50 | FIXED‐DURATION OUTPATIENT SUBCUTANEOUS MOSUNETUZUMAB + POLATUZUMAB VEDOTIN SHOWS ROBUST EFFICACY IN A PHASE II STUDY OF RELAPSED/REFRACTORY POST‐BTKi MANTLE CELL LYMPHOMA

Introduction: Patients (pts) with mantle cell lymphoma (MCL) who progress after Bruton tyrosine kinase inhibitor (BTKi) therapy have suboptimal outcomes, driving the development of new treatments (Eyre et al. Blood 2022). Mosunetuzumab (M), an off-the-shelf, outpatient treatment, plus polatuzumab vedotin (Pola) showed promising efficacy and manageable safety in an initial analysis in relapsed/refractory (R/R) MCL (NCT03671018; Wang et al. ASH 2023). We present primary data from the Phase II MCL cohort. Methods: Pts with R/R MCL and ≥ 2 prior therapies received subcutaneous M with step-up dosing on Days (D)1 (5 mg), 8 (45 mg) and 15 (45 mg) of Cycle (C)1, then 45 mg on D1 of each subsequent cycle every 3 weeks for 17 cycles. Intravenous Pola (1.8 mg/kg) was given on D1 of C1–6. Corticosteroid premedication was required for C1 (optional for C2+). Hospitalization to monitor for cytokine release syndrome (CRS) was not mandatory. Response was assessed by an independent review committee (IRC) using Lugano criteria. Results: As of November 8, 2024, 42 pts received M-Pola. Median age was 68 (range 44–82) years, 91% had Ann Arbor stage III/IV, and 48% had a simplified MIPI score of ≥ 6. Pts had high-risk factors including: Ki-67 proliferation index ≥ 50%, 67%; blastoid/pleomorphic variants, 38%; and TP53 mutation, 31%. Median prior lines of therapy was 3 (range 2–9). All pts received prior BTKi; 26% received prior chimeric antigen receptor (CAR) T-cell therapy and 93% were refractory to last therapy. Median time on study was 16 (range 0–41) months. IRC-assessed best overall response and complete response (CR) rates were 88% (95% CI 74–96) and 79% (95% CI 63–90), respectively. Median time to first response was 3 months. Median duration of response and of CR were both not reached. Median PFS and OS were 19 months (95% CI 14–not evaluable [NE]) and 21 months (95% CI 17–NE), respectively; efficacy was consistent across high-risk subgroups (Figure). Overall, 100%, 81% and 62% of pts reported ≥ 1 adverse event (AE), Grade (Gr) ≥ 3 AE and serious AE, respectively. The most common (≥ 30%) treatment-related AEs were injection site reaction (57%), fatigue (50%), CRS (43%) and neutrophil count decreased (33%). CRS occurred in 18 pts (43%; Gr 1, n = 12; Gr 2, n = 6; no Gr ≥ 3; all resolved). There were five Gr 5 AEs (pneumonia [n = 1], encephalopathy due to West Nile Virus [n = 1], and COVID-19 pneumonia [n = 3]). Gr 2 immune effector cell-associated neurotoxicity syndrome occurred in one patient (2%; resolved). Five pts (12%) had treatment-related AEs leading to any treatment discontinuation (Gr 2: upper respiratory tract infection [n = 1], peripheral neuropathy [n = 2]; Gr 3: uveitis, pneumonitis/C.diff colitis [n = 1 each]). Conclusions: Fixed-duration, outpatient M-Pola demonstrates robust efficacy and manageable safety in R/R MCL, including in high-risk subgroups and the post-CAR T-cell setting. M-Pola appears to be a suitable regimen for pts with R/R MCL in need of rapid disease control. Research funding declaration: This study was sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial assistance, under the direction of the authors, was provided by Rhiannon Owen, BSc (Hons) and Roisin Weaver, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Keywords: non-Hodgkin; combination therapies; combination therapies Potential sources of conflict of interest: L. E. Budde Consultant or advisory role: Kite Pharma, BMS, AstraZeneca, Roche, Crispr Therapeutics, AbbVie, Janssen, Nurix, Genmab. Other remuneration: Research funding: AstraZeneca. M. Kamdar Consultant or advisory role: Institution: AbbVie, AstraZeneca, Bristol-Myers Squibb, BeiGene, Genentech, Inc. Other remuneration: Research funding (institution): Novartis. Data Monitoring Committee member (institution): Celgene, Genentech, Inc. S. Assouline Consultant or advisory role: Novartis, BeiGene, Roche, AbbVie. Stock ownership: Immediate family member: Kura. Honoraria: Novartis, BeiGene, Roche, AbbVie. Other remuneration: Speaker's bureau: Novartis. Research