Engaging results with glofitamab

Abstract

0123456789();: Nature reviews | CliniCal OnCOlOgy The safety and preliminary efficacy data of glofitamab compare favourably with those of established third-line treatments... The prognosis of most patients with relapsed and/or refractory B cell non-Hodgkin lymphoma (R/R B-NHL), particularly those with aggressive histologies such as diffuse large B cell lymphoma or transformed follicular lymphoma, remains dismal. Now, data from the ongoing phase I NP30179 study demonstrate the encouraging activity of glofitamab, a novel bivalent CD20-targeted bispecific T cell-engager antibody, in this setting. “This trial included 171 heavily pretreated patients with R/R B-NHL, predominantly (74.3%) aggressive lymphoma subtypes; 90.6% had disease refractory to immediate prior therapy,” explains study lead Michael Dickinson. These patients received various fixed or step-up doses of glofitamab starting 1 week after a single dose of the anti-CD20 antibody obinutuzumab, which was used to deplete B cells and thereby reduce the risk of a glofitamab-induced cytokine storm. “The objective response rate (ORR) was 53.8% across all doses tested and 65.7% in 35 patients who received the recommended phase II dose (2.5–10–30 mg step-up dosing), with complete response (CR) rates of 36.8% and 57.1%, respectively,” Dickinson summarizes. “Notably, 34 (81.0%) of 42 CRs in patients with aggressive histologies are ongoing at up to 27.4 months.” In this group, the median progression-free survival (PFS) was 2.8 months, although PFS plateaued at ~25% beyond 8 months. Glofitamab-related grade ≥3 adverse events (AEs), mostly cytopenias and infections, occurred in 31.0% of patients. Despite obinut uzumab pretreatment, cytokine-release syndrome occurred in 50.3% of patients, and 5.3% had transient symptoms of immune effector cell-associated neurotoxicity syndrome; however, these AEs were of grade ≥3 in only 3.5% and 1.2%, respectively. Moreover, only 2.9% of patients discontinued treatment owing to AEs, and no treatment-related deaths were reported. “The safety and preliminary efficacy data of glofitamab compare favourably with those of established third-line treatments — and clear potential for improvement exists in that space,” states Dickinson. Multiple CD19-targeted chimeric antigen receptor (CAR) T cell products are approved for third-line treatment of B-NHLs, but challenges related to accessibility, manufacturing, toxicities and resistance continue to limit the benefits of these agents. “Glofitamab is a convenient and readily available non-chemotherapy treatment option,” adds Dickinson, concluding that: “this treatment has promising activity against both aggressive and indolent B-NHLs and is well-suited for evaluation in later-phase studies, as a single agent and in combination.” Glofitamab is being tested in various combinations, including with concurrent obinutuzumab as part of the NP30179 study and with gemcitabine plus oxaliplatin in the phase III STARGLO trial (NCT04408638). In addition, a role for glofitamab following, or even in combination with, anti-CD19 CAR T cell therapy can be envisaged, with the aim of overcoming antigen loss and other mechanisms of resistance. Indeed, a trial has been initiated in such a context (NCT04703686).