Tisagenlecleucel Follicular Lymphoma Data Impress, Regulatory Submission Is on Horizon

Stephen J. Schuster, MD

The CD19-directed CAR T-cell therapy tisagenlecleucel (Kymriah) led to high complete response rates that appear durable for heavily pretreated patients with relapsed or refractory follicular lymphoma, according to interim findings from the pivotal phase 2 ELARA trial (NCT03568461) that were presented during the 2021 ASCO Annual Meeting.

At a median follow-up of 10.9 months, the complete response (CR) rate per independent review was 66.0%, meeting the primary end point of the study. Moreover, the objective response rate (ORR) was 86.2%. Researchers calculated that the probability that a response remain ongoing for 6 months or more was 79% (95% CI, 66%-87%). In terms of safety, adverse events (AEs) were consistent with known profiles for tisagenlecleucel, and grade 3/4 potentially drug-related AEs were experienced by 45.4% of patients.

“Tisagenlecleucel demonstrated high rates of durable responses in patients with relapsed/refractory follicular lymphoma. These data indicate that tisagenlecleucel is an effective therapy in patients with relapsed/refractory follicular lymphoma, including high-risk subgroups,” lead study author Stephen J. Schuster, MD, director of the Lymphoma Program, director of Translational Research, and Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research at the University of Pennsylvania, said in a virtual presentation of the data.

“Our goal as researchers is to continue to explore the potential of CAR-T therapy, and the robust ELARA safety and efficacy findings suggest tisagenlecleucel may play an important role in the third-line treatment of relapsed or refractory follicular lymphoma,” Schuster noted in a statement.

Tisagenlecleucel consists of autologous T cells that have been manipulated with a lentivirus to express a CAR specific to CD19, which is expressed on many hematologic malignancies. The therapy uses a 4-1BB costimulatory domain to enhance expansion and persistence as well as a CD3 zeta intracellular signaling domain for activation and antitumor activity. The cell therapy has been approved for the treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and adult patients with relapsed/refractory diffuse large B-cell lymphoma.

In 2020, the FDA granted tisagenlecleucel a Regenerative Medicine Advanced Therapy (RMAT) designation, based on preliminary findings from the ELARA trial for patients with relapsed/refractory follicular lymphoma. This designation is mean to expedite the development of promising new therapies for patients with unmet needs. Based on the updated data, Novartis, the company developing the CAR T-cell therapy, plan to submit for global regulatory approval in the second half of 2021.

“The strength of these pivotal results from the ELARA trial underscore the promising potential of Kymriah in the treatment of patients with relapsed or refractory follicular lymphoma,” Stefan Hendriks, Global Head Cell & Gene, Novartis Oncology, said in a statement. “With deep experience in CAR-T cell therapy and the largest global manufacturing footprint, Novartis is boldly committed to bringing the benefits of Kymriah to more patients with advanced blood cancers, and we look forward to advancing global regulatory submissions in this indication as quickly as possible.”

ELARA Data at ASCO

The international, single-arm ELARA trial enrolled 98 patients at a median age of 57 years with grade 1, 2, or 3A relapsed/refractory follicular lymphoma without evidence of histological transformation or stage 3B disease who had not received prior CD19-directed therapy or allogeneic hematopoietic stem cell transplant. One patient discontinued before treatment and 97 were infused, with 94 available for efficacy analysis with at least 6 months of post-infusion follow-up assessment at the September 2020 data cutoff.

The median number of prior treatments was 4 (range, 2-13), the most common ECOG performance score was 0 (57.7%), and most were refractory to at least 2 regimens (76.3%). A total of 20.6% of patients had received prior treatment with a PI3K inhibitor.

Study treatment consisted of lymphodepleting chemotherapy by way of 25 mg/m2 of intravenous (IV) fludarabine daily for 3 days plus 250 mg/m2 of IV cyclophosphamide daily for 3 days or 90 mg/m2 of IV bendamustine daily for 2 days. Tisagenlecleucel was administered as a single IV infusion in doses ranging from 0.6 to 6 x 108 CAR-positive viable T cells, with a median dose of 2.06 x 108 CAR-positive viable T cells. Eighteen percent of patients received tisagenlecleucel in the outpatient setting. Bridging therapy was administered for disease stabilization in 44% of patients, and baseline imaging was also performed prior to infusion in patients who received bridging therapy.

The median duration of response was not reached at the assessment. Of the 31 partial responses achieved (20.2%), 12 later converted to CRs (38.7%) between month 3 and month 6. The median time to next antilymphoma treatment was not reached. CR rate was consistent across patient subgroups and was similar between those who had and had not had a prior stem cell transplant. The CR rate was also similar across lines of treatment.

The median progression-free survival was not reached (95% CI, 12.1-not evaluable [NE]), nor was median overall survival (95% CI, NE-NE). The 6-month PFS rate was 76% (95% CI, 65%-84%).

Regarding safety, all-grade and grade 3 or greater cytokine release syndrome (CRS) occurred in 48.5% vs 0% of treated patients, respectively. All-grade and grade 3 or greater neurological adverse reactions occurred in 9.3% vs 1.0% of patients, respectively. No treatment-related mortalities were reported. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) occurred within the first 8 weeks.

The median onset of neurologic events was 8.5 days (range, 4-190), and the median time to resolution was 2 days. The median onset of CRS was 4 days (range, 1-14), and all cases were low grade. Most CRS events and ICANS occurred in patients with bulky disease, at 74.5% vs 100%, respectively. All neurological and CRS events resolved with appropriate intervention. In terms of adverse effect management, 34% of patients received tocilizumab (Actemra) and 6.4% received corticosteroids.

“Tisagenlecleucel is a promising therapy for the treatment of adult patients with relapsed/refractory follicular lymphoma following 2 or more lines of therapy,” concluded Schuster. “Safety data were consistent with the established favorable safety profile of tisagenlecleucel.”

Reference

Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma: primary analysis of the phase 2 Elara trial. J Clin Oncol. 2021;39(suppl 15):7508. doi:10.1200/JCO.2021.39.15_suppl.7508