The FDA has granted a priority review designation to pembrolizumab (Keytruda) as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) following a platinum-based chemotherapy, according to a statement from Merck, the company developing the PD-1 inhibitor.
The application for pembrolizumab was based on updated data from the phase Ib KEYNOTE-012 trial that was presented at the 2015 European Cancer Congress. In the study, the objective response rate (ORR) was 23.7% in patients with HNSCC who received pembrolizumab at either 200 mg every 3 weeks or 10 mg/kg every 2 weeks. The stable disease rate by RECIST criteria was 25.4%.
Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the submission by August 9, 2016. The application for the HNSCC indication is specifically for the 200 mg dose administered intravenously every 3 weeks. Prior approvals for the PD-1 inhibitor have been for a 2-mg/kg dose.
“Starting in the early days of our development program, we have explored the role of Keytruda for patients with head and neck cancer, a difficult-to-treat and debilitating disease with very few treatment options,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement. “We are encouraged by the data emerging from our program in this type of cancer, and welcome today’s news as this is an important step toward making Keytruda available to these patients.”
The KEYNOTE-012 trial enrolled 192 patients with recurrent/metastatic HNSCC. In the 10-mg/kg arm of the study, all patients had PD-L1positive disease whereas those in the 200 mg every 3-week arm were enrolled regardless of PD-L1 status. Both cohorts included participants regardless of HPV status.
Overall, 62.5% of patients had received 2 or more prior lines of therapy for recurrent/metastatic disease, with 37.5% having received ≥3 lines. The median age of patients was 60 years (range, 20-84), and the majority were males (82.8%). The median sum of all target lesions at baseline was 67.1 mm (range 10.0-664.1).
The primary endpoint of the study was ORR per investigator assessment using modified RECIST criteria. Secondary endpoints looked at response by HPV status, progression-free survival (PFS), and safety by CTCAE v4.
In evaluable patients (n = 173), 2 experienced a complete response and 39 had partial responses (23.7%). Stable disease was achieved for ≥6 months for 9 patients, and 7 remained on therapy at the time of the data cutoff. The duration of stable disease was 16 to 515 days. Response rates were similar in HPV-negative and HPV-positive patients (24.1% and 23.6%, respectively).
Median PFS was 2.2 months with pembrolizumab (95% CI, 2.0-3.6), which was similar regardless of the number of prior therapies. The 6-month PFS rate was 27.6% and the 12-month rate was 18.2%. In the HPV-positive group (n = 55), median PFS was 3.4 months. In the HPV-negative arm (n = 116), median PFS was 2.1 months.
Median overall survival (OS) across evaluable patients was 9.6 months (95% CI, 6.6 - not reached). The 6-month OS rate was 60.2%. At 12 months, 47% of patients remained alive. Historically, the median OS in the second-line setting is 6 months.
For patients treated with prior platinum-based therapy (n = 155), the ORR was 23.2%. In patients who receive both platinum therapy and cetuximab (n = 94), the ORR was 19.1%. Those who received platinum therapy but not cetuximab (n = 61) had an ORR of 29.5%. The ORR in those who received ≤2 prior therapies was 29% versus 12.9% in those who received >2 therapies.
Patients with tumors that were smaller than or equal to 67.1 mm (n = 85) had an ORR of 32.9%. In those with larger tumors (n = 88), the ORR was 14.8%.
Treatment-related adverse events (AEs) were experienced by 60.9% of the 192 patients enrolled in the study. Grade 3/4 AEs occurred in 12.5% of patients. Immune-related AEs occurred in 17.2% of patients, with a majority being grade 1/2 in severity.
The most common treatment-related AEs were fatigue (17.2%), decreased appetite (7.3%), hypothyroidism (7.3%), rash (7.3%), pruritus (6.8%), nausea (6.3%), pyrexia (6.3%), and dry skin (5.2%). Treatment-related grade 3/4 AEs, which occurred in 2 patients each, were ALT and AST increase, hyponatremia, pneumonitis, and facial swelling.
A number of studies continue to assess pembrolizumab as a treatment for patients with HNSCC across treatment settings. The application for pembrolizumab was for an accelerated approval, meaning that a full indication would still be contingent upon confirmatory findings.
To this end, the phase II KEYNOTE-055 study explored pembrolizumab after platinum therapy and cetuximab for patients with HNSCC. The primary completion date for this study was set for April 2016, with results expected soon (NCT02255097). Additionally, the phase III KEYNOTE-040 is currently comparing pembrolizumab with standard treatment for patients with recurrent or metastatic HNCSS (NCT02252042).
In the first-line setting, the 3-arm phase III KEYNOTE-048 trial is exploring pembrolizumab alone or with platinum chemotherapy and 5-FU compared with cetuximab plus platinum therapy and 5-FU. The study plans to enroll 780 patients, with a primary endpoint of PFS. The estimated primary completion date is November 2017 (NCT02358031).