Efficacy and Safety Outcomes of CAR T-Cell Therapies in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Who Received Prior Treatment with Mosunetuzumab

Background: Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody that is being evaluated in patients with select B-cell non-Hodgkin lymphoma (B-NHL) histologies in a Phase I/II clinical trial (NCT02500407). Mosunetuzumab is approved by the FDA and EMA for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of systemic therapy. A key emerging question is the optimal treatment sequence of mosunetuzumab and CD19-targeted chimeric antigen receptor (CAR) T-cell therapies, and whether CAR T-cell therapies remain clinically active post mosunetuzumab treatment. Previous data are limited but have shown that the efficacy of CAR T-cell therapies is preserved in patients with B-NHL who progressed following treatment with bispecific antibodies (Crochet et al. Blood 2022; Iacoboni et al. Blood 2023). Here, we present a US multicenter, retrospective, case series to explore the outcomes of patients with R/R B-NHL treated with CAR T-cell therapy after prior mosunetuzumab treatment.

Methods: Patients from a Phase I/II clinical trial (NCT02500407) were included in this analysis, including patients across dose-escalation cohorts. Efficacy and safety outcomes were investigated in patients with R/R B-NHL who received CAR T-cell therapy for the first time following mosunetuzumab treatment. Eligible patients were treated with CAR T-cell therapy between March 21, 2019 and June 7, 2021.

Results: At data cut-off (May 2, 2023), 26 patients with R/R B-NHL from seven institutions had received CAR T-cell therapy after mosunetuzumab treatment. Data for 11 patients from a single institution are presented here. Median age was 70 years (range: 53-81) and most patients were male (72.7%). Six patients had indolent B-NHL (all FL) and 5 patients had aggressive B-NHL (mantle cell lymphoma, n=3; diffuse large B-cell lymphoma, n=2). The median number of therapies prior to mosunetuzumab was 4 (range: 2-6). Best overall response (BOR; complete response [CR] or partial response [PR]) to mosunetuzumab by investigator assessment was 66.7% (4/6 patients; CR, n=1; PR, n=3) in patients with indolent B-NHL and 60.0% (3/5 patients; CR, n=1; PR, n=2) in those with aggressive B-NHL. The median duration of mosunetuzumab treatment was 4.4 months (range: 1.9-13.5).

Median time from mosunetuzumab initiation to CAR T-cell therapy initiation was 16.6 months (range: 2.3-30.5). Median number of therapies prior to CAR T-cell therapy was 5 (range: 2-8); mosunetuzumab was the last line of treatment before CAR T-cell therapy in 6 (54.5%) patients. Two (18.2%) patients received bendamustine within 12 months prior to administration of CAR T-cell therapy. Three (27.3%) patients received bridging therapy with radiation. All patients received CAR T-cell therapy in the inpatient setting, with 8 (72.7%) receiving it in a clinical trial. The CAR T-cell therapies received were an investigational CD19-targeted CAR T-cell therapy (n=4), axicabtagene ciloleucel (n=3), brexucabtagene autoleucel (n=2), and tisagenlecleucel (n=2).

As of July 12, 2024, in patients with indolent B-NHL, the BOR rate with CAR T-cell therapy was 100% (6/6), with 3 (50.0%) patients achieving a CR; duration of response (DOR) ranged from 3.4 to 59.3 months, with 4 responses ongoing. In patients with aggressive B-NHL, the BOR rate with CAR T-cell therapy was 80% (4/5), with all 4 patients achieving a CR; DOR ranged from 1.4 to 52.3 months.

During follow-up, in the overall cohort, 3 patients died due to disease progression, pneumonia, or sepsis (n=1 each). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 54.5% (6/11) and 45.5% (5/11) of patients, respectively. All CRS and ICANS events were Grade (Gr) 1/2 (CRS: Gr 1, n=2; Gr 2, n=4; ICANS: Gr 1, n=1; Gr 2, n=4) and resolved by data cut-off.

