Introduction: Improved treatments are needed for relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) pts. Options are particularly limited for pts with B-cell NHLs who are R/R to CAR-T therapies or for whom a delay in effective therapy precludes this approach. Mosunetuzumab (M; RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). In an ongoing Phase I/Ib study (GO29781; NCT02500407), promising efficacy and favorable tolerability were observed in R/R NHL pts (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We report complete remissions (CRs) with M in NHL pts who are R/R to CAR-T therapy, as well as activity with M re-treatment. Methods: GO29781 is an open-label, multicenter, Phase I/Ib, dose escalation and expansion study of M in R/R B-cell NHL. Data is presented from Group B, in which M is administered with step-up dosing on Days 1, 8, and 15 of Cycle 1, and then as a fixed dose on Day 1 of each subsequent 21-day cycle (maximum 17 cycles). Outcome measures include best objective response rate (ORR) by revised International Working Group criteria, maximum tolerated dose (MTD), and tolerability. Results: As of June 4, 2019, 218 pts in Group B had received any amount of M. Indolent NHL (iNHL) pts (n=72) were mainly follicular lymphoma (FL, n=69). Aggressive NHL (aNHL) pts (n=141) were mainly diffuse large B-cell lymphoma (DLBCL, n=87) or transformed FL (trFL, n=29). Median prior systemic therapies was 3 (range: 1-14). Twenty-three pts had prior CAR-T therapy (12 DLBCL, 6 trFL, 5 FL), and 16 were efficacy evaluable (7 DLBCL, 5 trFL, 4 FL). ORR and CR rates were 43.8% (7/16) and 25.0% (4/16, 2 DLBCL and 2 FL), respectively. Expansion of previously administered CAR-Ts after M administration was detected by quantitative PCR, in line with the mechanism of action of M. Dose escalation is ongoing, supported by a positive exposure-response relationship for efficacy and broad therapeutic window with step-up dosing (Li et al. ASH 2019). Among efficacy-evaluable pts across all dose levels, ORR and CR rates were 64.1% (41/64) and 42.2% (27/64) in iNHL pts and 34.7% (41/119) and 18.6% (22/119) in aNHL pts, respectively. CRs appeared durable, with 25/27 (92.6%) iNHL pts (median time from first CR: 5.8 months; range: 0.2-28.9) and 15/22 (68.2%) aNHL pts (median time from first CR: 8.8 months; range: 0.0-25.4) who achieved CR remaining in remission. Re-treatment with M was allowed in CR pts who relapsed. Four pts, including 1 in Group A who was initially treated with a fixed, non-step-up dosing schedule, received M re-treatment. One CR and 2 partial responses were observed. All three responses are ongoing, with the CR pt in second remission for 314 days. The MTD of M has not been reached at doses up to 1/2/60mg (Cycle 1 Day 1, 8, and 15). Adverse events (AEs) leading to treatment withdrawal were uncommon (12/218, 5.5%). Cytokine release syndrome (CRS), graded by Lee criteria (Lee et al. Blood 2014;124:188-95), was observed in 28.4% of pts, and was mostly Grade (Gr) 1 (21.1%) or Gr 2 (6.0%); Gr 3 CRS occurred in 1.4% of pts. Most CRS events occurred in Cycle 1; 5 pts (2.7%) had CRS during or after Cycle 2. Three of 218 pts (1.4%) received tocilizumab for CRS management; all 3 events resolved without sequelae (for 1 pt, CRS resolved after the cutoff date). Neurological AEs (NAEs) were reported in 44% of pts (Gr 1, 28.0%; Gr 2, 12.8%; Gr 3, 3.2%). Common NAEs were headache (14.7%), insomnia (10.1%), and dizziness (9.2%). Potential immune effector cell-associated neurotoxicity syndrome (ICANS)-like NAEs of Gr 1 or Gr 2 confusional state occurred in 3 pts (1.4%) during cycles 1 and 2. The frequency of CRS and NAEs did not correlate with M exposure, likely due to step-up dosing, which effectively mitigates acute toxicities and allows administration of higher doses (Bartlett et al. ASCO 2019; Li et al. ASH 2019). Among the 4 pts who were re-treated with M, no CRS was observed and NAEs were reported in 1 pt (Gr 1 headache and insomnia). Among the 23 pts who were R/R to CAR-T therapy, CRS occurred in 5 pts (21.7%; Gr 1, 13.0%; Gr 2, 4.3%; Gr 3, 4.3%) and NAEs in 8 pts (34.8%; Gr 1, 17.4%; Gr 2, 13.0%; Gr 3, 4.3%), with no ICANS-like events. Conclusions: M has favorable tolerability and durable efficacy in pts with heavily pre-treated R/R B-cell NHL, including CRs in pts with disease progression after CAR-T therapies. Preliminary data support the possibility for re-treatment with M. Disclosures Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Nordic Nanovector: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding. Bartlett:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yoon:Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Janssen: Consultancy; Yuhan Pharma: Research Funding. Bosch:Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sehn:Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Cheah:Janssen: Honoraria; Acerta: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Loxo: Honoraria. Shadman:Mustang Biopharma: Research Funding; Gilead: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Bigene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding. Gregory:MSD: Other: grant pending, Research Funding; Beigene: Other: Grant pending, Research Funding; Celgene: Other: grant pending, Research Funding; Monash University: Research Funding; Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: grant pending, Research Funding; Janssen: Other: grant pending, Research Funding; Melbourne Haematology: Consultancy, Honoraria, Other: Travel fees and conference support, Speakers Bureau. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Yousefi:F. Hoffmann-La Roche Ltd: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Li:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Off Label Disclosure: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies.

