Keytruda was granted a priority review to a supplemental biologics license application (sBLA) to treat a subset of patients with classical Hodgkin lymphoma.
Keytruda (pembrolizumab) was granted a priority review to a supplemental biologics license application (sBLA) by the U.S. Food and Drug Administration (FDA) for the treatment of patients with refractory classical Hodgkin lymphoma (cHL) or who relapsed after three or more lines of therapy, according to a statement from the manufacturer of the anti-PD1 agent, Merk.
The application is based on results from the phase 2 KEYNOTE-087 and phase 1b KEYNOTE-013 trials, which evaluated Keytruda for the proposed indication in the sBLA. The specific regimen would be a fixed dosed of 200 mg of Keytruda every three weeks.
If approved, this would be the first FDA indication for Keytruda in a hematologic malignancy. The PD-1 inhibitor previously received a breakthrough therapy designation for cHL in April 2016. Under the priority review, the FDA is scheduled to make a final decision by March 15, 2017.
“Patients with refractory or relapsed classical Hodgkin lymphoma have limited treatment options,” Roger Dansey, M.D., senior vice president and therapeutic area head, Oncology Late-Stage Development, Merck Research Laboratories, said in a statement. “We believe that the expedited review of this sBLA granted by the FDA is an important step in helping us make Keytruda available as quickly as possible to patients living with this disease.”
Findings from the KEYNOTE-087 study showed overall response rates (ORRs) of about 70 percent to 80 percent in three separate cohorts of relapsed/refractory Hodgkin lymphoma patients, including patients who relapsed after treatment with Adcetris (brentuximab vedotin), patients who failed to respond to Adcetris, patients who relapsed or progressed after autologous stem cell transplant (ASCT), and those ineligible for ASCT.
KEYNOTE-087 was a multicenter, single-arm, nonrandomized study of Keytruda in three cohorts of patients with relapsed/refractory cHL. Cohort one included patients who failed to achieve a response to, or progressed after ASCT, and relapsed after treatment with or failed to respond to Adcetris post ASCT. Cohort two included patients who were unable to achieve a complete response (CR) or partial response (PR) to salvage chemotherapy and did not receive ASCT, but relapsed after treatment with or failed to respond to Adcetris. Finally, cohort three included patients who failed to achieve a response to or progressed after ASCT and did not receive Adcetris post ASCT.
Study participants were treated with Keytruda, 200 mg intravenously every three weeks on day one of each 21-day treatment cycle for up to 24 months. A flat dose was chosen because of the flat exposure-response relationship for efficacy and safety in the 2-mg/kg to 10-mg/kg dosage range across prior clinical studies.
A prespecified interim analysis, based on investigator-assessed response, was performed after 30 patients reached first response assessment in all three cohorts. The percentage of patients receiving greater than three prior lines of therapy was 73 percent in cohort one, 60 percent in cohort two, and 37 percent in cohort three. The median number of lines of systemic therapy was five, four and three in each cohort, respectively. By design, all patients in cohorts one and two had prior Adcetris failure, as did 40 percent in cohort three.
The best ORRs by investigator review were 73 percent in cohort one, 83 percent in cohort two, and 73 percent in cohort three. The ORR was 78 percent in the 37 patients with primary refractory disease. A CR as best response was observed in 27 percent, 30 percent, and 30 percent in cohorts one, two and three, respectively, and was 35 percent in patients with primary refractory disease. Most responses occurred at the first assessment at 12 weeks.
With a median of nine treatment cycles, the most common adverse events (AEs) in the combined cohorts were pyrexia (13 percent), diarrhea (10 percent), and neutropenia, fatigue and cough (8 percent each). In addition, 7 percent of patients experienced hypothyroidism, 6 percent suffered from dry skin, and 6 percent had nausea. There were eight grade 3/4 treatment-related AEs in four patients. One patient with an infusion-related reaction and one with pneumonitis discontinued Keytruda.
In the KEYNOTE-013 study, patients received Keytruda at 10 mg/kg every two weeks for up to two years. Sixty-eight percent of patients had received four or more prior lines of therapy and 71 percent had failed prior ASCT. All patients had progressed on prior Adcetris.
The ORR of 64.5 percent included 5 CRs (16.1 percent) and 15 PRs (48.4 percent). Additionally, 23 percent of patients experienced stable disease with Keytruda. After a median of 9.7 months of follow-up, median duration of response was not yet reached (range, 0-13.4+ months), with most responses (14 patients) ongoing at the time of the analysis. At the data cutoff, 45 percent of patients remained on therapy.
The most common treatment-related all-grade AEs were hypothyroidism (16 percent), diarrhea (13 percent), nausea (13 percent) and pneumonitis (10 percent). Five patients had grade 3 AEs; however, no grade 4 events or treatment-related deaths occurred. Altogether, two patients (6 percent) discontinued therapy due to AEs.
If approved, Keytruda would become the second anti-PD1 agent approved for cHL. In May 2016, the FDA granted Opdivo (nivolumab) an accelerated approval for the treatment of patients with cHL who have relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation Adcetris.