Conclusions: This real-world analysis in patients with R/R B-NHL demonstrates that the clinical activity of CAR T-cell therapy is preserved following treatment with mosunetuzumab, and that the safety profile was consistent with that previously reported. These results suggest that CAR T-cell therapy is a good treatment option post mosunetuzumab for patients with R/R B-NHL; however, larger studies are needed to fully characterize the efficacy and safety of CAR T-cell therapy after mosunetuzumab. Additional patient data, including from other institutions, will be presented.

Braun:City of Hope National Medical Center: Current Employment. Schuster:AbbVie, AstraZeneca, BeiGene, BioNTech, Caribou Biosciences, Celgene/Juno Therapeutics, Genentech/Roche, Genmab, Janssen, Kite Pharmaceuticals, Legend Biotech, Novartis, viTToria biotherapeutics: Consultancy; Celgene/Juno Therapeutics, Genentech/Roche, Merck, Novartis: Research Funding; AstraZeneca, BeiGene, Celgene/Juno Therapeutics, Genentech/Roche, Janssen, Legend Biotech, Nordic Nanovector, Novartis: Honoraria; Caribou Biosciences, Nordic Nanovector, Novartis: Membership on an entity's Board of Directors or advisory committees. Nastoupil:Caribou Biosciences: Honoraria, Research Funding; Denovo Biopharma: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Genmab: Honoraria, Research Funding; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Incyte Corporation: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Abbvie, BMS, Caribou Biosciences, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Regeneron, Takeda: Consultancy; BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Takeda: Research Funding; Abbvie, BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Novartis, Takeda: Honoraria. Bartlett:Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Autolus: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Washington University School of Medicine: Current Employment. Shadman:AbbVie/Pharmacyclics, Genentech, AstraZeneca, Genmab, Janssen, Beigene, Bristol Myers Squibb, Morphosys/Incyte, Kite Pharma, Eli Lilly, Fate Therapeutics, Nurix, Merck, ADC Therapeutics, MEI Pharma, MustangBio, Regeneron: Consultancy; Lilly: Consultancy; Mustang Bio, Genentech, AbbVie/Pharmacyclics, Beigene, AstraZeneca, Genmab, Morphosys/Incyte, Vincerx, BMS, TG Therapeutics: Research Funding; Fate Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Koi Biotherapeutics: Current holder of stock options in a privately-held company; Sunesis: Research Funding; Adaptimmune: Consultancy; Atara Biotherapeutic: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BMS: Other: Current employment of spouse; Epizyme: Consultancy; AstraZeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Innate Pharma: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; MorphoSys/Incyte: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Regeneron: Consultancy; Sound Biologics: Consultancy; TG Therapeutics: Consultancy, Research Funding; Celgene: Research Funding; Genmab: Research Funding; Gilead Sciences: Research Funding. Kumar:Loxo Oncology/Lily Pharmaceuticals: Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals, Janssen: Honoraria; Astra Zeneca: Honoraria, Research Funding; BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding; Adaptive Biotechnologies, Celgene, Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Tzachanis:BMS, Veraxa: Consultancy; BMS: Research Funding. Chihara:SymBio pharmaceutical: Honoraria; BeiGene: Honoraria; MorPhosys: Research Funding; BMS: Research Funding; Genmab: Research Funding; Ono pharmaceutical: Research Funding. Wu:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Wei:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Patents & Royalties. Yin:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Patents & Royalties. Hao:Genentech, Inc.: Consultancy. Zhu:Experis Inc.: Consultancy. Mun:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Budde:AstraZeneca, Mustang Therapeutics, Merck: Research Funding; ADC Therapeutics, AstraZeneca, AbbVie, F. Hoffmann-La Roche Ltd, Genentech, Inc., Genmab, Jenssen, Regeneron: Consultancy; City of Hope National Medical Center: Current Employment; ADC Therapeutics, AstraZeneca, AbbiVe, Roche, Genentech, Genmab, Jenssen, Regeneron: Consultancy; AstraZeneca, Mustang Therapeutics, Merck: Research Funding.

All study therapy constituted investigational or off-label use. Mosunetuzumab (Lunsumio) is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.