Introduction: Bruton's tyrosine kinase (BTK) is a downstream intermediary of B cell receptor (BCR) signaling. As revealed by ibrutinib, disruption of BCR signaling results in significant anti-tumor activity in various B cell malignancies. BGB-3111 is a potent, specific and irreversible BTK inhibitor. In biochemical and cellular assays, BGB-3111 was more selective than ibrutinib for BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. Activity against these other kinases is implicated in ibrutinib-associated toxicities such as diarrhea, bleeding, and atrial fibrillation. In preclinical animal studies, BGB-3111 demonstrated superior oral bioavailability, achieving higher exposure and more complete target inhibition in the tissues than ibrutinib. We report here the initial results of an ongoing phase 1 trial of BGB-3111 in patients (pts) with advanced B cell malignancies. Patients/Methods: This first-in-human, open label phase 1 study comprised a dose-escalation (DE) component, followed by an ongoing safety, schedule and efficacy expansion component. The results of the planned interim analysis performed at the end of DE are reported here. During DE, pts with relapsed or refractory World Health Organization (WHO) classification defined B-lymphoid malignancies were enrolled to 1 of 5 dose cohorts of BGB-3111 (40, 80, 160, 320mg PO QD; 160mg PO BID) in a modified 3+3 dose escalation design. Adverse events (AEs) were reported per CTCAE v4.03 (patients with baseline cytopenias remained evaluable for neutropenia and thrombocytopenia) and responses per histology-specific standard criteria (NHL IWG criteria 2014; modified CLL IWG criteria 2015; WM IWWM criteria 2013). BGB-3111 pharmacokinetics (PK) was analyzed by dose level, and BTK occupancy determined using an irreversible binding assay in PBMCs. Results: 25 pts were enrolled in DE: 40mg (n=4), 80mg (n=5), 160mg (n=6) and 320mg (n=6) QD, and 160mg BID (n=4). Pts had received a median 2 (range: 1-7) prior therapies, for diagnoses listed in Table 1. As of 30 July 2015, all were evaluable for AE and response. BGB-3111 exposure increased in a dose-proportional manner from 40mg to 320mg daily. The Cmax and AUC0-24h of BGB-3111 at 80mg QD was comparable to that reported for ibrutinib at 560mg QD, and the free drug concentration of BGB-3111 at 40mg QD was comparable for that reported for ibrutinib 560mg QD. Sustained 24 hour BTK occupancy in PBMCs was demonstrated in all pts at 40mg QD (24 hour BTK occupancy 98.6 +/-1.1%), and at all higher dose levels. No dose limiting toxicities (DLT) were encountered, and the maximum tolerated dose (MTD) was not reached. The recommended phase 2 dose (320mg daily) was determined based on the pharmacokinetics, pharmacodynamics, safety and efficacy of BGB-3111. Three pts discontinued BGB-3111 due to disease progression. There were no drug-related SAEs, AEs leading to drug discontinuation, or AE-related deaths. Of 21 ≥grade 3 AEs, 3 were assessed by investigators as potentially drug-related - all were self-limiting neutropenia in CLL pts, two of whom had neutropenia at baseline. No G3/4 bleeding events were recorded. Four pts had a baseline history of atrial fibrillation/flutter (AF); no exacerbation or new event of AF was reported. 16 responses, including 1 complete remission, have been observed. Response by histology is summarized in Table 1 and Figure 1. 22/25 pts remain on study treatment, free of progression, at a median of 204 days (range 138-321). Table. Response by Histology to BGB-3111 Histology n Objective Response (no. in CR) SD Continuing Treatment (as of 30th July 2015) Days on treatment (median; range) CLL 8 6 (0) 2 8 199 (140-252) MCL 6 4 (1) 1 5 227 (165-315) Waldenström's 6 5 (0) 0 5 232 (152-321) DLBCL 2 0 (0) 1 1 159 FL 1 0 (0) 1 1 194 MZL 1 0 (0) 1 1 138 HCL 1 1 (0) 0 1 285 Conclusions: These preliminary Phase 1 results suggest that the selective BTK inhibitor BGB-3111 is safe and highly clinically active. Complete blockade of BTK in PBMC at low doses and excellent tolerability at higher doses raises the possibility that BTK blockade in deep tissue sites will be complete. This question is currently being explored in the expansion phase. Figure 1. Best response in 22 pts evaluated by CT scan (SPD, CLL and NHL) or IgM levels (WM). Not included here are 1 responder with HCL (PR), and 2 pts who progressed before restaging. Figure 1. Best response in 22 pts evaluated by CT scan (SPD, CLL and NHL) or IgM levels (WM). Not included here are 1 responder with HCL (PR), and 2 pts who progressed before restaging. Disclosures Tam: Janssen: Consultancy, Honoraria, Research Funding. Off Label Use: BGB-3111 is not licensed for treatment of B-cell malignancies. Grigg:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Opat:Janssen Pharmaceuticals: Other: Provision of subsidized medications only. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hedrick:Beigene: Employment. Yang:Beigene: Employment, Equity Ownership. Wang:Beigene: Employment, Equity Ownership. Luo:Beigene: Employment, Equity Ownership. Xue:Beigene: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; AbbVie: Research Funding; Servier: Research Funding; Genentech: Research Funding.