FDA has approved Merck’s Keytruda as monotherapy in patients whose tumors express PD-L1 (Combined Positive Score ≥1) or in combination with platinum and fluorouracil for the first-line treatment of patients with metastatic or unresectable, recurrent head and neck squamous cell carcinoma.
The approval is based on results from pivotal phase III KEYNOTE-048 trial, where Keytruda demonstrated a significant improvement in overall survival compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus FU) as monotherapy in patients whose tumors expressed PD-L1 (CPS ≥1) (HR=0.78 [95% CI, 0.64-0.96]; p=0.0171) and in combination with chemotherapy in the total study population (HR=0.77 [95% CI, 0.63-0.93]; p=0.0067).
With these new indications, Keytruda is the first anti-PD-1 therapy approved in the first-line setting as monotherapy in patients whose tumors express PD-L1 (CPS ≥1) or in combination with chemotherapy regardless of PD-L1 expression for patients with metastatic or unresectable, recurrent HNSCC and the first anti-PD-1 therapy to demonstrate a statistically significant improvement in OS in these patients.
Keytruda was initially approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy in 2016 under the FDA’s accelerated approval process based on objective response rate data from the phase Ib KEYNOTE-012 trial.
In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in KEYNOTE-048 and has resulted in the FDA converting the accelerated approval to a full approval.
This approval is based on data from the prespecified interim analysis of the phase III KEYNOTE-048 trial, a randomized, multi-center, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy and who were considered incurable by local therapies.
Randomization was stratified by tumor PD-L1 expression (Tumor Proportion Score ≥50% or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG Performance Status (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:
Keytruda 200 mg intravenously every three weeks;
Keytruda 200 mg intravenously every three weeks, carboplatin AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100 mg/m2 intravenously every three weeks and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU);
Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100 mg/m2 intravenously every three weeks and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU).
Among the 882 patients, the study population characteristics were: median age of 61 years (range, 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian, and 2.4% Black; 61% had ECOG PS of 1; and 79% were former or current smokers. Twenty-two percent of patients’ tumors were HPV positive; 23% had PD-L1 TPS ≥50%; and 95% had stage IV disease (19% were stage IVA, 6% were stage IVB, and 70% were stage IVC). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1, and 43% had CPS ≥20.
Treatment with Keytruda continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization.
The main efficacy outcome measures were OS and progression-free survival as assessed by blinded independent central review according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1 and the overall population.
In KEYNOTE-048, the safety of Keytruda, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in patients with previously untreated, recurrent, or metastatic HNSCC.
The median duration of exposure to KEYTRUDA 200 mg every three weeks was 3.5 months (range, 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range, 3 days to 24.2 months) in the combination arm.
Keytruda was discontinued for adverse reactions in 12% of patients in the Keytruda single agent arm. The most common adverse reactions resulting in permanent discontinuation of Keytruda were sepsis (1.7%) and pneumonia (1.3%).