funding (institution): Novartis. N. Ghosh Consultant or advisory role: Genentech/Roche, BMS, AbbVie, AstraZeneca, Beigene, Ascentage Pharma, Galapagos, Kite Pharma, Loxo Oncology, Ipsen, Janssen, Lava Therapeutics. Honoraria: Genentech/Roche, BMS, AbbVie, AstraZeneca, Beigene, Ascentage Pharma, Galapagos, Kite Pharma, Loxo Oncology, Ipsen, Janssen, Lava Therapeutics. Other remuneration: Research funding (institution): Genentech/Roche, AstraZeneca, AbbVie, Pepromene. S. Naik Consultant or advisory role: Janssen Biotech. Honoraria: OncLive. S. K. Nakhoda Consultant or advisory role: BTG/SERB, AstraZeneca, BeiGene. Honoraria: BTG/SERB, AstraZeneca, BeiGene. Other remuneration: Research funding (institution): AstraZeneca, Roche, BeiGene, ADC. J. Chavez Consultant or advisory role: Kite/Gilead, Genentech, Novartis, Allogene, Cripsr, Autolus, BMS, AstraZeneca. Honoraria: Lilly, GenMab. Educational grants: Lilly. Other remuneration: Research funding: Merck, Kite, Genmab. T. A. Ollila Consultant or advisory role: ADC Therapeutics. Honoraria: ONO pharma. Educational grants: Genentech, Inc. Other remuneration: Research funding (institution): ONO pharma, site principal investigator. D. Hodson Consultant or advisory role: AstraZeneca. Honoraria: AstraZeneca. Other remuneration: Research funding: AstraZeneca, GSK. D. Modi Consultant or advisory role: ADC therapeutics, Genmab, Genentech, Inc. (spouse), Daiichi Sankyo (spouse), AstraZeneca (spouse). Other remuneration: Research funding (institution): For IIT: Genentech, Inc., Genmab, Karyopharm, AstraZeneca (spouse). Expert testimony: AstraZeneca. M. Bastos-Oreiro Consultant or advisory role: AbbVie, AstraZeneca, Incyte, Janssen, Kite, Novartis, Roche. Honoraria: AbbVie, AstraZeneca, Incyte, Janssen, Kite, Roche. Educational grants: Hospital General Universitario Gregorio Marañón. Other remuneration: Speaker's bureau: AbbVie, AstraZeneca, Incyte, Janssen, Kite, Roche, Takeda. Research funding (institution): AbbVie, Incyte, Kite, Roche. W. Ead Employment or leadership position: Genentech, Inc./F Hoffmann-La Roche Ltd. Stock ownership: Genentech, Inc./F Hoffmann-La Roche Ltd. Other remuneration: Research funding: Genentech, Inc./F Hoffmann-La Roche Ltd. I. To Employment or leadership position: Genentech, Inc. Stock ownership: Genentech, Inc. Other remuneration: Patents, royalties, other intellectual property: Genentech, Inc. S. Pham Employment or leadership position: Roche Canada. J. Wang Employment or leadership position: Genentech, Inc. Stock ownership: Roche. Other remuneration: Patents, royalties, other intellectual property: Roche. H. Wu Employment or leadership position: Genentech, Inc. Stock ownership: Genentech, Inc. S. Makadia Employment or leadership position: Genentech, Inc. Stock ownership: Genentech, Inc. C. L. Batlevi Employment or leadership position: Roche/Genentech. Consultant or advisory role: BMS, Seattle Genetics, Kite, Karyopharm, TG Therapeutics, ADC Therapeutics, AbbVie, Genentech, Inc., Treeline Bioscience. Stock ownership: Roche. Honoraria: Dava Oncology, TouchIME, Medscape. Other remuneration: Research funding: Epizyme, Autolus, Roche, Vincerx. M. C. Wei Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd. Other remuneration: Patents, royalties, other intellectual property: Genentech, Inc. M. L. Wang Consultant or advisory role: Acerta Pharma, AstraZeneca, Bristol Myers Squibb, Boxer Capital, Galapagos NV, Genmab, InnoCare, Janssen, Kite Pharma, Lilly, Merck, PER, Pfizer, Oncternal. Honoraria: AstraZeneca, BeiGene, Binaytara Foundation, Bristol Myers Squibb, CAHON, Editorial Medica AWWE SA, East Virtinia Medical School, Instituto Scientifico Romagnolo, Janssen, Kite Pharma, Mayo Clinic, MJH Life Sciences, Merck, MSC National Research Institute of Oncolgy, Pfizer, Physicians Education Resources (PER), Plexus Communications, PromCon S.R.E., Research to Practice, Studio ER Congressi, South African Clinical Hematology Society, Medscape/WebMD, VJHemonc. Other remuneration: Research funding: AbbVie, Acerta Pharma, AstraZeneca, Bantam Pharma, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Nurix Therapeutics, Oncternal, Pharmacyclics, Velosbio, Vincerx.

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