Glofitamab Plus Polatuzumab Vedotin Demonstrates Durable Responses and a Manageable Safety Profile in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: Glofitamab (Glofit) is a bispecific CD20:CD3 antibody which redirects T cells to eliminate malignant B cells. The CD79b targeted antibody-drug conjugate polatuzumab vedotin (Pola) is approved in combination with bendamustine and rituximab for the treatment of R/R DLBCL. Glofit and Pola have distinct yet complementary mechanisms of action, with little overlap in toxicity profiles. Initial data from an open-label, multicenter Phase Ib/II study (NCT03533283) support the manageable safety and encouraging efficacy of Glofit + Pola in R/R DLBCL (Hutchings et al. ASH, 2021). We present updated study results (data cutoff 25 January 2023). Methods: Patients (pts) received obinutuzumab 1000 mg on Day (D) 1 of the first 21-day cycle (C), to mitigate risk of cytokine release syndrome (CRS). Pola 1.8 mg/kg was given on C1D2 and D1 of C2–6. Glofit was given with C1 step-up dosing (C1D8 2.5 mg; C1D15 10 mg; C2–12 D1, 10/30 mg) for up to 12 cycles. Per protocol, 24-hour hospitalization was only mandatory after the first Glofit infusion. Primary objective: to establish the recommended Phase II dose of Glofit in combination with Pola (identified as 30 mg; Hutchings et al. ASH, 2021). Additional objectives: safety, efficacy, PK (secondary), and biomarkers (exploratory). Results: As of 25 January 2023, 111 pts received ≥1 dose of study drug. Median age was 68 yrs (range 23–82), 51.5% had R/R DLBCL, 24% R/R HGBCL, 23% R/R trFL, and 2% R/R PMBCL. 71% of pts were refractory to their last therapy, median prior lines of therapy was 2 (range 1–7; 39% received 1 prior line), and 25% of pts had prior CAR T-cell therapy. The most common AE was CRS (44%): majority ASTCT criteria Gr 1/2 (30%/14%). One pt had Gr 5 CRS in the context of urosepsis and herpetic stomatitis but declined intensive CRS management. Gr 3/4 AEs occurred in 61% of pts, most commonly neutropenia (30%; one febrile neutropenia event). Glofit-related neurologic AEs potentially consistent with ICANS occurred in 3 pts (Gr 1/2). Pola-related peripheral neuropathy was reported in 21% of pts (all Gr 1/2). SAEs occurred in 59% of pts and Gr 5 AEs in 6% (5/7 Gr 5 events due to COVID-19). 9% of pts discontinued treatment due to an AE (2% due to COVID-19). Of 109 efficacy-evaluable pts, best ORR (BORR) for both dosing cohorts (per Lugano 2014) was 78%, with best CR (BCR) rate of 56%. By histology, BORR and BCR, respectively were: R/R DLBCL 86% (48/56) and 61% (34/56); R/R trFL 77% (20/26) and 54% (14/26); R/R PMBCL 100% (2/2) and 100% (2/2); HGBCL 60% (15/25) and 44% (11/25). With median FU of 13.0 months (95% CI: 11.8–16.6), median PFS was 10.4 months (95% CI: 5.8–19.0; Figure) and median DoR was 17.9 months (95% CI: 10.1–NE). This study is sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of all authors, was provided by Fiona Fernando, PhD, contract medical writer at Ashfield MedComms, an Inizio company, and Molly Heitz, PhD, of Ashfield MedComms, and was funded by F. Hoffmann-La Roche Ltd. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy Conflicts of interests pertinent to the abstract M. Hutchings Consultant or advisory role: Takeda, Roche, Genmab, Janssen, Abbvie Research funding: Celgene, Genmab, Roche, Takeda, Novartis, Janssen, Merck, Abbvie, AstraZeneca A. Avigdor Consultant or advisory role: Takeda, Gilead, Novartis, Roche, BMS Honoraria: Abbvie Other remuneration: travel, accommodation, expenses—Roche A. Sureda Employment or leadership position: Institut Català d’Oncologia-L’Hospitalet, Barcelona, Spain Consultant or advisory role: Takeda, MSD, BMS/Celgene, Novartis, Kite, Sobi, Janssen, Sanofi, GenMab, Abbvie, Roche, Pierre Fabre Honoraria: Takeda, MSD, BMS/Celgene, Novartis, Kite, Janssen, Sanofi, GenMab, Abbvie, Roche, Pierre Fabre, Jazz Research funding: Takeda Other remuneration: speaker's bureau—Takeda; travel, accommodation, expenses—Kite, Jazz M. J. Terol Employment or leadership position: Department of Hematology, Hospital Clínico de Valencia, Conselleria de Sanitat, Valencia, Spain Consultant or advisory role: Roche, Janssen, Gilead, Abbvie, Astra-Zeneca, Lilly Honoraria: