Background: Glofitamab (Glofit) is a CD20xCD3 bispecific antibody which engages and redirects T cells to eliminate B cells. Glofit monotherapy recently received FDA and EMA approval for treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 prior lines of therapy. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that has a complementary mode of action to Glofit, with little toxicity overlap. In this open-label, multicenter Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and a manageable safety profile in patients with R/R DLBCL (Hutchings et al. ICML 2023). We present updated results with longer follow-up in patients with R/R DLBCL, including high-grade B-cell lymphoma (HGBCL), and in patients with prior chimeric antigen receptor (CAR) T-cell therapy.

Methods: Patients receivedobinutuzumab 1000mg on Cycle (C) 1 Day (D) 1 to mitigate the risk of severe cytokine release syndrome (CRS). Pola 1.8mg/kg was given on C1D2 and D1 of C2-6 (21-day cycles). Glofit was given with step-up dosing in C1 (C1D8 2.5mg; C1D15 10mg; D1 of C2-12 10/30mg) for up to 12 cycles. The primary objective was to establish the recommended Phase II dose of Glofit when combined with Pola; this was previously identified as 30mg based on the dose-escalation phase and the NCT03075696 study (Hutchings et al. ASH 2021; Hutchings et al. J Clin Oncol 2021).

Results: At the data cut-off (Jan 25, 2023), 111 patients had received ≥1 dose of study drug (safety population). The median age was 68 (range 23-82) years; 61.3% of patients were male; 50.5% had DLBCL not otherwise specified (NOS), 24.3% had HGBCL, 23.4% had transformed follicular lymphoma (trFL), and 1.8% had primary mediastinal large B-cell lymphoma (PMBCL). Most patients were refractory to their last prior therapy (71.2%). Median number of prior lines of therapy was 2 (range 1-7; 61.3% of patients had received ≥2), 24.3% had received prior CAR T-cell therapy.

The overall response rate (ORR) in 109 efficacy-evaluable patients was 78.0%, with a complete metabolic response (CMR) rate of 56.0%. In patients with DLBCL NOS (n=56), ORR and CMR rate were 85.7% and 60.7%, respectively. In patients with trFL (n=26), ORR and CMR rate were 76.9% and 53.8%, respectively. In patients with HGBCL (n=25), ORR and CMR rate were 60.0% and 44.0%, respectively. The two patients with PMBCL achieved a CMR. In patients who had prior CAR T-cell therapy (n=27), ORR was 77.8% and CMR rate was 44.4%. In 61 patients who had a complete response, estimated 6- and 12-month duration of complete response (DOCR) rates were 89.2% and 73.1%, respectively ( Figure). Estimated 6-month and 12-month DOCR rates in patients with DLBCL NOS (n=34) were 84.2% and 59.2%, respectively; with trFL (n=14), were 92.9% and 85.7%; with HGBCL (n=11), both were 100%. In patients with PMBCL (n=2), the estimated 6-month DOCR was 100%. With a median follow-up of 13.0 months, median progression-free survival was 10.4 (95% confidence interval [CI]: 5.8-19.0) months ( Figure). Median overall survival was not reached after a median survival follow-up of 15.2 months.

In 108/111 patients who had received ≥1 dose of Glofit, the most common adverse event (AE) was CRS (45.4% [Grade 1, 30.5%; Grade 2, 13.9%]). One patient had Grade 5 CRS in the context of an unresolved infection; the patient declined further CRS management when the event was Grade 3.

Of 111 safety-evaluable patients, 27 (24.3%) had peripheral neuropathy (all Grade 1/2, 8 events were resolved). Glofit-related AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 patients and were all Grade 1/2. Grade 3/4 AEs were reported in 61.3% of patients, with neutropenia the most common event (29.7%). Serious AEs occurred in 58.6% of patients, and Grade 5 AEs occurred in 6.3% of patients (5/7 events due to COVID-19); 9.9% of patients discontinued any treatment due to an AE (6.3% discontinued Pola; 9.0% discontinued Glofit).

