Barnes, Jeffrey A.

Abstract Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post–CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell–associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

Introduction CD19-directed CAR T-cell therapies are an important option for the management of relapsed/refractory (R/R) DLBCL. Studies suggest that ~50% of pts receiving CAR T-cell therapies will relapse within 6 months, with an estimated overall survival (OS) of only 5 months. Additionally, 25-35% of pts do not receive subsequent treatment, indicating a high unmet need. CD19 loss is a potential mechanism of resistance to CAR T-cell therapies; thus, treatments that target alternate B-cell antigens are an attractive option. Here, we report for the first time the primary analysis of the ELM-1 expansion cohort investigating the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in pts with R/R DLBCL progressing after CAR T-cell therapy (NCT02290951). Methods Pts aged ≥18 with DLBCL and disease progression after CAR T-cell therapy received intravenous odronextamab weekly in 21-day (D) cycles during Cycles (C) 1-4, with steroid prophylaxis and step-up dosing in C1 (described previously), followed by 160 mg on D 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg Q2W until disease progression or unacceptable toxicity. Pts with complete response (CR) for ≥9 months transitioned to Q4W dosing. All pts received infection prophylaxis. The primary analysis was conducted when all pts had completed ≥9 months of follow-up. Primary endpoint was objective response rate (ORR), as assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and OS. Exploratory endpoints included immune biomarker assessment. Results As of January 22, 2024, 60 pts were treated and evaluable for efficacy and safety, with median follow-up of 16.2 months. Prior CAR T-cell therapies were axi-cel (50%), tisa-cel (12%), liso-cel (10%), and not specified (28%). Median time since prior CAR T-cell therapy was 6.5 months (range 1.2-46.2). Median age was 63 years (range 27-82; aged ≥75 years: 10%), and 65% were male. Pts had received a median of 3 prior lines of therapies (range 2-9); 77% of pts were refractory to their last therapy, 77% were double refractory, and 72% were refractory to prior CAR T-cell therapy. 48% of pts relapsed within 90 D of CAR T-cell therapy, and 67% relapsed within 180 D. Of the 20 pts with available tumor biopsies at baseline, 10 were CD19(-) and only 2 were CD20(-). 92% of pts completed C1 and 52% completed ≥4 C of treatment. The median duration of treatment was 12 weeks (range 0.7-154.1). The ORR and CR rate by ICR were 48% and 32%, respectively, and were consistent across pts with high-risk features and across prior CAR T products. ORR in pts relapsing in ≤90 D was 21% (6/29) and in pts relapsing in ≤180 D was 33% (13/40). ORR was observed even in pts with low CD20. Median DOR was 14.8 months (95% CI 2.8-not estimable [NE]) and median duration of CR was not reached (NR) (95% CI 3.3-NE); the probability of maintaining CR for 24 months was 68%. Median PFS was 4.8 months (95% CI 2.6-5.4) and median OS was 10.2 months (95% CI 4.6-15.8). Median PFS and OS in complete responders was NR. T-cell counts increased at Week 14 and demonstrated a functional phenotype (CD69 expression and TEMRA count), which was confirmed by ex vivo stimulation. T-cell expansion was observed regardless of CAR T product or time from CAR T administration. The most common TEAE was CRS (any grade [G]: 48%; G1: 25%; G2: 23%; G≥3: 0%). G≥3 TEAEs occurred in 77% of pts (most common: neutropenia 17%, anemia 13%, and neutrophil and white blood cell count decrease 10% each). Five pts (8%) permanently discontinued odronextamab due to AEs (COVID-19, pneumonia, encephalopathy, epilepsy, and gait disturbance [n=1 each]). There was one treatment-related death (COVID-19 pneumonia). No cases of ICANS were reported. G≥3 infections occurred in 12 pts (20%); 2 were due to COVID-19. No cases of tumor flare or TLS were reported. Conclusions ELM-1 is the only study to prospectively evaluate efficacy and safety of a CD20×CD3 bispecific antibody in pts with R/R DLBCL progressing after CAR T-cell therapy. Odronextamab monotherapy was associated with encouraging efficacy and generally manageable safety in a setting with limited treatment options and historically dismal outcomes. Efficacy was observed even in pts relapsing in ≤90 D, supporting the potential of odronextamab as an accessible, off-the-shelf option in the post-CAR T setting.

