Background: TheCD20xCD3 bispecific antibody glofitamab (Glofit) engages and redirects T cells to eliminate B cells. Polatuzumab vedotin (Pola), an antibody-drug conjugate targeting CD79b, has a complementary mechanism of action to Glofit. In this open-label, multicenter, Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and manageable safety in patients (pts) with R/R LBCL (Hutchings, et al. ASH 2023). We present updated results with longer follow-up in a greater number of pts with R/R LBCL, including pts with HGBCL and prior chimeric antigen receptor (CAR) T-cell therapy, at the previously confirmed recommended Phase II dose of Glofit (30mg, from Part I of the study) when combined with Pola.

Methods: Pts received 1000mg obinutuzumab pre-treatment (Gpt) on Cycle (C)1 Day (D)1, 7 days prior to the first Glofit dose to mitigate risk of cytokine release syndrome (CRS). Pola 1.8mg/kg was given on C1D2 and D1 of C2-6 (21-day cycles), and Glofit as step-up dosing in C1 (D8, 2.5mg; D15, 10mg) followed by the target dose (30mg) on D1 of C2-12 (21-day cycles). Fixed treatment of 6 cycles of Pola and 12 cycles of Glofit were administered, unless pts discontinued treatment due to disease progression, unacceptable toxicities, or withdrawal of consent.

Results: At the clinical cutoff date (CCOD; Feb 16, 2024), 129 pts had received ≥1 dose of study treatment (DLBCL, n=57; HGBCL, n=44; transformed follicular lymphoma [trFL], n=26; primary mediastinal LBCL [PMBCL], n=2). Median age was 67 years (range: 23-84), 64% were male (n=82), median prior lines of therapy was 2 (range: 1-7), 71% were refractory to the last line of prior therapy (n=92), and 22% received prior CAR T-cell therapy (n=28; 17% were refractory [n=22]); 43% of pts completed treatment (n=56), 7% had treatment ongoing, and 50% discontinued treatment (n=64; primarily due to progressive disease [33%; n=42/129]). Of 128 efficacy-evaluable pts, best overall response rate (ORR; per Lugano 2014) was 80%, with a complete response (CR) rate of 62%. By histology, best ORR and CR rate, respectively, were: DLBCL 84% (48/57) and 61% (35/57); HGBCL 79% (34/43) and 65% (28/43); trFL 73% (19/26) and 54% (14/26); PMBCL 100% for ORR and CR (2/2). In pts who had prior CAR T-cell therapy (n=28), ORR was 75% and CR rate was 50%. With a median follow-up of 23.5 months (range: 0-46), median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI]: 8.8-23.5). Median PFS by histology was 10.4 months (95% CI: 7.0-22.8) for DLBCL, 9.6 months (95% CI: 5.1-33.0) for trFL, and 15.5 months (95% CI: 9.3-not reached [NR]) for HGBCL. Median PFS follow-up was 26.3, 30.3, and 9.3 months for DLBCL, trFL, and HGBCL, respectively. Median duration of response was 21.9 months (95% CI: 14.3-37.8). Median duration of complete response was 31.8 months (95% CI: 21.1-NR); 64.6% of complete responders were in remission at CCOD. Median overall survival (OS) was 39.2 months (95% CI: 20.6-NR), with a 24-month OS event free rate of 54%. The most common adverse event (AE) was CRS (43%), which was mostly Grade (Gr) 1-2 (Gr 1 27%, Gr 2 15% per ASTCT criteria); one pt had Gr 3 CRS and one had fatal Gr 5 CRS (occurred in the context of unresolved infection; pt declined further CRS management at Gr 3). CRS events were managed with tocilizumab (34%), fluids (23%), low flow oxygen (20%), or corticosteroids (14%) and 3 pts (5.4%) were admitted to intensive care. Neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 4 pts (Gr 1, n=2; Gr 2, n=1; Gr 3, n=1 [syncope]), all in the context of CRS. Gr 3-4 AEs occurred in 59% of pts, mostly neutropenia (32%); febrile neutropenia was reported in 2 pts (1.6%). Serious AEs occurred in 60% of pts and 8% of pts had Gr 5 AEs (5/10 due to COVID-19). In total, 11% of pts discontinued Glofit due to AEs (3/14 due to COVID-19; 1 pt due to COVID-19 pneumonia); 5% of pts withdrew from Glofit treatment due to Glofit-related AEs and 5% withdrew due to Pola-related AEs. Exploratory biomarker analyses including response in molecular subgroups and circulating tumor DNA kinetics will be presented.

Conclusions: Heavily pretreated pts with R/R LBCL treated with Glofit+Pola continued to demonstrate high and durable response rates across all histologies, including pts with HGBCL and those who had received prior CAR T-cell therapy. The safety profile was manageable and consistent with the known profiles of the individual drugs.

