Glofitamab Step-up Dosing Induces High Response Rates in Patients with Hard-to-Treat Refractory or Relapsed Non-Hodgkin Lymphoma
Authors: Hutchings Martin , Carlo-Stella Carmelo , Bachy Emmanuel , Offner Fritz C. , Morschhauser Franck , Crump Michael , Iacoboni Gloria , Sureda Balari Anna , Martinez-Lopez Joaquin , Lundberg Linda , Dixon Mark , Perez Callejo David , Relf James , Carlile David , Piccione Emily , Humphrey Kathryn , Dickinson Michael 
Published: November 2020

Introduction : Glofitamab (RG6026) is a novel T-cell-engaging, bispecific, full-length antibody with a 2:1 molecular configuration that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Preclinically, glofitamab had superior potency compared with other tested bispecifics with 1:1 formats (Bacac, et al. Clin Cancer Res 2018). NP30179 (NCT03075696) is an ongoing multicenter, Phase I/Ib, dose-escalation and dose-expansion trial evaluating the safety, tolerability, pharmacokinetics, biomarker responses, and efficacy of glofitamab in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in pts with heavily pre-treated R/R NHL (Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). Step-up dosing of glofitamab was used in addition to Gpt to further reduce the risk of CRS. For the first time, we present clinical data of glofitamab step-up dosing with Gpt in pts with R/R NHL.
Methods: Pts received 1000mg obinutuzumab 7 days prior to first glofitamab administration. Glofitamab was given intravenously with step-up dosing on Cycle (C) 1 Day (D) 1 and 8 and then at the target dose from C2D1, every 3 weeks for up to 12 cycles (2.5/10/16mg or 2.5/10/30mg). Response rates reported are based on the Lugano criteria (Cheson, et al. J Clin Oncol 2014).
Results: As of April 17, 2020, 38 pts received step-up doses of glofitamab; 17 pts received 2.5/10/16mg, and 21 pts received 2.5/10/30mg. Twenty-eight pts (73.7%) had aggressive NHL (aNHL) histologies and ten pts had indolent NHL (iNHL; Table). The median age was 68 years (range 52-85) and median number of prior lines of therapy was 3 (range 1-12). Twenty-seven (71.1%) pts were refractory to their last therapy, and 28 (73.7%) pts were refractory to prior CD20 therapy.
After a median follow-up of 2.8 months, across all efficacy-evaluable pts (n=32) the overall response rate (ORR) and complete metabolic response (CMR) rate was 62.5% and 40.6%, respectively. For pts with aNHL (n=24), the ORR was 50.0% with CMR rates of 29.2%. As of the data cut-off date, 17 pts with aNHL (70.8%) had reached the first response assessment only (C3) and remain on treatment; four pts (16.7%) had reached the second response assessment (C6). For pts with iNHL (n=8), the ORR was 100.0% with 75.0% of pts achieving CMR.
Across the safety-evaluable population (n=38), the most common AEs were CRS (57.9%), pyrexia (31.6%), neutropenia, thrombocytopenia and hypophosphatemia (28.9% each). No AEs led to treatment discontinuation. Of 22 patients who experienced CRS events, the CRS events only occurred in C1 and C2; 15 had CRS after the 2.5mg dose, 12 after the 10mg dose, and 5 during C2 (16 or 30mg dose; Figure). Eight pts (21.1%) and 13 pts (34.2%) experienced Grade (Gr) 1 and 2 CRS, respectively; none experienced Gr 3 CRS. One pt (2.6%) experienced Gr 4 CRS after the 30mg dose. No CRS events occurred after C2. Tocilizumab was used to manage CRS in six (15.8%) pts: n=2 for 2.5/10/16mg and n=4 for 2.5/10/30mg cohorts. CRS events were manageable and resolved for 21 pts (95.4%) at data cut-off. No Gr ≥3 neurologic adverse events were reported.
Consistent with prior biomarker data from fixed-dose regimens (Bröske, et al. EHA 2020), glofitamab administered with step-up dosing induced a transient T-cell redistribution.
Conclusions: Step-up dosing of glofitamab allowed escalation up to 30mg to maximize efficacy, while minimizing the risk of increased CRS. High ORR and CMR rates were observed in pts with NHL who had failed several lines of treatment. Toxicity was manageable with the main safety signal being low-grade CRS observed in early cycles. Updated results will be presented at the congress which will include data from at least 50 pts receiving glofitamab step-up dosing with Gpt.

Disclosures
Hutchings: Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy. Bachy:Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Genentech, Inc.: Consultancy. Crump:Kite/Gilead: Consultancy; Roche: Consultancy; Servier: Consultancy. Iacoboni:Novartis, Gilead, Celgene, Roche: Honoraria. Sureda Balari:BMS: Speakers Bureau; Roche: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Martinez-Lopez:Novartis: Consultancy; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Dixon:Roche Products Limited: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Perez Callejo:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Relf:Roche Products Ltd: Current Employment. Carlile:AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Piccione:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Dickinson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy.

OffLabel Disclosure:
Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.