Conclusions: Glofit+Pola demonstrated high response rates and durable responses in heavily pre-treated patients, the majority of whom were refractory to their last prior therapy, across all histologies, including in patients with HGBCL and those with prior CAR T-cell therapy. The safety profile was manageable and consistent with the individual drugs. The rates of CRS events and AEs potentially consistent with ICANS were low. Updated data will be presented.

Hutchings:Martin Hutchings has a Consulting or Advisory Role at Takeda, Roche and Genmab and has received Research Funding from Celgene, Genmab, Roche, Takeda and Novartis.: Consultancy; AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, F. Hoffmann-La Roche Ltd, Takeda: Consultancy; AbbVie, AstraZeneca, Bristol Myers-Squibb, Celgene, Genentech, Genmab, Incyte, Janssen, Merck, Novartis, F. Hoffmann-La Roche Ltd, Takeda: Research Funding; AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, F. Hoffmann-La Roche Ltd, Takeda: Honoraria; AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, F. Hoffmann-La Roche Ltd, Takeda: Membership on an entity's Board of Directors or advisory committees. Avigdor:BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Sureda Balari:Astra Zeneca: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; MSD: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria; Jannsen: Consultancy, Honoraria; Pierre Fabre: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Kite: Consultancy, Honoraria. Terol:Gilead: Research Funding; F. Hoffmann-La Roche Ltd, Janssen, Gilead, Takeda, Abbvie, Beigene: Speakers Bureau; F. Hoffmann-La Roche Ltd, Janssen, Gilead, Takeda, Abbvie, Beigene: Membership on an entity's Board of Directors or advisory committees; Beigene, Gilead, F. Hoffmann-La Roche Ltd, Abbvie, Janssen: Consultancy; Hematologist, Head of the lymphoma Unit, Department of Hematology, Insitute of Research INCLIVA, University of Valencia, Spain: Current Employment. Bosch:F. Hoffmann-La Roche Ltd, Genentech, Inc., Novartis, Janssen, Abbvie, Gilead Kite, Mundipharma, Takeda, Celgene/BMS, AstraZeneca, Lilly, BeiGene, TG Therapeutics, Advantage Allogene, LAVA Therapeutics, Enterome: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, Novartis, Janssen, Abbvie, Gilead, Mundipharma, Celgene/BMS, Takeda, AstraZeneca: Other; F. Hoffmann-La Roche Ltd, Genentech, Inc., Novartis, Janssen, Abbvie, Gilead Kite, Mundipharma, Takeda, Celgene/BMS, AstraZeneca, Lilly, BeiGene, TG Therapeutics, Advantage Allogene, LAVA Therapeutics, Enterome: Consultancy; F. Hoffmann-La Roche Ltd, Genentech, Inc., Novartis, Janssen, Abbvie, Gilead Kite, Mundipharma, Takeda, Celgene/BMS, AstraZeneca, Lilly, BeiGene, TG Therapeutics, Advantage Allogene, LAVA Therapeutics, Enterome: Honoraria; F. Hoffmann-La Roche Ltd, Genentech, Inc., Abbvie, Janssen, Lilly, AstraZeneca, Novartis, Kite, BMS, Takeda, TG therapeutics, BeiGene,Advantage, Allogene, LAVA therapeutics, Enterome: Research Funding; F. Hoffmann-La Roche Ltd, Genentech, Inc., Novartis, Janssen, Abbvie, Gilead Kite, Mundipharma, Takeda, Celgene/BMS, AstraZeneca, Lilly, BeiGene, TG Therapeutics, Advantage Allogene, LAVA Therapeutics, Enterome: Speakers Bureau; Head, Department of Hematology, Vall d'Hebron University Hospital, Barcelona (Spain): Current Employment. Corradini:Celgene: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; Incyte: Other: Honoraria (Consulting, advisory role, or lecturer); Kyowa Kirin: Other: Honoraria (Consulting, advisory role, or lecturer); Nerviano Medical Science: Other: Honoraria (Consulting, advisory role, or lecturer); Janssen: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; Novartis: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; Gilead/Kite: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; Daiichi Sankyo: Other: Honoraria (Consulting, advisory role, or lecturer); Amgen: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; Sanofi: Other: Honoraria (Consulting, advisory role, or lecturer); Pfizer: Other: Honoraria (Consulting, advisory role, or lecturer); Roche: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; ADC