Abstract A026: Uncovering the biological contribution of polatuzumab vedotin when combined with glofitamab in R/R large B-cell lymphoma

Abstract Background: Glofitamab (Glofit) is a CD20xCD3 bispecific antibody approved for the treatment of patients (pts) with R/R LBCL. Polatuzumab vedotin (Pola) is a CD79b antibody-drug conjugate also approved for the treatment of LBCL. Preliminary data from an open-label, multicenter, Phase Ib study demonstrate that Glofit-Pola has a manageable safety profile and encouraging efficacy in pts with R/R LBCL after >1 prior lines of therapy (Hutchings et al. 2025). Here, we present an exploratory biomarker analysis to determine the biological contribution of adding Pola to Glofit. Methods: R/R LBCL (DLBCL NOS, HGBCL, trFL) pts treated with Glofit-Pola enrolled in NCT03533283 or Glofit monotherapy (mono) pts treated with a target dose (30mg) or efficacious dose (>10mg) enrolled in NCT03075696 were included in this analysis. In pts with available biomarker samples, peripheral T cells were evaluated by flow cytometry. Bulk RNA sequencing (RNAseq) from tumor biopsies (Glofit-Pola n=88; Glofit mono n=147) was analyzed using gene set variation analysis for tumor intrinsic pathways, and xCell for immune and stromal cell types. LymphoMAPs and dark zone signature (DZsig) were derived as previously described (Li et al. 2025, Ennishi et al. 2018). Inverse probability weighting was applied when comparing biomarker-evaluable populations from Glofit+Pola and Glofit mono studies. Results: In pts who received the Glofit-Pola combination, high complete response (CR) rates were observed across molecular subtypes ABC (73.1%), DZsig+ (53.6%) and GCB DZsig- (57.7%). Similar CR rates were also observed across LymphoMAP archetypes Lymph Node (LN, 70.4%), T exhausted (Tex, 59.1%) and Fibroblast/Macrophage (FMAC, 59.0%).To gain insights into the biological contribution of Pola to the Glofit MoA, we compared the association between outcomes and gene signatures related to intrinsic tumor features and tumor microenvironment in pts treated with Glofit-Pola vs Glofit mono, in a weighted and matched population (3L+ LBCL). High proliferation signatures (including E2F and MYC targets) were associated with shorter PFS in Glofit mono (E2F HR 1.58, 95% CI: 1.1-2.3) and longer PFS in Glofit-Pola (E2F HR 0.62, 95% CI: 0.3-1.3). Immune cell deconvolution showed high relative abundance of immune cells (CD4, CD8 T cells) associated with longer PFS in Glofit mono (CD4 HR 0.46, 95% CI: 0.3-0.8), however this association was not observed with Glofit-Pola (CD4 HR 1.60, 95% CI: 0.6-4.0). Additionally, comparison of T-cell pharmacodynamics in the periphery showed increased activation (HLA-DR+ CD4 T cells) by cycle 4 of treatment and decreased exhaustion markers (PD1+ CD8 T cells), suggest enhanced activation of T cells by the Glofit-Pola combination compared to Glofit mono. Conclusion: Biomarker analyses in pts with R/R LBCL treated with Glofit-Pola showed improved clinical efficacy in high-risk molecular subgroups. Exploratory results suggest that pts treated with Glofit-Pola may be less dependent on immune contexture and tumor proliferation status for outcomes than those treated with Glofit mono. Citation Format: Wilfred Leung, Malgorzata Nowicka, Anton Belousov, Gila Sellam, Martine Kallemeijn, Anna Sureda, Linda Lundberg, Estefania Mulvihil, Martin Hutchings, Giuseppe Gritti, Alessia Bottos. Uncovering the biological contribution of polatuzumab vedotin when combined with glofitamab in R/R large B-cell lymphoma [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A026.