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)

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 >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. [Formula presented] 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;Roch 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 21 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.