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734 Fixed Duration Mosunetuzumab Plus Polatuzumab Vedotin Has Promising Efficacy and a Manageable Safety Profile in Patients with BTKi Relapsed/Refractory Mantle Cell Lymphoma: Initial Results from a Phase Ib/II Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Prospective Clinical Trials in Mantle Cell Lymphoma Incorporating Novel Agents
Hematology Disease Topics & Pathways:
Bispecific Antibody Therapy, Immunotherapy
Monday, December 11, 2023: 10:45 AM

Michael L. Wang, MD1, Sarit Assouline, MD2, Manali Kamdar, MD3*, Nilanjan Ghosh, MD, PhD4, Seema Naik, MD5*, Shazia K. Nakhoda, MD6*, Julio C. Chavez, MD7*, Ting Jia, MD8*, Song Pham, MSc9*, Ling-Yuh Huw, PhD10*, Jing Jing, PhD10*, Wahib Ead, PharmD10*, Iris To, PharmD10*, Connie Lee Batlevi, MD10*, Michael C. Wei, MD, PhD10 and Elizabeth Lihua Elizabeth Budde, MD, PhD11

1University of Texas MD Anderson Cancer Center, Houston, TX
2Jewish General Hospital, McGill University, Montreal, QC, Canada
3Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, Denver, CO
4Atrium Health Levine Cancer Institute, Charlotte, NC
5Penn State Cancer Institute, Hershey, PA
6Fox Chase Cancer Center, Philadelphia, PA
7Moffitt Cancer Center, Tampa, FL
8Roche (China) Holding Ltd, Shanghai, China
9Hoffmann-La Roche Ltd, Mississauga, ON, Canada
10Genentech, Inc., South San Francisco, CA
11City of Hope National Medical Center, Duarte, CA

Background: New treatment options are needed for patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially for pts with progressive disease (PD) after Bruton’s tyrosine kinase inhibitor (BTKi) therapy. Outcomes for R/R MCL pts with PD after the BTKi ibrutinib are very poor, demonstrated by a median overall survival of 2.9 months (Martin et al. Blood 2016). While chimeric antigen receptor (CAR) T-cell therapies are approved for pts with R/R MCL; treatment is associated with high toxicity and difficulty with accessibility. Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that inhibits cell division and induces apoptosis in B cells. This ongoing Phase Ib/II study (NCT03671018) is investigating Mosun in combination with Pola (M-Pola) in pts with R/R B cell non-Hodgkin lymphoma. Here, we report initial safety and efficacy data from an ongoing Phase II expansion cohort of pts with R/R MCL who had received prior BTKi therapy.

Methods: Eligible pts had histologically confirmed R/R MCL and had received ≥2 prior regimens (including an anti-CD20 agent, BTKi, and anthracycline- or bendamustine-based therapy). Mosun was administered subcutaneously (SC) by step-up dosing on Days (D) 1 (5mg), 8 (45mg), and 15 (45mg) of Cycle (C) 1, then 45mg on D1 of every cycle from C2D1, every 3 weeks for a total of 17 cycles. Pola (1.8mg/kg intravenous [IV] infusion) was administered on D1 of C1–6. All pts received corticosteroid premedication prior to C1 of treatment. From C2, premedication was optional for pts who did not experience cytokine release syndrome (CRS) in the previous cycle. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014).

Results: As of October 27, 2022, 20 pts had received M-Pola (n=10 active on treatment, n=1 completed treatment, n=9 discontinued Mosun treatment). Median age of all pts was 68.0 (range: 44–82) years, 75% were male, 95% had Ann Arbor stage III/IV disease, and 40% had a MIPI score ≥6 at study entry. Median number of prior lines of therapy (LOT) was 3 (range: 2–9). All pts had received prior BTKi therapy; 7 pts (35%) had received prior CAR T-cell therapy; and 85% (17/20) of pts were refractory to their last LOT. Median time since last LOT was 1.6 (range: 0–39) months. The proportions of pts with high-risk MCL factors at baseline were: 65% of pts with Ki-67 proliferation index ≥50%; 50% with blastoid/pleomorphic variants; and 20% with TP53 mutation. The overall median time on study was 7.2 (range: 0.4–17.5) months.

The most common (≥25%) Mosun and/or Pola-related adverse events (AEs) in all pts (n=20) were CRS (50%), injection site reaction (50%), fatigue (45%), dyspnea (35%), paresthesia (30%), diarrhea (30%), myalgia (30%), infusion-related reaction (25%), and nausea (25%). Two (10%) Grade (Gr) 5 AEs occurred, both of which were due to COVID-19 pneumonia; neither were deemed treatment-related by the investigator. Ten pts (50%) experienced CRS events; 9 pts experienced Gr 1 events, and 1 pt experienced a Gr 2 event, which was managed with tocilizumab and low-flow oxygen. One pt was managed with corticosteroids and no pts required pressors or ICU admission. All CRS events resolved by the data cut-off. Treatment-related neurologic AEs, potentially consistent with ICANs, occurred in 3 pts (15%; Gr 1 confusional state and Gr 2 amnesia, 1 pt; Gr 1 agitation, 1 pt; and Gr 2 memory impairment, 1 pt). Neuropathy occurred in 3 pts (15%); all events were Gr 1. Four pts (20%) had AEs leading to treatment discontinuation: 1 pt with Gr 3 uveitis (related to M-Pola); 1 pt with Gr 3 pneumonitis (related to M-Pola); and 2 pts with Gr 5 COVID-19 pneumonia (both unrelated to M-Pola).

