The Food and Drug Administration granted a priority review to a supplemental biologics license application for Kymriah (tisagenlecleucel) to be used to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma who either relapse or are not eligible for an autologous stem cell transplant.
The Food and Drug Administration (FDA) granted a priority review to a supplemental biologics license application (sBLA) for Kymriah (tisagenlecleucel) to be used to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who either relapse or are not eligible for an autologous stem cell transplant (ASCT).
The sBLA is based on the phase 2 JULIET study, in which the CD19-directed therapy Kymriah, a chimeric antigen receptor (CAR) T cell therapy, reached an overall response rate (ORR) of 53.1 percent in adult patients with relapsed/refractory DLBCL.
Based on the JULIET findings, the European Medicines Agency (EMA) has also granted an accelerated assessment to a marketing authorization application (MAA) for Kymriah for the same DLBCL indication. The MAA also includes an indication for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). The FDA already approved Kymriah in August 2017 for use in patients with ALL.
"The priority review designation and accelerated assessment signal that the FDA and EMA have recognized the potential of Kymriah to provide a much-needed therapeutic option for these patients with relapsed or refractory B-cell ALL and DLBCL. We are now focused on working with these regulatory agencies to bring this potentially transformative therapy to more patients,” Samit Hirawat, M.D., head, Novartis Oncology Global Drug Development, said in a press release.
Patients in JULIET were enrolled at 27 study centers in 10 countries on four continents. At the March 8, 2017, data cutoff, 147 patients were enrolled, 99 of whom were infused with a single dose of Kymriah transduced cells. Ninety percent of patients received bridging therapy. Before infusion, patients underwent restaging and 93 percent received lymphodepleting chemotherapy.
The median patient age was 56 years (range, 22-76) and 77 percent of patients had stage 3/4 disease at baseline. Forty-seven percent of patients had received ASCT. Patients had received a median of three (range, one to six) prior lines of antineoplastic therapy, with 95 percent of patients having received at least two lines of therapy and 51 percent having received three or more.
The 53.1 percent ORR occurred in 81 infused patients and included a complete response (CR) rate of 39.5 percent and a partial response (PR) rate of 13.6 percent. The CR rate for all 81 patients at month three was 32 percent and the PR rate was 6 percent. The rates were 30 percent and 7 percent, respectively, among patients evaluable at six months (46 patients).
The investigators observed consistent response rates across prognostic subgroups, including prior ASCT and patients with double-hit lymphoma. The median duration of response had not been reached. The probability of being relapse-free at 6 months was 73.5 percent. Among the patients achieving a CR or a PR, none proceeded to allogenic stem cell transplant or ASCT.
Median overall survival (OS) had not been reached, with the probability of OS at six months being 64.5 percent. Among responders, Kymriah was detected in peripheral blood by quantitative PCR for up to 367 days.
The incidence of adverse events of special interest (AESI) was evaluated in 99 patients. Common AESIs included cytokine release syndrome (CRS; 58 percent; grade 3, 15 percent; grade 4, 8 percent), neurological events (21 percent; grade 3, 8 percent; grade 4, 4 percent), prolonged cytopenia (36 percent; grade 3, 15 percent; grade 4, 12 percent), infections (34 percent; grade 3, 18 percent; grade 4, 2 percent) and febrile neutropenia (13 percent; grade 3, 11 percent; grade 4, 2 percent).
There were no deaths due to Kymriah, CRS, or cerebral edema. Twenty-six patients were infused as outpatients, with 20 of these patients remaining outpatients for three or more days after infusion.
The indication for ALL in the MAA is based on phase 2 results from the single-arm, international ELIANA trial of 63 patients who received a single dose of Kymriah. The targeted dose of each Kymriah infusion was 0.2 to 5.0 x 106 transduced viable T cells/kg for patients up to 50 kg and 0.1 to 2.5 x 108transduced viable T cells/kg for those greater than 50 kg.
The overall remission rate was 82.5 percent in treated subjects. Forty patients (63 percent) had CR and 12 (19 percent) had CR with incomplete hematologic recovery.