Novartis Submits sBLA for Tisagenlecleucel in Adults With Relapsed/Refractory DLBCL

Stephen J. Schuster, MD

Novartis has filed a supplemental biologics license application (sBLA) with the FDA to expand the indication for tisagenlecleucel (Kymriah) to include adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant (ASCT).

The FDA granted a breakthrough therapy designation for tisagenlecleucel in this population in April 2017. The agency approved the chimeric antigen receptor (CAR) T-cell immunocellular therapy for the treatment of children and adults up to age 25 with B-cell precursor acute lymphoblastic leukemia in August 2017, making it the first CAR T-cell therapy approved for use in the United States.

“The approval of tisagenlecleucel in the treatment of children and young adults with second relapse or refractory B-cell ALL was a watershed moment in the journey for researchers to develop immunocellular therapies,” said Stephen Schuster, MD, director of the Lymphoma Program and Lymphoma Translational Research, University of Pennsylvania Perelman School of Medicine. Investigators there and at the Children’s Hospital of Philadelphia developed tisagenlecleucel along with Novartis.

“The data show this therapy could change the treatment paradigm for patients with relapsed/refractory DLBCL, as we've seen durable complete responses in patients who previously relapsed or were refractory to prior therapies, and this second filing is a significant step toward realizing its potential for even more patients who are currently battling fatal blood cancers.”

The sBLA is based on results from the global, multicenter, phase II JULIET study. In findings presented in June 2017 at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland, tisagenlecleucel was associated with an objective response rate (ORR) of 59% (95% CI, 44.2%-72.4%; P <.0001) in 51 patients with DLBCL at a median follow-up of 3.7 months.

Nearly half (43%) of patients had a complete response (CR) and 16% achieved a partial response (PR). Approximately one-quarter of patients experienced disease progression. Moreover, 79% of patients who demonstrated a CR or PR at 3 months remained relapse free at 6 months. The median duration of response was not reached as of the data cutoff of December 2016.

This analysis included data from 51 of the 141 enrolled adult patients with DLBCL who had ≥3 months of follow-up. The final primary analysis is expected to include data from all 81 treated patients who completed follow-up or discontinued early.

All patients underwent restaging and lymphodepleting chemotherapy with 25 mg/m² of fludarabine and 250 mg/m2 of cyclophosphamide daily for 3 days or 90 mg/m² of bendamustine daily for 2 days. Thereafter, 81 patients received a single dose of median 3.1 × 10⁸ CTL019 transduced cells.

Patients had received a median of 3 (range, 2-7) prior lines of antineoplastic therapy, including 51% who received ASCT. Seventy-six patients received bridging chemotherapy.

The safety cohort included 85 treated patients, 57% of whom experienced any grade of cytokine release syndrome (CRS); 17% of patients had grade 3 CRS and 9% experienced grade 4 levels. CRS was managed by a protocol-specific algorithm and 16% of patients received tocilizumab.

Additionally, grade 3/4 neurologic adverse events occurred in 13% patients and were managed with supportive care. Moreover, grade 3/4 cytopenia lasting >28 days occurred in 21% of patients, and 14% experienced grade 3/4 febrile neutropenia. Grade 3 tumor lysis syndrome was reported in 1% of patients.

Three patients died from disease progression within 30 days of infusion; however, there were no treatment-related deaths reported. There were no deaths due to CRS nor incidents of cerebral edema.

DLBCL is the most common form of non-Hodgkin lymphoma (NHL) that accounts for up to 40% of all cases worldwide. Approximately 50% to 60% of patients with DLBCL achieve and maintain complete remission after frontline therapy, but approximately one-third of patients relapse after receiving first-line treatment. Furthermore, only 25% of patients with relapsed/refractory DLBCL are eligible for ASCT, which is a standard secondary treatment. Untreated relapsed/refractory DLBCL has a life expectancy of 3 to 4 months.

Schuster SJ, Bishop MR, Tam, et al. Global pivotal phase 2 trial of the cd19-targeted therapy ctl019 in adult patients with relapsed or refractory (r/r) diffuse large b-cell lymphoma (DLBCL)—an interim analysis [published online ahead of print June 7, 2017]. Hematol Oncol. 2017,35(suppl S2).