Roche, Janssen Research funding: Janssen, Gilead Other remuneration: leadership—Secretary of Spanish group of CLL; Head of the lymphoproliferative unit at the Hospital Clinico; travel, accommodation, expenses—Roche, Janssen, Gilead, Abbvie, Astra-Zeneca, Lilly F. Bosch Employment or leadership position: Head of Department of Hematology, Hospital Vall d’Hebron, Barcelona Consultant or advisory role: Roche, Celgene, Karyospharm, Takeda, Astrazeneca, Novartis, Abbvie, Janssen Honoraria: Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, Beigene Research funding: Roche, Celgene, Karyospharm, Takeda, Astrazeneca, Novartis, Abbvie, Janssen Other remuneration: speaker's bureau—Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, Beigene; Expert Testimony—Abbvie; travel, accommodation, expenses—Abbvie, Roche, Janssen, AstraZeneca, Celgene/BMS P. Corradini Consultant or advisory role: Abbvie, Amgen, Celgene, Daiichi Sankyo, Gilead Sciences, Incyte, Janssen, Jazz Pharmaceuticals, Kite/Gilead, Kyowa Kirin, Novartis, Roche, Sanofi, Takeda, Nerviano Medical Sciences Honoraria: Abbvie, Amgen, Celgene, Daiichi Sankyo, Gilead Sciences, Kite/Gilead, Janssen, Kyowa Kirin, Novartis, Roche, Sanofi, Takeda Other remuneration: travel, accommodation, expenses—Abbvie, Celgene, Gilead Sciences, Janssen, Kite/Gilead, Novartis, Takeda T. Stauffer Larsen Consultant or advisory role: Roche, Gilead, Novartis, Celgene/BMS Research funding: Genentech A. Rueda Domínguez Consultant or advisory role: Roche, BMS, Takeda, Merck, Gilead Other remuneration: speaker's bureau—Roche, BMS, Takeda, Merck, Gilead A. Skarbnik Consultant or advisory role: Alexion, AstraZeneca, Abbvie, Celgene, Epizyme, Genentech, Janssen, GenMab, Pharmacyclics, Kite Pharma, Jazz Pharmaceuticals, Lilly, Beigene Other remuneration: speaker's bureau—AstraZeneca, Abbvie, Beigene, ADC Therapeutics, Genentech, Janssen, Kite Pharma, Jazz Pharmaceuticals, Pharmacyclics, SeaGen J. Jørgensen Consultant or advisory role: Roche, BMS/Celgene, Novartis, Gilead/Kite, Orion, Abbvie, Incyte, Sobi Other remuneration: travel, accommodation, expenses—Gilead, Abbvie N. Goldschmidt Other remuneration: all disclosures to be confirmed R. Gurion Employment or leadership position: Rabin Medical Center, Petach Tikva, ISRAEL Consultant or advisory role: Novartis, Gilead, Medison, Roche Honoraria: Takeda, Roche, MSD, Novartis, AsraZeneca, Sanofi, Janssen, Medison, Gilead Research funding: Roche P. L. Zinzani Consultant or advisory role: MSD, Eusapharma, Novartis, Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, AstraZeneca, Takeda, Roche, Kyowa-Kirin, ADC Therapeutics, Incyte, Beigene Other remuneration: speaker's bureau—Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, Eusapharma, Kyowa-Kirin, Novartis, Incyte, Beigene A. Pinto Consultant or advisory role: scientific advisory boards (F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte) Honoraria: speaking engagements—Educational Lectures (F. Hoffmann-La Roche AG, Incyte –Italy, Merck Sharp and Dohme, Servier Affaires Medicales, BMS-CELGENE) Other remuneration: speaker's bureau—Incyte, F. Hoffmann-La Roche AG R. Cordoba Consultant or advisory role: AbbVie, Janssen, AstraZeneca, Kite, BMS, Genmab, Roche, Takeda, Kyowa-Kirin, Beigene, Lilly Research funding: Pfizer Other remuneration: speaker's bureau—AbbVie, Janssen, AstraZeneca, Kite, BMS, Roche, Takeda A. Bottos Employment or leadership position: F. Hoffmann-La Roche Stock ownership: F. Hoffmann-La Roche Z. Huang Employment or leadership position: Roche Stock ownership: Roche S. Simko Employment or leadership position: Genentech Stock ownership: Roche J. Relf Employment or leadership position: Roche Products Limited Stock ownership: Roche, F-Star Therapeutics and Harpoon Therapeutics A. Filézac de L’Etang Employment or leadership position: F. Hoffmann-La Roche AG Stock ownership: F. Hoffmann-La Roche AG G. Sellam Employment or leadership position: Roche Stock ownership: Roche Other remuneration: travel, accommodation, expenses—Roche G. Gritti Consultant or advisory role: Roche, Takeda, Gilead/Kite, Ideogen, Genmab Other remuneration: speaker's bureau—Clinigen, Ideogen, Beigene, Incyte, Novartis; travel, accommodation, expenses—Janssen, Beigene, Sandoz