Glofitamab in Combination with Polatuzumab Vedotin Maintains Durable Responses and a Manageable Safety Profile in Patients with Heavily Pre-Treated Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Including High-Grade B-Cell Lymphoma (HGBCL): Extended Follow-up of a Phase Ib/II Study
Authors: Hutchings Martin , Sureda Balari Anna , Bosch Francesc , Larsen Thomas Stauffer , Corradini Paolo , Avigdor Abraham , Terol María José , Rueda Dominguez Antonio , Pinto Antonio , Skarbnik Alan P , Cordoba Raul , Joergensen Judit Mészáros , Zinzani Pier Luigi , Gurion Ronit , Goldschmidt Neta , Leung Wilfred , Li Donghang , Relf James , Tandon Maneesh , Sellam Gila , Gritti Giuseppe 
Published: December 2024

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.