Disclosures

Hutchings:AbbVie, AstraZeneca, Genmab, Johnson & Johnson, Merck, F. Hoffmann-La Roche Ltd, Takeda: Consultancy; AbbVie, AstraZeneca, Bristol Myers-Squibb, Celgene, Genentech, Inc., Genmab, Incyte, Johnson & Johnson, Merck, Novartis, F. Hoffmann-La Roche Ltd, Takeda: Research Funding; AbbVie, AstraZeneca, Genmab, Johnson & Johnson, Merck, F. Hoffmann-La Roche Ltd, Takeda: Honoraria. Sureda Balari:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau; Takeda Pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Other: Travel Expenses; Alexion: Honoraria; GETH-TC: Other: President; EBMT: Other: President; GSK: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Consultancy; Bluebird: Membership on an entity's Board of Directors or advisory committees. Bosch:F. Hoffmann-La Roche Ltd, Janssen, AbbVie, Novartis, Celgene, Gilead, Takeda, AstraZeneca, BeiGene, Lilly: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, Novartis, Janssen, AbbVie, Gilead, Mundipharma, Celgene, Takeda, AstraZeneca, Celgene/BMS, BeiGene, Lilly: Other; F. Hoffmann-La Roche Ltd, Novartis, Janssen, AbbVie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, Ascentage, Lilly, BeiGene: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd, Celgene/BMS, Karyopharm, Takeda, AstraZeneca, Novartis, AbbVie, Janssen: Research Funding; Vall d'Hebron University Hospital (Barcelona, Spain): Current Employment; F. Hoffmann-La Roche Ltd, Novartis, Janssen, AbbVie, Gilead, Mundipharma, Takeda, Celgene/BMS, AstraZeneca, Lilly, BeiGene, TG Therapeutics, Ascentage: Consultancy. Larsen:Roche: Consultancy; Kite/Gilead: Consultancy; Genentech: Research Funding. Corradini:Sanofi: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); SOBI: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Takeda: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Novartis: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Pfizer: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Roche: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Kyowa Kirin: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Janssen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Daiichi Sankyo: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Gilead/Kite: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; GlaxoSmithKline: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Incyte: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Celgene: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Amgen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; AbbVie: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Bristol Myers Squibb: Other: Support for travel and accommodations. Avigdor:Eli Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Karyospharm: Research Funding; TG Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Ascentage: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Terol:AWAITING DOI: Current Employment. Rueda Dominguez:BMS/Celgene: Research Funding; Roche, Takeda, BMS, Gilead, MSD, Incyte, Merck C.O.: Speakers Bureau; Roche and MSD: Other: Travel expenses. Pinto:Merck Sharp and Dohme: Honoraria; Incyte: Honoraria; IGM Biosciences: Current holder of stock options in a privately-held company; Autolus Therapeutics: Current holder of stock options in a privately-held company; Hoffmann-La Roche AG: Consultancy, Honoraria; Kite-Gilead: Honoraria; Bristol Myers Squibb: Honoraria; BeiGene: Honoraria; Eli Lilly: Honoraria. Skarbnik:Kite: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Acerta Pharma: Research Funding; Gilead Sciences: Honoraria; Novartis: Honoraria; Epizyme: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; SeaGen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Verastem: Honoraria, Research Funding. Cordoba:Genmab: Consultancy; BMS: Consultancy, Speakers Bureau; Kite: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Kyowa Kirin: Consultancy; Pfizer: Research Funding. Joergensen:Kite/Gilead: Consultancy; Novo Nordisk: Current holder of stock options in a privately-held company; Sobi: Consultancy; Caribou: Consultancy; Incyte: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Zinzani:SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASTRAZENECA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC THERAPEUTICS: Membership on an entity's Board of Directors or advisory committees; INCYTE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BEIGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SECURA BIO: Membership on an entity's Board of Directors or advisory committees. Gurion:F. Hoffmann-La Roche Ltd, Medison, AbbVie, Takeda, Eli Lilly, Novartis: Consultancy; F. Hoffmann-La Roche Ltd, Medison, AbbVie, Takeda, Eli Lilly, Novartis: Honoraria. Goldschmidt:Abbvie, Janssen, AstraZeneca: Consultancy. Leung:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Li:Roche (China) Holding Ltd: Current Employment. Relf:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Roche Products Ltd: Current Employment; F-star Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Tandon:Roche Products Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Sellam:F. Hoffmann-La Roche Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Gritti:Janssen, Beigene, Kite-Gilead, Roche, Sandoz: Other: Support for attending meetings; Ideogen, Takeda: Speakers Bureau; Takeda, Abbvie, Roche, Kite-Gilead, Ideogen, Genmab: Membership on an entity's Board of Directors or advisory committees.

Off Label Disclosure:

All study therapy constituted investigational or off-label use. Glofitamab (Columvi) is a bispecific CD20-directed CD3 T-cell engager approved for treating adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), or large B-cell lymphoma from follicular lymphoma (FL), after two or more lines of systemic therapy. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated for use in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients with previously untreated DLBCL, NOS, or high-grade B-cell lymphoma (HGBL) with an International Prognostic Index (IPI) score of 2 or higher. It is also indicated for use with bendamustine and a rituximab product in adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies.

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2024
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