Theraputics (DSMB): Other: Honoraria (Consulting, advisory role, or lecturer); AbbVie: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; SOBI: Other: Honoraria (Consulting, advisory role, or lecturer); Takeda: Other: Honoraria (Consulting, advisory role, or lecturer), Travel and accomodations; GlaxoSmithKline: Other: Honoraria (Consulting, advisory role, or lecturer); BeiGene: Honoraria; Bristol Myers Squibb: Other: Travel and accomodations. Larsen:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd, Gilead, Novartis, BMS: Consultancy; Genentech: Research Funding; BMS: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy. Rueda Dominguez:Roche: Speakers Bureau. Skarbnik:Epizyme: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Genentech, Inc.: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; ADC therapeutics: Honoraria, Speakers Bureau. Joergensen:Incyte: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Genmab: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; SOBI: Consultancy; Roche: Consultancy; Orion: Consultancy. Lavie: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; Roche: Honoraria, Other: Advisory Board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation expenses, lecture; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board and Travel/Accommodation expenses. Gurion:Rabin Medical Center: Current Employment; F. Hoffmann-La Roche Ltd, Gilhead, Novartis, Takeda, Medison, Abbvie: Consultancy. Zinzani:SANDOZ: Membership on an entity's Board of Directors or advisory committees; SECURA BIO: Membership on an entity's Board of Directors or advisory committees; GILEAD: 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; ASTRAZENECA: 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; BMS: 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; MSD: 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; EUSAPHARMA: Consultancy, 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; SERVIER: 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. Pinto:BRISTOL-Myers Squibb, Helssin Healthcare, Janssen, Gilead-Science, Servier, Takeda: Honoraria; Scientific Advisory Boards (F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte- Italy, Ely-Lilly-Italy): Membership on an entity's Board of Directors or advisory committees; Incyte-Italy, F. Hoffmann-La Roche AG: Speakers Bureau; Speaking engagements - Educational Lectures (F. Hoffmann-La Roche AG, Incyte -Italy, Merck Sharp and Dohme, Beigene-Italy, BMS- CELGENE, Ely-Lilly-Italy): Honoraria. Cordoba:F. Hoffmann-La Roche Ltd, Takeda, Abbvie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, Genmab, Incyte, Gilead: Speakers Bureau; European Hematology Association (EHA), Spanish Society Hematology (SEHH): Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, Takeda, Abbvie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, Genmab, Incyte, Gilead: Consultancy; Fundacion Jimenez Diaz University Hospital: Current Employment. Bottos:F. Hoffmann La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Li:Roche (China) Holding Ltd: Current Employment. Relf:F. Hoffmann La Roche Ltd.: Current equity holder in publicly-traded company; F-Star Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Roche Products Ltd: Current Employment. Filézac De L'Étang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Sellam:F. Hoffmann La Roche Ltd (stock, non voting rights): Current equity holder in publicly-traded company; F. Hoffmann La Roche Ltd: Current Employment. Gritti:F. Hoffmann-La Roche Ltd, Takeda, Kite-Gilead, Ideogen, Genmab, Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Clinigen, Sandoz, Beigene, Incyte, Janssen, Novartis: Other; Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, Genmab: Other: Advisory Board; Roche, Sandoz, Beigene, Janssen: Other: Support for attending meetings; Takeda, Clinigen, Ideogen, Beigene, Incyte, Novartis: Other: Training activity; Takeda: Consultancy.

Glofitamab (Columvi) is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS or large B-cell lymphoma arising from 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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