Overall response rate (ORR) and complete response (CR) rates were 75% and 70%, respectively (Figure). Best ORR and CR rates were generally consistent in high-risk MCL subgroups (Figure). Median duration of CR was not evaluable (NE; 95% confidence interval: 3.8–NE).

Conclusions: Fixed-duration Mosun SC in combination with Pola IV induced high CR rates in pts with R/R MCL who had previously received BTKi therapy, including those in high-risk subgroups and those who had received prior CAR T-cell therapy. CRs were observed early and persisted during the follow up period. M-Pola had a manageable safety profile, and all CRS events were low grade.

Disclosures: Wang: Meeting Minds Experts: Honoraria; MD Education: Honoraria; Medscape: Honoraria; IDEOlogy Health: Honoraria; i3Health: Honoraria; Genmab: Honoraria, Research Funding; Eastern Virginia Medical School: Honoraria; Dava Oncology: Honoraria, Other: Travel; CAHON: Honoraria; Bantam Pharmaceutical: Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Pepromene Bio: Consultancy; Parexel: Consultancy; Oncternal: Consultancy, Research Funding; Milken Institute: Consultancy; Miltenyi Biomedicine: Consultancy; Merck: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; InnoCare: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Deciphera: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Be Biopharma: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, Research Funding; Amphista Therapeutics Limited: Consultancy; ADC Therapeutics America: Consultancy; Acerta Pharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; MJH Life Sciences: Honoraria; Moffit Cancer Center: Honoraria; NIH: Honoraria; Nurix: Honoraria; Oncology Specialty Group: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria, Other: Travel; Practice Point Communications (PPC): Honoraria; Scripps: Honoraria; Studio ER Congressi: Honoraria; WebMD: Honoraria; Celgene: Other: Travel, Research Funding; Genentech: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology: Consultancy, Research Funding; Molecular Templates: Research Funding; Vincerx: Research Funding; Anticancer Association: Honoraria; BGICS: Honoraria; Clinical Care Options: Honoraria; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Imedex: Honoraria; TS Oncology: Honoraria; Mumbai Hematology Group: Honoraria; OMI: Honoraria; Pharmacyclics: Honoraria; Physicians Education Resources: Honoraria; Practice Point Communications: Honoraria; CSTone: Consultancy. Assouline: AbbVie: Honoraria; Novartis Canada: Research Funding; BeiGene: Consultancy; Janssen: Honoraria; Roche-Genentech: Honoraria; Ipsen: Consultancy; AstraZeneca: Honoraria; Gilead: Honoraria; Palladin: Honoraria. Kamdar: AbbVie, AstraZeneca, Celgene/ Bristol-Myers Squibb, Adaptive Biotechnologies, ADC therapeutics, BeiGene, Genentech, Inc., syncopation, caribou biosciences: Consultancy; Novartis: Research Funding; Seagen: Speakers Bureau; Genentech, Inc., Celgene for IDMC: Membership on an entity's Board of Directors or advisory committees. Ghosh: AstraZeneca, Janssen, Pharmacyclics, Kite pharma, BMS, Epizyme: Speakers Bureau; TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, Morphosys, AbbVie, Pharmacyclics: Research Funding; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Kite Pharma, Beigene, Incyte, Lava Therapeutics, Incyte, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Adaptive Biotech, ADC Therapeutics, Morp: Honoraria; Roche NHL solutions panel: Membership on an entity's Board of Directors or advisory committees; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Kite Pharma, Beigene, Incyte, Lava Therapeutics, Incyte, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Adaptive Biotech, ADC Therapeutics: Consultancy. Naik: KPC Therapeutics: Honoraria; Genentech, Inc., Abbvie: Research Funding; Penn State Cancer Institute: Current Employment. Nakhoda: BMS, BTG/SERB, ADC Therapeutics: Honoraria; Fox Chase Cancer Center: Current Employment; BTG/SERB: Research Funding. Chavez: Genmab: Consultancy; Merck: Research Funding; Lilly: Honoraria, Speakers Bureau; ADC Therapetics: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Adicet: Consultancy; TG Therapeutics: Consultancy; Cellectar: Consultancy; Genentech, Inc: Consultancy; AstraZeneca: Consultancy, Research Funding; Epizyme: Honoraria; BeiGene: Honoraria, Speakers Bureau; Adaptive: Research Funding; Janssen: Research Funding; Merck, AstraZeneca, Adaptive, Janssen: Research Funding; Lilly, Epizyme, BeiGene: Honoraria; Genmab, ADC Therapetics, Kite/Gilead, BMS, Novartis, Adicet, TG Therapeutics, Cellectar, Genentech, Inc., AstraZeneca: Consultancy. Jia: F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current Employment. Pham: F. Hoffmann-La Roche Ltd (Cananda): Current Employment. Huw: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Jing: Genentech, Inc.: Current Employment. Ead: F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current Employment. To: Genentech, Inc.: Current Employment. Batlevi: F. Hoffmann-La Roche Ltd / Genentech, Inc.: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd / Genentech, Inc.: Current Employment. Wei: F. Hoffmann-La Roche Ltd: Patents & Royalties; Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Budde: Roche: Consultancy; Merck: Research Funding; Amgen: Research Funding; ADC Therapeutics: Consultancy; MustangBio: Research Funding; Novartis, Gilead, F. Hoffmann-La Roche Ltd, BeiGene, Genentech, Inc.: Consultancy; AstraZeneca: Consultancy, Research Funding.

OffLabel Disclosure: 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. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated: in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients who have previously untreated DLBCL, NOS or HGBL and who have an IPI score of 2 or greater; and in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, NOS after at least two prior therapies.

*signifies non-member of ASH