A priority review designation was granted to Keytruda for some patients with head and neck cancer. A decision submission is due in August.
After a trial presented in 2015, the FDA granted a priority review designation to Keytruda (pembrolizumab) as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) following a platinum-based chemotherapy, Merck, the company developing the PD-1 inhibitor said in a statement.
The application for Keytruda was based on updated data from the phase 1b KEYNOTE-012 trial that was presented at the 2015 European Cancer Congress. In the study, the objective response rate (ORR) was 23.7 percent in patients with HNSCC who received Keytruda at either 200 mg every three weeks or 10 mg/kg every two weeks. The stable disease rate by RECIST criteria was 25.4 percent.
Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the submission by Aug. 9, 2016. The application for the HNSCC indication is specifically for the 200 mg dose administered intravenously every three weeks. Prior approvals for the PD-1 inhibitor have been for a two-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, 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-L1—positive disease whereas those in the 200 mg every three-week arm were enrolled regardless of PD-L1 status. Both cohorts included participants regardless of HPV status.
Overall, 62.5 percent of patients had received two or more prior lines of therapy for recurrent/metastatic disease, with 37.5 percent having received at least three lines. The median age of patients was 60 years (range, 20-84), and the majority were males (82.8 percent). 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 173 evaluable patients, two experienced a complete response and 39 had partial responses (23.7 percent). Stable disease was achieved for six or more months for nine patients, and seven 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 percent and 23.6 percent, respectively).
Median PFS was 2.2 months with Keytruda, which was similar regardless of the number of prior therapies. The six-month PFS rate was 27.6 percent and the 12-month rate was 18.2 percent. In the HPV-positive group of 55 patients, median PFS was 3.4 months. In the HPV-negative arm consisting of 116 patients, median PFS was 2.1 months.
Median overall survival (OS) across evaluable patients was 9.6 months. The six-month OS rate was 60.2 percent. At 12 months, 47 percent of patients remained alive. Historically, the median OS in the second-line setting is six months.
For the 155 patients treated with prior platinum-based therapy, the ORR was 23.2 percent. In 94 patients who receive both platinum therapy and Erbitux (cetuximab), the ORR was 19.1 percent. The 61 patients who received platinum therapy but not Erbitux had an ORR of 29.5 percent. The ORR in those who received at least two prior therapies was 29 percent versus 12.9 percent in those who received more than two therapies.
Eighty-five patients with tumors that were smaller than or equal to 67.1 mm had an ORR of 32.9 percent. In the 88 patients with larger tumors, the ORR was 14.8 percent.
Treatment-related adverse events (AEs) were experienced by 60.9 percent of the 192 patients enrolled in the study. Grade 3/4 AEs occurred in 12.5 percent of patients. Immune-related AEs occurred in 17.2 percent of patients, with a majority being grade 1/2 in severity.
The most common treatment-related AEs were fatigue (17.2 percent), decreased appetite (7.3 percent), hypothyroidism (7.3 percent), rash (7.3 percent), pruritus (6.8 percent), nausea (6.3 percent), pyrexia (6.3 percent) and dry skin (5.2 percent). Treatment-related grade 3/4 AEs, which occurred in two patients each, were ALT and AST increase, hyponatremia, pneumonitis, and facial swelling.
A number of studies continue to assess Keytruda as a treatment for patients with HNSCC across treatment settings. The application for Keytruda was for an accelerated approval, meaning that a full indication would still be contingent upon confirmatory findings.
To this end, the phase 2 KEYNOTE-055 study explored Keytruda after platinum therapy and Erbitux for patients with HNSCC. The primary completion date for this study was set for April 2016, with results expected soon (NCT02255097). Additionally, the phase 3 KEYNOTE-040 is currently comparing Keytruda with standard treatment for patients with recurrent or metastatic HNCSS (NCT02252042).
In the first-line setting, the three-arm phase 3 KEYNOTE-048 trial is exploring Keytruda alone or with platinum chemotherapy and 5-FU compared with Erbitux 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).
Chow LQ,Mehra R, Haddad R, et al. Antitumor Activity of the Anti—PD-1 Antibody Pembrolizumab in Subgroups of Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC): Exploratory Analyses From KEYNOTE-012. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2866.