A Comparison of Overall Survival with Brexucabtagene Autoleucel (Brexu-cel) CAR T-Cell Therapy (ZUMA-2) and Standard of Care (SCHOLAR-2) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor (BTKi)

Introduction: Patients with MCL typically require multiple lines of therapy and have poor prognosis, especially after failure with BTKi therapy. SCHOLAR-2 was a retrospective, observational study reporting overall survival (OS) among patients with R/R MCL who had disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. Data from SCHOLAR-2 reflects recent clinical practice (excluding chimeric antigen receptor [CAR] T-cell therapies) and thus provide a benchmark for indirect treatment comparisons of newer agents to standard of care (SOC). In a phase 2 multicenter, single-arm trial (ZUMA-2; NCT02601313), brexu-cel (formerly known as KTE-X19), an autologous anti-CD19 CAR T-cell therapy, demonstrated long-term OS benefit in patients with R/R MCL who had 1-5 prior therapies, including a BTKi (Wang et al. JCO 2022). Here, we present results of an updated indirect treatment comparison of brexu-cel versus SOC using individual patient data from both ZUMA-2 and SCHOLAR-2 before and after adjusting for differences in the underlying patient populations.

Methods: Updated clinical efficacy results for brexu-cel based on 3-year follow-up in ZUMA-2 were used for this analysis. Real-world evidence on the effectiveness of SOC was based on a subset of the SCHOLAR-2 population of 288 patients with R/R MCL who received covalent BTKi therapy between July 2012-July 2018 across 24 centers in 7 European countries (Denmark, France, Germany, Italy, Spain, Sweden, and the United Kingdom). Key eligibility criteria from the ZUMA-2 trial were first applied to the SCHOLAR-2 population to construct an SOC cohort that resembled patients included in ZUMA-2. Comparisons of OS were then conducted using three different statistical methods which adjusted for imbalances in prognostic factors between the two non-randomized study populations: 1) inverse probability weighting (IPW) with ZUMA-2 as the target population, 2) multivariable regression (MVR), and 3) doubly robust (DR). The pre-specified prognostic factors considered for adjustment included duration of prior BTKi therapy, response to prior BTKi therapy, number of prior lines of therapy, and prior autologous stem cell transplant. All variables included in the final models are listed in Table 1. The primary outcome was OS, which was summarized for each study using the Kaplan-Meier method. As there was no strong evidence of non-proportional hazards based on Schoenfeld residuals and visual inspection of plots of the log cumulative hazards, relative treatment effects were estimated from Cox models and summarized as hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: Data from 68 treated patients in ZUMA-2 and 59 patients in the SCHOLAR-2 SOC cohort (ECOG performance score 0-1 and ≥1 year of potential follow-up time from start of first post-BTKi therapy) were analyzed. Median follow-up times for ZUMA-2 and SCHOLAR-2 were 35.6 and 27.6 months, respectively. At baseline, patients in ZUMA-2 and SCHOLAR-2 were similar in terms of median age (65 vs 63 years) and objective response rate to prior BTKi therapy (38% vs 40%). Differences were observed between ZUMA-2 vs SCHOLAR-2 patients in median duration of prior BTKi therapy (6.5 vs 7.3 months), lines of prior therapy (2 prior: 18% vs 36%; 3 prior: 44% vs 32%; ≥4 prior: 37% vs 27%), percentage of males (84% vs 73%), and the percentage of patients with ECOG 1 (35% vs 54%), stage III-IV disease (97% vs 82%), and prior autologous stem cell transplant (43% vs 36%). Baseline characteristics before and after applying weights in the base-case analysis (IPW approach) are shown in Table 1.

Median OS was 46.6 months (95% CI: 24.9-not reached) with brexu-cel and 15.7 months (95% CI: 10.0-30.9) with SOC. The IPW-adjusted median OS with SOC was 14.2 months (95% CI: 6.8-30.9). All unadjusted and adjusted comparisons showed a statistically significant improvement in OS for brexu-cel versus SOC (Figure 1). Findings were robust across adjustment methods with HRs of 0.38 (95% CI: 0.23-0.63; p < 0.001) for IPW, 0.46 (95% CI: 0.28-0.75; p = 0.002) for MVR, and 0.36 (95% CI: 0.22-0.58; p <0.001) for DR.

Conclusion/Summary: Despite the limitations of an unanchored indirect comparison based on non-randomized data, these updated results continue to suggest improved OS with brexu-cel versus SOC in patient with R/R MCL post-BTKi and may help inform treatment decisions in this high unmet need population.

Hess:BeiGene: Honoraria; Takeda: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; MorphoSys: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genmab: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; ADC Therapeutics: Consultancy; Abbvie: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Research Funding; Celgene: Research Funding. Dreyling:Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche: Research Funding; Amgen, Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche: Honoraria; Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche: Consultancy. Oberic:Roche: Consultancy, Honoraria, Other; Takeda: Consultancy; Janssen-Cilag: Honoraria, Other. Gine:Janssen: Honoraria, Research Funding; Genmab: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria. Zinzani:Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: 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; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; University of Bologna: Current Employment. Linton:BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; Roche: Consultancy; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Consultancy. Jerkeman:Genmab: Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Orion: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Stilgenbauer:AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding. Thieblemont:Takeda: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Novartis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Support; AbbVie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support. Lambert:Takeda: Other: Travel, Accommodations, Expenses; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Meyer -Squibb: Other: Other (Travel and conference fees). Zilioli:Roche: Consultancy; MSD: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Speakers Bureau; Janssen: Other: travel expenses, Speakers Bureau. Sancho:Bristol Myers Squibb: Honoraria; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lilly & Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biomedicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Kern Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jimenez-Ubieto:Novartis: Consultancy. Eyre:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Speakers Bureau; PeerView: Speakers Bureau; Loxo Oncology @ Lilly: Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wu:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company, Other: Travel/meeting support; Amgen: Current equity holder in publicly-traded company, Other: Travel/meeting support; Abbott: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Curis: Current equity holder in publicly-traded company; Avid Biosciences: Current equity holder in publicly-traded company; Evofem: Current equity holder in publicly-traded company; Lensar: Current equity holder in publicly-traded company; VBI Vaccines: Current equity holder in publicly-traded company; Viracta Therapeutics: Current equity holder in publicly-traded company. Siddiqi:Amgen: Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Castaigne:Kite, a Gilead Company: Current Employment. Salles:Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys AG, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol-Myers Squibb, BeiGene, Incyte, Miltenyi Biotec, Ipsen, Kite, a Gilead Company, Loxo, Rapt: Consultancy; AbbVie, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Kite, a Gilead Company, Miltenyi, MorphoSys, Takeda, and VelosBio: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSys AG, Amgen, Bayer, Epizyme, Regeneron, Kite, a Gilead Company: Honoraria.