Glofitamab monotherapy induces durable complete remissions and has a manageable safety profile in patients with richter’s transformation

Introduction: Richter's transformation (RT) is characterized by transformation of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly CD20+ large B-cell lymphoma (LBCL). Prognosis for patients (pts) with RT is poor and no standard of care exists; there remains a major unmet medical need. Glofitamab is a T-cell engaging bispecific antibody (Ab) with a novel 2:1 (CD20:CD3) format. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy demonstrated durable responses and a manageable safety profile in pts with relapsed/refractory LBCL (Dickinson et al. 2022). We report the efficacy and safety of glofitamab monotherapy in pts with RT after a median follow-up of 40.6 months (range: 0.3–53.9). Methods: All pts had RT and had received ≥1 prior regimen including ≥1 anti-(a) CD20 Ab. Pts received obinutuzumab pretreatment (1000 or 2000mg) 7 days before the first glofitamab dose and intravenous glofitamab at a fixed dose (0.6, 16, or 25mg) or with step-up dosing (SUD) in Cycle 1 (target dose 16 or 30mg) every 3 weeks for up to 12 cycles. Responses were assessed using Lugano 2014 criteria. Cytokine release syndrome (CRS) events were graded by ASTCT criteria. Results: As of 10 October 2022, 11 pts had received glofitamab at a fixed dose (0.6–25 mg, n = 5) or with SUD (2.5/10/16 mg, n = 3; 2.5/10/30 mg, n = 3). Median age was 71 years (range: 48–76); six pts were aged >70 years. Overall, 91.0% of pts had Ann Arbor stage III–IV disease and 45.5% had an IPI score ≥3. Median number of prior therapies was 3 (range: 1–4) and 54.6% of pts had ≥3 prior therapies. Most pts were refractory to a prior aCD20 Ab-containing regimen (90.9%) and all to their most recent regimen (100%); 54.5% of pts were refractory to their initial therapy. Investigator-assessed overall response rate and complete response (CR) rate were 63.6% and 45.5%, respectively. Median time to CR was 3 months (95% CI: 2.5–not estimable [NE]). Complete responses were durable and most (4/5; 80%) had been ongoing for ≥24.9 months at data cut (Figure). CRS occurred in 72.7% of pts, was primarily associated with the initial doses, and was mostly Grade (Gr) 1 (27.3%) or Gr 2 (27.3%); Gr 3 (9.1%, n = 1) or Gr 4 (9.1%, n = 1) events were uncommon. Glofitamab-related neurologic adverse events (AEs) potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 5 pts (Gr 3, n = 1 [syncope]; Gr 1, n = 4). No glofitamab-related Gr 5 (fatal) AEs or glofitamab-related AEs leading to discontinuation were reported. The research was funded by: NCT03075696 is sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of all authors, was provided by Dikeledi Matlebjane, MSc of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract C. Carlo-Stella Employment or leadership position: Humanitas University Consultant or advisory role: Sanofi, ADC Therapeutics, Karyopharm Tx, Celgene/BMS, Roche, Merck Sharp & Dohme, Scenic Biotech, Novartis Honoraria: Celgene/BMS, Incyte, Roche, Janssen Oncology, Merck Sharp & Dohme, Astra-Zeneca, Gilead Research funding: Sanofi, ADC Therapeutics, Roche Other remuneration: Travel, accommodation, expenses - Takeda, Janssen Oncology M. Hutchings Consultant or advisory role: Takeda, Roche, Genmab, Janssen, Abbvie Research funding: Celgene, Genmab, Roche, Takeda, Novartis, Janssen, Merck, Abbvie, AstraZeneca E. Mulvihill Employment or leadership position: F. Hoffmann-La Roche Stock ownership: F. Hoffmann-La Roche Other remuneration: Travel, accommodation, expenses - F. Hoffmann-La Roche J. Relf Employment or leadership position: Roche Products Limited Stock ownership: Roche, F-Star Therapeutics and Harpoon Therapeutics B. Byrne Employment or leadership position: Roche Products Ltd, Welwyn Garden City, United Kingdom Stock ownership: Roche Products Ltd, Welwyn Garden City, United Kingdom L. Lundberg Employment or leadership position: F. Hoffmann-La Roche Stock ownership: F. Hoffmann-La Roche Other remuneration: Patent with F. Hoffmann-La Roche M. Dickinson Consultant or advisory role: Novartis, BMS, Gilead, Roche, Janssen, Abbvie, Genmab Honoraria: Roche, Amgen, MSD, Janssen, BMS, Novartis, Gilead, Abbvie Research funding: Novartis, Roche, Takeda, Celgene, MSD, Abbvie, Lilly Other remuneration: Travel, accommodation, expenses - Roche