Keytruda (pembrolizumab) was granted a priority review to a supplemental biologics license application (sBLA) to be used to treat adult and pediatric patients with relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL).
Merck, the manufacturer of Keytruda, issued a press release announcing the agency's decision on Dec. 11, 2017. The findings were first presented at the 14th International Conference on Malignant Lymphoma and updated data were recently presented at the 2017 ASH Annual Meeting.
The FDA approved the sBLA based on results from a cohort of the phase 2 KEYNOTE-170 trial evaluating the anti–PD-1 agent in 29 patients with PMBCL. The trial is an ongoing, non-randomized, international, two-cohort, multicenter study investigating Keytruda every three weeks in patients who relapsed after, were refractory to, or were ineligible for autologous stem cell transplant (ASCT) and failed two or more prior lines of therapy, and in patients with relapsed or refractory Richter syndrome.
Median duration of follow-up was 10.5 months. Keytruda was associated with an overall response rate (ORR) of 41 percent by blinded independent central review (BICR) and 38 percent by investigator review. Additionally, there was a 24 percent complete response rate and a 17 percent partial response rate. Median time to response was 2.8 months. Median duration of response was not reached. Twelve-month overall survival (OS) was 62 percent and median OS was not reached.
Among all 22 evaluable patients, 16 (73 percent) had target lesion reductions of 50 percent or more from baseline.
“There is a significant unmet need for patients with relapsed or refractory primary mediastinal large B-cell lymphoma,” Pier Luigi Zinzani, M.D., Ph.D., 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 Keytruda 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 1b KEYNOTE-013 trial, which is investigating the efficacy, safety, and tolerability of single-agent Keytruda 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 percent to 4 percent of all non-Hodgkin lymphomas (NHL) in the United States.
In KEYNOTE-170, patients were assigned to receive 200 mg of Keytruda every three 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 at least one dose of study drug and the efficacy population of all safety patients who were expected to have 24 weeks or more of follow-up by the analysis cutoff date.
Median patient age was 33 years (range, 20-61) and 55 percent of the cohort was female. Patients had received a median of three lines of prior therapy (range, two to eight) including 31 percent with prior radiation, 100 percent with prior Rituxan rituximab (rituximab), and 70 percent ASCT-ineligible due to chemorefractory disease.
Overall, 29 patients (59 percent) were PD-L1 positive, 2 (4 percent) PD-L1 negative and 18 (37 percent) had missing baseline PD-L1 status. Of patients in the efficacy population, 76 percent 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 percent experienced TRAEs, including 21 percent who experienced grade 3/4 TRAEs.
The most common TRAEs (5 percent or more) 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 (24 patients) or AEs (three patients).
“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, M.D., 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.”
Keytruda is approved for classic Hodgkin lymphoma and six 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.