The FDA has granted a priority review to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) for use as a treatment for patients with refractory classical Hodgkin lymphoma.
Roger Dansey, MD
The FDA has granted a priority review to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) for use as a treatment for patients with refractory classical Hodgkin lymphoma (cHL) or those who have relapsed after ≥3 lines of therapy, according to a statement from Merck, the manufacturer of the antiPD-1 agent.
The application is based on results from the phase II KEYNOTE-087 and phase Ib KEYNOTE-013 trials, which evaluated pembrolizumab for the proposed indication in the sBLA. The specific regimen would be a fixed dosed of 200 mg of pembrolizumab every 3 weeks.
If approved, this would be the first FDA indication for pembrolizumab 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, MD, 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% to 80% in 3 separate cohorts of relapsed/refractory Hodgkin lymphoma patients, including patients who relapsed after treatment with brentuximab vedotin (Adcetris), patients who failed to respond to brentuximab vedotin, 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 pembrolizumab in 3 cohorts of patients with relapsed/refractory cHL.1Cohort 1 included patients who failed to achieve a response to, or progressed after ASCT, and relapsed after treatment with or failed to respond to brentuximab vedotin post ASCT. Cohort 2 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 brentuximab. Finally, cohort 3 included patients who failed to achieve a response to or progressed after ASCT and did not receive brentuximab vedotin post ASCT.
Study participants were treated with pembrolizumab, 200 mg intravenously every 3 weeks on day 1 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 3 cohorts. The percentage of patients receiving greater than 3 prior lines of therapy was 73% in cohort 1, 60% in cohort 2, and 37% in cohort 3. The median number of lines of systemic therapy was 5, 4, and 3 in each cohort, respectively. By design, all patients in cohorts 1 and 2 had prior brentuximab failure, as did 40% in cohort 3.
The best ORRs by investigator review were 73% in cohort 1, 83% in cohort 2, and 73% in cohort 3. The ORR was 78% in the 37 patients with primary refractory disease. A CR as best response was observed in 27%, 30%, and 30% in cohorts 1, 2, and 3, respectively, and was 35% in patients with primary refractory disease. Most responses occurred at the first assessment at 12 weeks.
With a median of 9 treatment cycles, the most common adverse events (AEs) in the combined cohorts were pyrexia (13%), diarrhea (10%), and neutropenia, fatigue, and cough (8% each). In addition, 7% of patients experienced hypothyroidism, 6% suffered from dry skin, and 6% had nausea. There were 8 grade 3/4 treatment-related AEs in 4 patients. One patient with an infusion-related reaction and 1 with pneumonitis discontinued pembrolizumab.
In the KEYNOTE-013 study, patients received pembrolizumab at 10 mg/kg every 2 weeks for up to 2 years.2Sixty-eight percent of patients had received ≥4 prior lines of therapy and 71% had failed prior ASCT. All patients had progressed on prior brentuximab vedotin.
The ORR of 64.5% included 5 CRs (16.1%) and 15 PRs (48.4%). Additionally, 23% of patients experienced stable disease with pembrolizumab. 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 (n = 14) ongoing at the time of the analysis. At the data cutoff, 45% of patients remained on therapy.
The most common treatment-related all-grade AEs were hypothyroidism (16%), diarrhea (13%), nausea (13%), and pneumonitis (10%). Five patients had grade 3 AEs; however, no grade 4 events or treatment-related deaths occurred. Altogether, 2 patients (6%) discontinued therapy due to AEs.
If approved, pembrolizumab would become the second anti-PD1 agent approved for cHL. In May 2016, the FDA granted nivolumab (Opdivo) an accelerated approval for the treatment of patients with cHL who have relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin.