Yesterday, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) 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 with or without cisplatin after surgery, and then used 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 was evaluated in KEYNOTE-689 (ClinicalTrials.gov identifier NCT03765918), a randomized, multicenter, open-label trial in 714 patients with resectable, locally advanced (stage III–IVA) HNSCC [American Joint Committee on Cancer, 8th edition]. Patients were randomly assigned (1:1) to receive one of the following regimens:
- Neoadjuvant pembrolizumab every 3 weeks for 2 cycles followed by adjuvant pembrolizumab every 3 weeks for 3 cycles with radiotherapy (with or without cisplatin) and then every 3 weeks for 12 cycles of pembrolizumab as a single agent
- No neoadjuvant treatment prior to surgery followed by adjuvant radiotherapy (with or without cisplatin).
On both treatment arms, patients received cisplatin with adjuvant radiotherapy if high-risk pathologic features (ie, positive margins < 1 mm or extranodal extension) were present at surgery.
The major efficacy measure was event-free survival 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 from any cause. An additional efficacy outcome measure was overall survival.
For patients whose tumors expressed PD-L1 CPS ≥ 1 (n = 682), median event-free survival was 59.7 months (95% confidence interval [CI] = 37.9 months to not reached) in the pembrolizumab arm and 29.6 months (95% CI = 19.5–41.9 months) in the control arm (hazard ratio = 0.70, 95% CI = 0.55–0.89, P = .00140).
Overall survival results were immature at the time of the current analysis, with 76% of prespecified deaths in the CPS ≥ 1 population. However, no trend toward a detriment was observed.
Of the patients who received neoadjuvant pembrolizumab, 1.4% were unable to receive surgery because of 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 embryofetal toxicity. Adverse reactions were consistent with prior experience with pembrolizumab.
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.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at these agencies.
