Second-line tisagenlecleucel equivalent to standard of care for relapsed or refractory aggressive Non-Hodgkin Lymphoma
Although the CAR-T cell therapy tisagenlecleucel (tisa-cel) has previously demonstrated to be effective in the third-line setting of patients with aggressive non-Hodgkin lymphoma, an analysis of the phase III BELINDA trial now demonstrated that tisa-cel could not improve event-free survival over standard of care as a second-line treatment for patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.
To date, patients with aggressive non-Hodgkin lymphoma’s (aNHLs) who are relapsed or refractory within twelve months of first-line treatment still have a very poor prognosis. The standard of care (SOC) second-line treatment option for these patients includes platinum-based immunochemotherapy (PCT), followed by high-dose chemotherapy and autologous haematopoietic cell transplantation (aHCT). However, more than half of the patients cannot receive aHCT due to an inadequate response to PCT.
Tisagenlecleucel (tisa-cel) is an autologous anti-CD19 CAR-T cell therapy approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) after at least two lines of treatment. BELINDA is a global, phase III, randomised trial comparing the safety and efficacy of tisa-cel to the current SOC in patients with R/R aNHL within twelve months of first-line therapy.
BELINDA study design
Adults with histologically confirmed R/R aNHL within 12 months after first-line chemo-immunotherapy were eligible to participate in this study. All patients underwent leukapheresis for tisa-cel production and were randomised 1:1 to receive tisa-cel (Arm A) or SOC (Arm B).
Patients in the tisa-cel arm received optional bridging therapy (investigator choice of protocol-defined PCT regimens) followed by lymphodepletion (LD; generally, fludarabine 25 mg/m2/day + cyclophosphamide 250 mg/m2/day for 3 days) and followed by a single tisa-cel infusion (0.6-6×108 CAR-T cells). Patients in the SOC arm received investigator’s choice of PCT regimen followed by aHCT in responders or a second PCT in nonresponders.
Disease assessments were performed at 6 and 12 weeks, and then planned every 3 months for year 1 and every 6 months for year 2. The primary endpoint was event-free survival (EFS), defined as time from randomisation to stable disease (SD) or progressive disease (PD), at or after week 12 assessment, or death at any time. SD/PD at week 6 was not considered an event on either arm. Arm A’s week 6 assessment evaluated disease burden before tisa-cel infusion and after bridging therapy, if administered. Arm B’s week 6 assessment determined if response was sufficient for aHCT, or if a second PCT regimen was needed prior to aHCT.
Results
In total, 162 patients were randomised to tisa-cel and 160 patients to SOC. Approximately one third of patients were ≥65 years, respectively 66.0% and 66.9% of patients in the tisa-cel and SOC arm had primary refractory disease and an additional 20% of patients relapsed within six months of initial treatment. Baseline characteristics indicated imbalances with more high-grade B-cell lymphomas (24% vs. 17%) and IPI ≥2 (65% vs. 58%) in the tisa-cel vs. SOC arm.
Approximately 96% of patients in the tisa-cel arm did actually receive tisa-cel infusion. In the SOC arm, 32.5% received aHCT, including 10% requiring at least two different PCT regimens before aHCT. In the tisa-cel arm, 48% received ≥2 cycles of bridging PCT, 36% received 1 cycle, and 17% received no bridging. Corresponding values in the SOC arm were 97%, 2% and 1%, respectively.
The median time to infusion for all patients in the tisa-cel arm was 52 days (range, 31-135), although there was a difference between US (median of 41 days) and non-US regions (median of 57 days). At a median follow-up of 10 months, median EFS was 3.0 months in both arms and thus was not significantly different (HR[95%CI]: 1.07[0.82-1.40], p= 0.69).
Of note, longer time to infusion and delayed responses confounded EFS for six patients, as they were found to have either stable or progressive disease at the twelve week mark but subsequently responded to tisa-cel. Both pre-infusion response status and disease diagnosis were found to influence EFS outcomes.
At week 6 assessment, 25.9% had PD upon treatment with tisa-cel, as compared to 13.8% with SOC. Overall response rate (ORR) at week 12 in the tisa-cel arm was 46.3% vs. 42.5% in the SOC arm. Complete response rate in both arms was 28%.
Grade ≥3 adverse events (AEs) were reported in 84.0% of patients treated with tisa-cel, as compared to 90.0% of patients with SOC. In total, 52 (32.1%) and 45 (28.1%) of patients in the tisa-cel and SOC arms died on study, including 42 (25.9%) and 32 (20.0%) deaths due to progressive disease. Ten patients in the tisa-cel arm and 13 patients in the SOC arm died because of AEs. Cytokine release syndrome (CRS) was reported in 95 (58.6%) of patients in the tisa-cel arm, including 8 patients (4.9%) with CRS of grade ≥3. Neurological events of all grade and grade ≥3 were reported in respectively 10.3% and 1.9% of patients.
Conclusion
Results of the BELINDA study demonstrate that EFS was not significantly different between tisa-cel and SOC strategies in patients with aNHL that was refractory or relapsed after first-line therapy. Results suggest the importance of preventing progressive disease prior to infusion. Furthermore, effective bridging therapy prior to CAR-T cell infusion and a shorter time to infusion for this chemotherapy-refractory patient population could be critical to improve outcomes.
Reference
Bishop M, 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 ASH 2021; Abstract LBA6.
