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 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.
ABSTRACT
Background: Axicabtagen Ciloleucel (axi-cel) is approved in Europe for the treatment of adults with R/R large B-cell lymphoma (LBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (tFL). In Spain, nationwide CAR-T administration requests are reviewed centrally within the Ministry of Health. We analyzed the real-world outcomes of patients treated with axicel under the commercial label in Spanish centers. Methods: Six designated centers for commercial CAR-T administration collected data on behalf of GETH-GELTAMO. Data were collected retrospectively from consecutive patients in whom apheresis was performed for axi-cel treatment from Febrruary-2019 to November-2020. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Results: 106 patients with R/R lymphoma underwent apheresis for axi-cel. At data cutoff, 92 (87%) received infusion. The reasons for not undergoing infusion were progression-related death in 12 (86%), tumor lysis syndrome in 1 (7%) and complete response after bridging therapy in 1 (7%). Of note, 14 patients were conditioned and infused during the peak of COVID-19 epidemic in Spain (March-April 2020). Median time from Ministry approval to infusion was 54 days. Histology consisted of 74% DLBCL with 11% tFL, and 15% PMBCL. Disease status at lymphodepletion was PD in 69%, SD in 22% and PR in 9%. All patients received lymphodepletion. Median time from leukapheresis to start of lymphodepletion was 34 days. Median time from leukapheresis to infusion was 39 days. Median hospitalization period was 21 days. Any grade of CRS occurred in 86% of pts (18% grade 2, 6.5% grades 3-4). Tocilizumab was used in 58% of patients who developed CRS, corticosteroids in 19%. ICANS was diagnosed in 42.5% of pts (10% grade 2, 15% grade 3-4). Treatment for ICANS included corticosteroids in 78%, tocilizumab in 31%, siltuximab in 15%, and anakinra in 21%. ICU admission was needed in 20 patients (22%). 4 patients died in the context of ICANS, 1 due to CRS, and 1 due to infection. Of 80 patients evaluable and restaged at day 30, ORR was 78% with 40% CR, 38% PR, 11% PD and 11% SD or indeterminate. Of 58 patients evaluable at day 100, 66% had ongoing response (CR 48%, PR 18%). Of 23 patients evaluable at day 180, 65% presented CR. Of 39 patients who showed PR/SD at day 30, 9 (23%) converted to CR. After a median follow-up of 6.3 months, EFS and OS were 55.5% and 78%, respectively in the infused population, with an estimated median EFS and OS of 13.1 and 7.3 months. In the intention-to-treat analysis for all patients who underwent apheresis, median estimated OS and EFS were 12.3 (95%CI 8.9-15.7) and 6.6 months (95%CI 4.6-8.5), respectively (Figure 1). Conclusions: This Spanish multicenter retrospective analysis shows encouraging results of axi-cell treatment in patients with R/R aggressive B-cell lymphoma in the real-world setting. Significant toxicity events were less frequent than those reported in the pivotal trial, however events of mortality associated to toxicity occurred. With a limited follow-up time, response outcomes are favorable.