Merck, the manufacturer of pembrolizumab, issued a press release announcing the agency's decision on December 11, 2017. The findings were first presented at the 14th International Conference on Malignant Lymphoma and updated data were recently presented at the 2017 American Society for Hematology (ASH) Annual Meeting.
The FDA approved the sBLA based on results from a cohort of the phase II KEYNOTE-170 trial evaluating the anti–PD-1 agent in 29 patients with PMBCL. The trial is an ongoing, non-randomized, international, 2-cohort, multicenter study investigating pembrolizumab every 3 weeks in patients who relapsed after, were refractory to, or were ineligible for autologous stem cell transplant (ASCT) and failed 2 or more prior lines of therapy, and in patients with relapsed or refractory Richter syndrome.
Median duration of follow-up was 10.5 months (range, 0.1-17.7). Pembrolizumab was associated with an overall response rate (ORR) of 41% (95% CI, 0.24-0.61) by blinded independent central review (BICR) and 38% by investigator review. Additionally, there was a 24% complete response rate and a 17% partial response rate. Median time to response was 2.8 months (range, 2.4-5.5). Median duration of response was not reached (range, 1.1-13.6 months). Twelve-month overall survival (OS) was 62% and median OS was not reached.
Among all 22 evaluable patients, 16 (73%) had target lesion reductions of >50% from baseline.
“There is a significant unmet need for patients with relapsed or refractory primary mediastinal large B-cell lymphoma,” Pier Luigi Zinzani, MD, PhD, associate professor of hematology, Institute of Hematology, University of Bologna, said in a news release. “These encouraging results represent another step in understanding the potential of [pembrolizumab] to help these patients who have already tried and progressed on prior therapies.”
Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the approval by April 3, 2018. The sBLA is also based on data from the phase Ib KEYNOTE-013 trial, which is investigating the efficacy, safety, and tolerability of single-agent pembrolizumab across various hematologic malignancies.
PMBCL is a rare subtype of diffuse large B-cell lymphoma that starts in the mediastinum. PMBCL mainly affects young adults and occurs slightly more often in women. PMBCL accounts for 2% to 4% of all non-Hodgkin lymphomas (NHL) in the United States.
In KEYNOTE-170, patients were assigned to receive 200 mg of pembrolizumab every 3 weeks until disease progression, unacceptable toxicity, or completion of 35 treatment cycles. Treatment response was assessed every 12 weeks by PET scan and computed tomography using IWG 2007 response criteria. The primary endpoint was ORR as assessed by BICR.
Key secondary endpoints were complete response rate, ORR by investigator assessment, duration of response, OS, and safety/tolerability. The safety population consisted of all patients who received ≥1 dose of study drug and the efficacy population of all safety patients who were expected to have ≥24 weeks of follow-up by the analysis cutoff date.
Median patient age was 33 years (range, 20-61) and 55% of the cohort was female. Patients had received a median of 3 lines of prior therapy (range, 2-8) including 31% with prior radiation, 100% with prior rituximab (Rituxan), and 70% ASCT-ineligible due to chemorefractory disease.
Overall, 29 patients (59%) were PD-L1 positive, 2 (4%) PD-L1 negative, and 18 (37%) had missing baseline PD-L1 status. Of patients in the efficacy population, 76% were PD-L1 positive.
Merck said treatment-related adverse events (TRAEs) were consistent with previously reported safety data. Of the 53 patients evaluated for safety, 57% experienced TRAEs, including 21% who experienced grade 3/4 TRAEs.
The most common TRAEs (≥5%) were neutropenia, hypothyroidism, asthenia, and pyrexia. Eleven percent of patients experienced immune-mediated AEs of all grades, including hypothyroidism, hyperthyroidism, pneumonitis, and thyroiditis.
There were no treatment-related deaths. Twenty-nine patients discontinued treatment, mostly due to clinical or radiological progression (n = 24) or AEs (n = 3).
“These findings in patients with PMBCL are promising for a rare lymphoma that affects mainly young adults and has few effective treatment options in the relapsed or refractory treatment setting,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a news release. “If approved by the FDA, this would be our second blood cancer indication for Keytruda, following FDA approval for certain patients with classical Hodgkin lymphoma earlier this year.”
Pembrolizumab is approved for classic Hodgkin lymphoma and 6 other indications, including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and locally advanced or metastatic urothelial carcinoma patients who are ineligible for cisplatin-containing chemotherapy.