Tisagenlecleucel Does Not Prolong EFS in R/R Aggressive B-Cell Non-Hodgkin Lymphoma

Michael R. Bishop, MD

An analysis of the phase 3 BELINDA trial (NCT03570892) demonstrated lack of event-free survival (EFS) advantage when tisagenlecleucel (Kymriah) was administered as second-line treatment for patients relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) and compared with the standard of care (SOC) platinum-based chemotherapy followed by autologous stem cell transplant (ASCT) or additional chemotherapy.¹

“EFS was identical between the 2 arms,” said lead study author Michael R. Bishop, MD, a professor of medicine and director of the Hematopoietic Stem Cell Transplantation Program at the University of Chicago Medicine, during the press briefing at the ASH Annual Meeting 2021.

“[Therefore], unfortunately, BELINDA did not meet its primary end point of improved EFS with tisagenlecleucel and the therapy was not found to be better than current available SOC,” Bishop added.

Approximately two-thirds of patients with B-cell NHL are essentially cured with frontline chemoimmunotherapy; however, a subset of patients who do not respond to initial therapy or relapse within 12 months following frontline therapy have poor outcomes and an expected survival of less than 12 months, Bishop explained.

In this subset, SOC options include platinum-based chemotherapy followed by ASCT in patients with chemotherapy-sensitive disease. However, more than half of these patients will not receive ASCT because of inadequate responses to second-line therapy.

Tisagenlecleucel, a CD19-directed CAR T-cell therapy, was FDA approved on May 1, 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 lines of prior systemic therapy.² The regulatory indication included patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOC), high grade B-cell lymphoma (HGBL), and DLBCL arising from follicular lymphoma.

As tisagenlecleucel is an autologous CAR T-cell therapy, patients undergo leukapheresis to remove their T cells, which are then modified to effectively target the cancer. The modified cells are then infused back into the patient.

“Our hypothesis was that based upon the results in more advanced DLBCL that moving tisagenlecleucel treatment into up-front therapy for this poor-risk group of patients would result in improved outcomes, specifically EFS,” Bishop said.

The BELINDA trial randomized patients with confirmed relapsed/refractory aggressive NHL who recurred within 12 months following induction chemoimmunotherapy to tisagenlecleucel vs standard of care platinum-based chemotherapy followed by ASCT.

Overall, 396 patients were included in the screened set, but 74 patients did not complete screening to go onto leukapheresis. Therefore, 322 patients were included in the full analysis and safety sets. These patients were randomized 1:1 to tisagenlecleucel (n = 162; Arm A) or SOC (n = 160; Arm B). Ultimately, the tisagenlecleucel infused patient set included 236 patients comprised of 155 who were randomized to tisagenlecleucel and 81 who crossed over from Arm B.

In Arm A, 6 patients (3.7%) discontinued treatment without undergoing tisagenlecleucel infusion for reasons including physician decision (n = 2; 1.2%), progressive disease (PD; n = 2; 1.2%), manufacturing issue (n = 1; 0.6%), and patient decision (n = 1; 0.6%). In Arm B, 102 patients discontinued treatment without undergoing ASCT for reasons including progressive disease (n = 76; 47.5%), physician decision (n = 14; 8.8%), death (n = 7; 4.4%), patient decision (n = 2; 1.3%), technical problems (n = 2; 1.3%), and protocol deviation (n = 1; 0.6%).

Patients who received tisagenlecleucel underwent optimal bridging therapy with investigator’s choice of protocol-defined platinum-based chemotherapy regimens followed by lymphodepletion with, generally, 25 mg/m² of daily fludarabine plus 250 mg/m² of daily cyclophosphamide for 3 days. A single infusion of tisagenlecleucel was then given at a dose of 0.6 to 6 x 10⁸ CAR T cells.

Patients who received SOC received investigator’s choice of platinum-based chemotherapy followed by ASCT in responders or a second platinum-based chemotherapy regimen in nonresponders.

The primary end point of the study was EFS, defined as the time from randomization to stable disease (SD) or PD at or after assessment at 12 weeks or death at any time. Moreover, SD or PD at 6 weeks was not considered an EFS event; however, the 6-week assessment evaluated disease burden before tisagenlecleucel infusion and after bridging therapy in patients enrolled to Arm A and determined whether patients enrolled to Arm B had a sufficient response to platinum-based chemotherapy to undergo ASCT.

Disease assessment was performed at 6 and 12 weeks; additional assessments were planned for every 3 months in the year following therapy and every 6 months in the second year following therapy.

Patients were stratified by first-line duration of response, International Prognostic Index (IPI), and geographic region.

Regarding baseline patient characteristics, disease subtypes in the tisagenlecleucel arm vs SOC arm, respectively, included DLBCL-NOS (62.3% vs 70%), HGBL with MYC and BCL2 and/or BCL6 (19.8% vs 11.9%), primary mediastinal large B-cell lymphoma (7.4% vs 8.1%), HGBL-NOS (4.3% vs 5%), grade 3B follicular lymphoma (3.1% vs 0.6%), and other (3.1% vs 4.4%). DLBCL cell of origin in the tisagenlecleucel arm vs SOC arm, respectively, was germinal center B-cell like (GCB; 28.4% vs 39.4%), non-GCB/activated B-cell (32.1% vs 26.3%), or unclassified/missing (1.9% vs 4.4%).

Remission durations in the tisagenlecleucel arm showed that 66% of patients were refractory, 18.5% relapsed less than 6 months following frontline treatment, and 15.4% of patients relapsed within 6 to 12 months. In the SOC arm, these rates were 66.9%, 20%, and 13.1%, respectively.

Most patients across arms were not based in the United States (70.5%), male (62.5%), younger than 65 years of age (68.9%), had IPI scores of at least 2 (61.5%), and had stage IV disease at the time of study entry (47.2%). Additionally, 43.2% of patients who received tisagenlecleucel vs 40.6% of patients who received SOC had an ECOG performance status of 1.

Most patients in both arms received 1 prior line of therapy for current lymphoma (98.8%) and did not have transformation of prior lymphoma (84.8%).

The median time since initial diagnosis was 8.4 months with tisagenlecleucel (Q1-Q3, 6.8-11.1) vs 8.2 months with SOC (Q1-Q3, 5.9-11.4). The median time since most recent relapse or PD was 1.4 months (Q1-Q3, 0.9-2.2) vs 1.1 months (Q1-Q3, 0.8-1.8), respectively.

The median time to randomization was 92 days (range, 61-158), and the median follow-up was 10 months (range, 2.9-23.2).

The safety profile of tisagenlecleucel was consistent with previously reported studies evaluating the therapy.

“We hope that the results of this study will be used to help design further trials in patients with DLBCL,” said Bishop.

Further details of the study will be published in the New England Journal of Medicine, Bishop concluded.

_References

_{1. Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel vs standard of care as second-line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: analysis of the phase III BELINDA study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract LBA-6.}

_{2. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. May 1, 2018. Accessed December 13, 2021. https://bit.ly/3E0sxg5}