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 (2021)

Abstract Background: Standard of care (SOC) for second-line (2L) therapy (tx) of relapsed/refractory aggressive B-cell non-Hodgkin lymphomas (R/R aNHL) includes platinum-based chemotherapy (PCT) followed by autologous hematopoietic cell transplantation (aHCT) in responders. Outcomes are poor for patients (pts) with R/R aNHL who experience progression during or within 12 months (mo) of 1L tx. Tisagenlecleucel (tisa-cel) is an autologous chimeric antigen receptor (CAR) T-cell tx targeting CD19 approved for pts with large B-cell lymphoma (LBCL; US) and diffuse LBCL (non-US) after ≥2 lines of tx. BELINDA (NCT03570892) is a Phase III, randomized, global (18 countries) study of tisa-cel vs SOC as 2L tx for R/R aNHL. Methods: Adults with confirmed R/R aNHL within 12 mo after 1L chemo-immunotherapy were eligible. All pts underwent leukapheresis for tisa-cel production and were randomized 1:1 to receive tisa-cel (Arm A) or SOC (Arm B) and stratified by 1L duration of response, International Prognostic Index (IPI), and geographic region. Arm A received optional bridging tx (investigator choice of protocol-defined PCT regimens) followed by lymphodepletion (LD; generally, fludarabine 25 mg/m 2/day [d] + cyclophosphamide 250 mg/m 2/d for 3 d) and followed by a single tisa-cel infusion (0.6-6×10 8 CAR-T cells). Arm B received investigator choice of PCT regimen followed by aHCT in responders or a second PCT in nonresponders. Disease assessments were performed at 6 and 12 weeks (wk), then planned every 3 mo for year (y) 1 and every 6 mo for y 2. The primary endpoint was event-free survival (EFS), defined as time from randomization to stable disease (SD) or progressive disease (PD) at or after wk 12 assessment or death at any time. SD/PD at wk 6 was not considered an event on either Arm. Arm A's wk 6 assessment evaluated disease burden before tisa-cel infusion and after bridging if administered. Arm B's wk 6 assessment determined if response was sufficient for aHCT or if a second PCT regimen was needed prior to aHCT. Results: As of May 6, 2021, 322 pts were randomized: 162 to Arm A and 160 to Arm B. In Arms A and B, 33% and 29% were ≥65 y, and 66% and 67% had primary refractory disease, respectively. Baseline characteristics indicated imbalances with more high-grade B-cell lymphomas (24% vs 17%) and IPI ≥2 (65% vs 58%) in Arm A vs B. In Arm A, 47% received ≥2 cycles of bridging PCT, 36% received 1 cycle, and 17% received 0. In Arm A, 96% received tisa-cel; the median dose was 2.9×10 8 cells. In Arm B, 96% received ≥2 PCT cycles and 54% received ≥2 different PCT regimens; 33% received aHCT, including 10% requiring ≥2 different PCT regimens before aHCT. Median time from randomization to aHCT was 92 d (range, 61-158 d). Median follow-up was 10 mo (range, 2.9-23.2 mo). At wk 6 assessment, 26% had PD in Arm A vs 14% in Arm B. Median EFS in Arms A and B was 3 mo (HR 1.07; 95% CI, 0.82-1.40; P=0.69); Arm A pts with PD at wk 6 had shorter EFS. Overall response rate (ORR) at wk 12 in Arm A was 46% vs 43% in Arm B; complete response rate in both arms was 28%. Some pts responded to tisa-cel after SD/PD at wk 12 without additional tx but were counted as an event in EFS analysis. In Arm B, 81 pts (51%) crossed over to receive tisa-cel, 71 without receiving aHCT. Of 72 crossover pts with response assessment, ORR to tisa-cel was 40%. Overall survival was immature at data cutoff. In Arm A, 84% had a grade ≥3 adverse event (AE; vs 90% in Arm B), including grade ≥3 cytokine release syndrome in 5% (CRS; Lee 2014) and grade ≥3 neurologic events (NE) in 3% (CTCAE v5.0), with no grade 5 CRS/NE. Median times to CRS and NE onset were 4 and 5 d, respectively; median time to resolution was 5 and 9 d. Fifty-two (32%) and 45 (28%) pts in Arms A and B died on study, including 42 (26%) and 32 (20%) deaths due to PD, respectively. Ten pts in Arm A and 13 in Arm B died of AEs. Conclusions: Tisa-cel as 2L tx in R/R aNHL pts did not have a higher EFS vs SOC. Possible contributing factors include study design elements, such as optional PCT bridging tx in Arm A with potential delay of tisa-cel infusion until after wk 6 assessment, allowance of a different PCT regimen to reach aHCT in Arm B after inadequate response to first PCT, and imbalances in relevant pt characteristics. Insights from this randomized Phase III study will inform use of cellular tx in the 2L R/R aNHL setting and the design of future CAR-T trials. Figure 1 Figure 1. Disclosures Bishop: Arcellx, Autolus, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis: Consultancy, Research Funding; Bristol-Myers Squibb and Kite/Gilead: Other: fees for non-CME/CE services . Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Amgen: Honoraria. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Santoro: Arqule: Consultancy, Speakers Bureau; Sanofi: Consultancy; Takeda: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli-Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kato: Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp &amp; Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: