Background: Treatment options for elderly unfit/frail (U/F) patients (pts) with diffuse large B-cell lymphoma (DLBCL) are often limited due to comorbidities or functional decline. Less toxic, efficacious alternatives to full-dose chemoimmunotherapy (CIT) are needed. Mosunetuzumab (Mosun) is a first-in-class CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells. Mosun monotherapy has demonstrated efficacy, durable complete responses (CR), and manageable safety in U/F pts with untreated DLBCL (NCT03677154; Olszewski et al. ASH 2022). Subgroup analysis from an ongoing Phase Ib/II study (NCT03671018) of Mosun plus polatuzumab vedotin (Pola; M-Pola) in pts with relapsed/refractory DLBCL demonstrated efficacy and a manageable safety profile in pts ≥65 years (yrs) (Olszewski et al. ASH 2022). We report preliminary efficacy and safety data from the M-Pola cohort of study NCT03677154 in elderly U/F pts with newly diagnosed DLBCL.

Methods: Eligible pts were ≥80 yrs, or 65-79 yrs and ineligible for full-dose CIT/unfit per simplified Geriatric Assessment (sGA; Merli et al. J Clin Oncol 2021) ( Table). Pre-phase prednisone was allowed. Pts were enrolled in two safety cohorts with escalating doses of Mosun subcutaneous (SC; Cohort 1 and 2), followed by an expansion (Exp) phase. Pts received Cycle (C) 1 step-up dosing with Mosun SC on Day (D) 1/8/15 (Cohort 1: 5/15/45mg; Cohort 2 and Exp: 5/45/45mg) then 45mg on D1 of C2-8 plus 1.8mg/kg intravenous Pola on D1 of C1-6. Pts with CR stopped Mosun after 8 cycles; pts with partial response (PR) or stable disease could continue Mosun for up to 17 cycles in the absence of progressive disease (PD). Primary endpoints included safety and objective response rate (ORR) by independent review committee (IRC; assessed by positron emission tomography-computed tomography [Lugano 2014 criteria]) at end of treatment (EOT). CR rate, progression-free survival, and overall survival were secondary endpoints (IRC- and investigator [INV]-assessed). Best overall response (BOR) and EOT responses are reported in pts who received first treatment with a sufficient time interval to be eligible for the relevant response evaluation. Cytokine release syndrome (CRS) was assessed by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019).

Results: Pts were enrolled from Feb 2021 to Jan 2023. As of the clinical cutoff date (CCOD; Feb 17, 2023), 108 pts received M-Pola (Cohort 1: n=7; Cohort 2: n=13; Exp: n=88). Median age was 81 yrs (range: 66-94); 52% of pts were female; 81% had an ECOG PS of 0-1; and 66% had Ann Arbor stage III-IV disease. Per sGA, 59% were unfit and 40% frail ( Table). Median (range) number of cycles was 7.5 (1-14) for Mosun and 6 (1-6) for Pola.

Most frequent treatment-emergent adverse events (AEs) (≥20%) were neutropenia (32%), CRS (30%), and injection site reaction (20%). Grade (Gr) 3-4 AEs occurred in 43% of pts (most frequent: neutropenia [28%]). Serious AEs occurred in 41% of pts; most frequent (≥5%) were CRS (14%) and infections (21%), including COVID-19 pneumonia (10%) and COVID-19 infection (7%). Most CRS events occurred in C1; 30/32 pts had Gr 1-2 events; two pts had Gr 3 events. All CRS events resolved within a median of 2 days (range: 1-6); management included tocilizumab (7/32) and corticosteroids (3/32). AEs leading to discontinuation of Mosun or Pola occurred in 15% and 12% of pts, respectively. Fatal AEs occurred in 15 pts (14%): eight COVID-19/COVID-19 pneumonia events; two unexplained deaths; and one event each of Staphylococcal bacteremia, sepsis, pneumonia, pulmonary embolism, and suicide. Range of onset date for fatal AEs was D8-251.

At the CCOD, median follow-up was 7.5 months (range: 0-21). In 90 evaluable pts from Cohort 2 and Exp, BOR and best CR rate per INV were 80% (72/90) and 61% (55/90), respectively. EOT response assessments per INV in 56 evaluable pts showed ORR in 55% (31/56); CR in 45% (25/56); PD in 9% (5/56); PR in 11% (6/56); and 36% (20/56) without EOT assessment (withdrawal of consent: 4/20; AEs: 13/20; early discontinuation per INV: 2/20; PD in C1: 1/20) ( Figure).

Conclusions: Chemotherapy-freeM-Pola demonstrated preliminary efficacy in elderly U/F pts with previously untreated DLBCL. Overall, the safety profile of M-Pola was consistent with that of the individual drugs. However, COVID-19 remains a high risk in elderly U/F pts treated for DLBCL. Biomarker analyses and long-term follow-up data will be presented.

Olszewski:Genmab, Blue Cross/Blue Shield of Rhode Island, Schrodinger, ADC Therapeutics, BeiGene: Consultancy; Leukemia & Lymphoma Society, Genetech, Inc. / F. Hoffmann-La Roche Ltd, Adaptive Biotechnologies, Precision Biosciences, Genmab: Research Funding. Eradat:AbbVie, Genentech, Inc., Kite, Gilead Sciences, Takeda, Acerta, AstraZeneca, BeiGene, Juno: Consultancy, Honoraria, Research Funding. Avigdor:Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodations/Expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: 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; MSD: Research Funding. Horowitz:F. Hoffmann-La Roche Ltd: Honoraria; F. Hoffmann-La Roche Ltd: Research Funding. McKinney:ADC therapeutics, BeiGene, Kite/Gilead: Speakers Bureau; BeiGene, Janssen, F. Hoffmann-La Roche Ltd / Genentech, Inc., Celgene/BMS, Incyte: Research Funding; Bayer, ADC therapeutics, Epizyme, Genentech, Inc. / F. Hoffmann-La Roche Ltd, Incyte: Consultancy. Bergua Burgues:Fundesalud. Grants of Europena funds.Daychii: Research Funding; Daychii: Consultancy; Hospital San Pedro de Alcántara. Servicio de Hematologia. Cáceres. SPAIN: Current Employment. Rodriguez Izquierdo:Takeda: Research Funding. Bastos-Oreiro:Incyte, Kite: Consultancy; F. Hoffmann-La Roche Ltd, Kite, SEHH, AMHH: Research Funding; BMS, Kite, Novartis, F. Hoffmann-La Roche Ltd, Incyte, Abbvie: Honoraria, Speakers Bureau; SEHH, AMHH: Membership on an entity's Board of Directors or advisory committees; Gregorio Maranon Hospital: Current Employment, Membership on an entity's Board of Directors or advisory committees. Ganzel:Investigator initiated study, supported by JAZZ company.: Research Funding. Kim:Boryung: Consultancy, Other: Uncompensated relationship; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMBDx, Inc.: Honoraria, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Uncompensated relationship; Regeneron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Uncompensated relationship; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy; MedImmune: Consultancy, Honoraria, Other: Uncompensated relationship; BeiGene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Uncompensated relationship, Research Funding; Yuhan: Consultancy; Samsung Bioepis: Consultancy. Jeon:Catholic University of Korea, Yeouido ST. Mary hospital: Current Employment; Janssen, F. Hoffmann-La Roche Ltd, Antengene, Celltrion, Vigencell: Consultancy; Korean research fundings: Research Funding; Catholic University of Korea (10-2018-0112511, 10-1718380): Patents & Royalties; Korean Society of Experimental Hematology: Membership on an entity's Board of Directors or advisory committees. Taszner:Takeda: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy. Narkhede:Genentech, Inc. / F. Hoffmann-La Roche Ltd: Speakers Bureau; Genentech, Inc. / F. Hoffmann-La Roche Ltd, ADC Therapeutics, KITE, Abbvie: Honoraria; Genentech, Inc. / F. Hoffmann-La Roche Ltd, Gilead, T.G Therapeutics, Kite, Beigene, EUSA, ADC Therapeutics, Adaptive: Research Funding. Kim:Donga: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Boryong: Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Kyowa-Kirin: Research Funding. Lavie:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation expenses, lecture; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture; Roche: Honoraria, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board and Travel/Accommodation expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture; Medisson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dunshee:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Kapp:F. Hoffmann-La Roche Ltd: Divested equity in a private or publicly-traded company in the past 24 months; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Zhou:F. Hoffmann-La Roche Ltd: 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. Ead:F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current Employment. Sellam:F. Hoffmann La Roche Ltd: Current Employment; F. Hoffmann La Roche Ltd (stock, non voting rights): Current equity holder in publicly-traded company. Jurczak:BeiGene: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; Takeda: Research Funding.

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.

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2023
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