randomized, multicenter, open-label trial in 714 patients with resectable locally advanced (Stage III-IVA) HNSCC [AJCC, 8th edition]. Patients were randomized (1:1) to either of the following:
•neoadjuvant pembrolizumab every 3 weeks for 2 cycles followed by adjuvant pembrolizumab every 3 weeks for 3 cycles with RT, with or without cisplatin, and then every 3 weeks for 12 cycles of pembrolizumab as a single agent, or
•no neoadjuvant treatment prior to surgery followed by adjuvant RT with or without cisplatin.
On both treatment arms, patients received cisplatin with adjuvant RT if high-risk pathological features (i.e., positive margins <1 mm or extranodal extension) were present at surgery.
The major efficacy measure was event-free survival (EFS) by blinded independent central review defined as the time from randomization to the first occurrence of any of the following events: disease progression precluding definitive surgery, local or distant disease progression or recurrence, or death due to any cause. Additional efficacy outcome measures included overall survival (OS). For patients whose tumors express PD-L1 CPS ≥1 (n=682), median EFS was 59.7 months (95% CI: 37.9, not reached [NR]) in the pembrolizumab arm and 29.6 months (95% CI: 19.5, 41.9) in the control arm (hazard ratio 0.70 [95% CI: 0.55, 0.89]; p-value 0.00140).
While OS results were immature at the current analysis, with 76% of pre-specified deaths in the CPS ≥1 population, no trend towards a detriment was observed.
Of the patients who received neoadjuvant pembrolizumab, 1.4% were unable to receive surgery due to adverse reactions compared with 1.4% on the control arm. The prescribing information for pembrolizumab includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, and embryo-fetal toxicity. Adverse reactions were consistent with prior experience with pembrolizumab.
Recommended dosage;
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks. Pembrolizumab should be administered prior to chemotherapy when given on the same day.
