Glofitamab (Glofit) in Combination with Polatuzumab Vedotin (Pola): Phase Ib/II Preliminary Data Support Manageable Safety and Encouraging Efficacy in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Hutchings Martin , Sureda Anna , Terol María José , Bosch Albareda Francesc , Corradini Paolo , Larsen Thomas Stauffer , Rueda Dominguez Antonio , Panchal Anesh , Bottos Alessia , Carlile David , Wang Yanjie , Filézac De L'Étang Audrey , Tandon Maneesh , Sellam Gila , Gritti Giuseppe 
Published: November 2021

Abstract
Background: Glofit is a novel, CD20xCD3 T-cell-engaging bispecific antibody that provides monovalent binding to CD3 on T cells and bivalent binding to CD20 on B cells. As monotherapy, Glofit has shown promising response rates with manageable safety in R/R B-cell non-Hodgkin lymphoma (B-NHL) patients (pts; [Carlo-Stella et al. EHA 2021]). Because of their distinct and complementary mechanism of action, there is a rationale for combining Glofit with the anti-CD79b-targeted antibody-drug conjugate, Pola. NP39488 (NCT03533283) is a Phase Ib/II, open-label, multicenter, dose-escalation (DE) and expansion study evaluating Glofit + Pola or atezolizumab in R/R B-NHL pts (Hutchings et al. ASH 2019). Here, we report preliminary safety and efficacy data for Glofit + Pola in pts with R/R DLBCL during DE and expansion at the recommended Phase II dose (RP2D).
Methods: To mitigate the risk of cytokine release syndrome (CRS), a single 1000mg dose of obinutuzumab pre-treatment was administered on Cycle (C) 1 Day (D) 1 alongside step-up dosing (SUD) of Glofit on C1D8 and C1D15. Glofit was subsequently administered at the target dose from C2D1, every 3 weeks up to C12. Pola was administered at 1.8mg/kg on C1D2 and then on D1 of each subsequent cycle up to C6. The primary objective was to establish the RP2D of Glofit in combination with Pola.
Results: As of June 10, 2021 (clinical cut-off date [CCOD]), 44 pts were treated with ≥1 cycle; median follow-up was 3.2 months (95% confidence interval: 1.4-3.5). In the first DE cohort, 7 pts had received Glofit at 2.5mg (C1D8)/10mg (C1D15)/10mg (C2D1 onwards) plus Pola. In the second DE cohort, 4 pts received the Glofit target dose of 30mg on C1D15 and this was established as the RP2D. During the expansion phase at RP2D, an additional 34 pts were treated with ≥1 cycle. Of 44 pts, 29 (66%) had histology of R/R DLBCL, 8 (18%) had R/R high-grade B-cell lymphoma (HGBCL; 2 HGBCL not otherwise specified; 5 double-hit DLBCL; 1 triple-hit DLBCL) and 7 (16%) had R/R transformed follicular lymphoma. Pts (61% male) had a median age of 65.5 years (range: 29-82) and received a median of two prior lines (range: 1−5). Twenty-eight (64%) pts were refractory to their last therapy; 2 pts had not been treated with Glofit at the CCOD. The most frequent adverse event (AE) was CRS (55%; 23/42 pts): Grade (Gr) 1 (n=18); Gr 2 (n=7); no Gr ≥3 CRS events were observed (Lee et al. 2019 ASTCT criteria). Of the 7 pts with Gr 2 CRS, 5 were treated with tocilizumab and fluids for hypotension, and 4 pts were treated with low-flow oxygen due to hypoxia. None of the pts required vasopressors or intensive care unit admission. Gr &gt;3 AEs occurred in 52% (n=23) of pts; most commonly, neutropenia (27%) and anemia (23%). For neurological AEs (NAEs), 13 events were reported in 13 patients (29.5%, 13/44 pts), all were limited to Gr 1−2. The most common NAEs were headache and (11%, 5/44 pts) and insomnia (4.5%, 2/44 pts). No immune effector cell-associated neurotoxicity syndrome-like AEs were reported. Peripheral neuropathy due to Pola was reported in 5/44 pts (11%); all events were Gr 1. Serious AEs occurred in 22 pts (52%); none were CNS or neurological events. One pt experienced fatal COVID-19 pneumonia (not related). Study treatment was discontinued in 2 pts due to AEs (Gr 4 thrombocytopenia, and Gr 3 worsening of pre-existing renal impairment; both events were related to Glofit and Pola). At CCOD 33/44 pts were evaluable for interim (after 2 cycles, 1 target dose of Glofit) or primary (after 8 cycles) response; 6/33 pts had experienced progressive disease and discontinued study treatment. Overall response (OR) rate for both dosing cohorts was 73% (24/33) and complete response (CR) rate, per investigator was 51.5% (17/33). Of 7 pts treated with 2.5/10/10mg SUD Glofit, OR and CR rates were both 86% (6/7); durable responses at ≥6 months post-end of treatment were observed. Of 26 pts treated with 2.5/10/30 mg SUD Glofit, OR rate was 73% (19/26) and CR rate was 46% (12/26); 11.5% (3/26) pts had stable disease after 2 cycles of therapy. Duration of response and time on study by dosing cohort is shown in Figure. Biomarker and pharmacokinetic data will be provided.
Conclusions: Glofit in combination with Pola showed tolerable safety and encouraging preliminary efficacy in R/R DLBCL pts. CRS and NAEs were limited to Gr 1 or 2, no new safety signals were detected for this combination, and the safety profile was consistent with that of the individual drugs. Updated data will be presented.
Figure 1 Figure 1.

Disclosures
Hutchings: Genmab: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Terol: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; BMS: Consultancy; Hospital Clinico Valencia: Current Employment; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Corradini: KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Larsen: Novartis: Consultancy; Gilead: Consultancy; Odense University Hospital, Denmark: Current Employment; Celgene: Consultancy; BMS: Consultancy. Rueda Dominguez: Hospital Regional Universitario de Malaga: Current Employment; Roche: Consultancy; Takeda: Consultancy; Gilead: Consultancy; Merck Serono: Consultancy; BMS: Consultancy; MSD: Consultancy. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Bottos: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Wang: F. Hoffmann-La Roche Ltd: Current Employment; Peking University Third Hospital, Beijing, China: Ended employment in the past 24 months. Filézac De L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Tandon: Roche Products Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sellam: Roche: Current Employment, Current equity holder in publicly-traded company. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy.

OffLabel Disclosure:
Glofitamab is a full-length, humanized immunoglobulin G1 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. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, not otherwise specified, after at least two prior therapies.