Background: Mosunetuzumab (Mosun) is an anti-CD3xCD20 bispecific antibody with FDA accelerated approval as intravenous (IV) treatment for patients with relapsed/refractory (r/r) follicular lymphoma (FL) after 2+ lines of therapy. Recent studies of Mosun demonstrated safety and efficacy of fixed-duration subcutaneous (SC) dosing. Polatuzumab vedotin (Pola) is an anti-CD79b antibody-drug conjugate approved as IV treatment in combination with rituximab and chemotherapy in frontline and r/r diffuse large B cell lymphoma. A phase 1/2 study of Mosun plus Pola in r/r B cell lymphoma showed promising efficacy and a reasonable safety profile (Budde Nat Med 2024). Given non-overlapping toxicities and motivation to spare patients from traditional chemotherapy, we designed a study of Mosun plus Pola as frontline systemic therapy for patients with high tumor burden FL.

Methods: This is a single center, open label, investigator initiated phase 2 trial planning to enroll 34 patients. Key inclusion criteria include diagnosis of FL (gr 1-3A), no prior systemic therapy, high tumor burden by GELF criteria, and stage II-IV disease. Mosun is administered by SC injection on 21 day cycles without mandatory hospitalization. In Cycle (C) 1, Mosun is given on Day (D) 1 (5 mg), D8 (45 mg) and D15 (45 mg). In C2+, Mosun is given on D1 only (45 mg). Pola is administered by IV infusion C1-C6 on D1 at 1.8 mg/kg. Premedications are acetaminophen and diphenhydramine on all treatment days, with palonosetron added before Pola doses. Dexamethasone 20 mg is mandated before all C1 Mosun doses and optional thereafter. GCSF was optional. All patients receive concurrent Mosun plus Pola, with interim assessment by FDG PET-CT pre-C3 (PET2). Patients experiencing PD or inadequate response by PET2 discontinue study therapy; all others complete Mosun through C8 and Pola through C6 before another FDG PET-CT (PET8). Patients achieving complete response (CR) by PET8 discontinue study treatment and enter follow-up; patients with partial response or stable disease by PET8 can continue Mosun through C17 at physician discretion. The primary endpoint is CR rate by Lugano 2014 criteria.

Results: At data cutoff (July 7, 2024), 23 patients had been enrolled (age >60: 65%; stage III: 26%; stage IV: 70%; bulky >7 cm: 26%; B symptoms: 22%; FLIPI 0-1: 13%; FLIPI 2-3: 83%; FLIPI 4-5: 4%). Median follow-up was 7.1 months (range: 1.4-18.0). All patients underwent at least one post-baseline tumor assessment, with 91.3% (21/23; 95% CI: 72.0%-98.9%) achieving an objective response, including 82.6% (19/23; 95% CI: 61.2%-95.1%) who achieved CR as best response. All objective responses were observed at PET2. At data cutoff, four patients are still receiving study treatment; 18 of 19 patients achieving CR as best response remain in CR. Common adverse events (AEs), irrespective of attribution, included injection site reaction (61%; gr 1: 57%, gr 2: 4%; no gr 3+), cytokine release syndrome (CRS; 52%; gr 1: 48%; gr 2: 4%; no gr 3+), nausea (48%; all gr 1), fatigue (44%), diarrhea (39%), constipation (39%), upper respiratory infection (35%; all gr 1-2), and peripheral neuropathy (30%; gr 1: 26%; gr 2: 4%; no gr 3+). Gr 3+ neutropenia occurred in 22% of patients. Serious AEs were CRS (n=3), gr 2 pneumonitis (n=1), gr 2 infusion extravasation (n=1), gr 3 diarrhea (n=1), gr 4 neutropenia (n=1), and febrile neutropenia (n=1). Mosun AEs of special interest included gr 2 ALT increase (n=2), gr 2 CRS (n=1), febrile neutropenia (n=1), gr 2 headache (n=1), and gr 2 pneumonitis (n=1). Pola AEs of special interest included gr 2 peripheral neuropathy (n=1). Treatment discontinuation due to AEs occurred in one patient (gr 2 pneumonitis). No patient experienced AEs consistent with ICANS. No deaths, irrespective of attribution, have been observed. Correlative studies include pre-treatment tissue- and plasma-based genomic profiling, with MRD assessment via PhasED-seq (Foresight Dx). Using pre-treatment plasma for phased variant profiling in the first 11 enrolled patients, 7 of 8 patients with PET2 CR achieved undetectable MRD at 1e-6 prior to C3D1.

Conclusions: Analysis of Mosun plus Pola for frontline systemic treatment in high tumor burden FL demonstrates a high CR rate and toxicity profile aligning with prior studies. With 19 of the first 23 patients having achieved CR as best response, this phase 2 trial has met its prespecified primary endpoint, and this regimen appears encouraging for further study.

Disclosures

Russler-Germain:AstraZeneca: Consultancy; Genentech: Research Funding; Regeneron: Consultancy. Kahl:Genentech: Consultancy; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kite: Consultancy; ADCT: Consultancy; Lilly: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Merck: Consultancy; BeiGene: Consultancy, Research Funding. Mehta-Shah:Morphosys: Research Funding; Genetech/Roche: Consultancy, Research Funding; Innate Pharmaceuticals: Research Funding; Johnson & Johnson/Janssen: Consultancy; Pfizer: Consultancy; Dizal Pharmaceuticals: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; C4 Therapeutics: Consultancy, Research Funding; Bristol Myers-Squibb: Research Funding; Astra Zeneca: Consultancy, Research Funding; Secura Bio: Consultancy, Research Funding; Yingli Pharmaceuticals: Research Funding; Verastem Oncology: Research Funding; Corvus Pharmaceuticals: Research Funding; Kyowa Hakko Kirin, Karyopharm Therapeutics: Consultancy. Fehniger:Affimed: Other: Scientific Advisory Board; Wugen: Consultancy, Current holder of stock options in a privately-held company, Research Funding; Orca Bio: Current holder of stock options in a privately-held company; Indapta: Current holder of stock options in a privately-held company; Smart Immune: Other: Scientific Advisory Board; AI Proteins: Other: Scientific Advisory Board, Research Funding. Bartlett:Washington University School of Medicine: Current Employment; Autolus: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; Celegne: Research Funding; Forty Seven: 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; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Janssen: Research Funding; BMS: Research Funding.

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2024
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