Background Chimeric antigen receptor (CAR) T-cell therapies have recently been established as an important option for the management of relapsed/refractory (R/R) DLBCL. However, real-world studies suggest that approximately half of all patients (pts) receiving commercial CAR-T therapies will relapse within 6 months. These pts have a poor prognosis, with estimated overall survival (OS) of only 5 months, indicating a significant unmet need. Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated activity in both R/R follicular lymphoma and R/R DLBCL. We have previously reported encouraging results with odronextamab from the Phase 1 ELM-1 study (NCT02290951) in pts with R/R DLBCL post CAR-T therapy (Bannerji R, et al. Lancet Haematol. 2022). These results were consistent with the antitumor activity seen in pts with R/R DLBCL from the Phase 2 ELM-2 study (Kim WS, et al. ASH 2022). Here, we present an updated analysis of outcomes in a prespecified cohort of post CAR-T patients from ELM-1. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Revisions to the step-up regimen were reported previously (Bannerji R, et al. Lancet Haematol. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 160 mg on Days (D) 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Those pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing with 320 mg every 4 weeks. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DoR), progression-free survival (PFS), and OS. Immune biomarker assessment was an exploratory endpoint. Results As of Dec 20, 2022, 46 pts were treated (safety-evaluable), with 44 pts evaluable for efficacy. For safety-evaluable pts, median age was 63 years (range 27-82), 67% male, 74% Ann Arbor stage III-IV, and 72% were refractory to CAR-T therapy administered in any prior line. 44 pts were evaluable for efficacy after 4.9 months median duration of follow-up. The ORR and CR rate by ICR were 48% (21/44) and 30% (13/44), respectively. Responses were durable, and both median DoR and median duration of CR were not reached. The probability of maintaining a response for 12 months was 62% and the probability of maintaining a CR for 9 months was 86%.A responder analysis of the subgroup of pts who achieved a CR will be presented. The CAR-T treated pts with DLBCL who were evaluable for biomarker analysis (n=10) had lower T-cell counts at baseline compared with CAR-T naive DLBCL pts (n=41 comparable pts who received odronextamab in ELM-2), yet the fold-change of T-cell expansion at C4D15 was greater in CAR-T treated pts versus CAR-T naive pts. T-cell dynamics, such as changes in activation, exhaustion, and memory subsets, will be presented. Safety was generally consistent with that previously reported. Six (13%) pts permanently discontinued odronextamab due to a treatment-emergent AE (device-related infection, pneumonia, dysphagia, gait disturbance, leukemia, and encephalopathy [n=1 each]). The most common treatment-emergent AE was CRS (any grade, 52%). The highest grade of CRS reported was Grade 2, and low-grade CRS events occurred in 46% of pts with the 0.7/4/20 mg step-up regimen. No cases of ICANS were reported in pts with the 0.7/4/20 mg regimen. Grade ≥3 infections occurred in 10 (22%) pts, with no Grade 5 events. No cases of tumor flare were reported. Conclusions Odronextamab monotherapy demonstrates encouraging antitumor activity in heavily pretreated pts who have progressed after CAR-T therapy, with a generally manageable safety profile. Durable CRs were achieved in this difficult-to-treat setting. These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase–positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase–negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. Dose escalation is complete and a recommended Ph 2 dose has been determined. We report Ph 1 safety and efficacy results of REGN1979 in patients (pts) with R/R B-NHL previously treated with anti-CD20 Abs, including pts with progressive disease after anti-CD19 CAR T-cell (CAR T) therapy. Methods Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total). Results As of June 3, 2019, 96 pts (diffuse large cell B-cell lymphoma [DLBCL] [n=53], follicular lymphoma [FL] grade [Gr] 1-3a [n=25], mantle cell lymphoma [n=6], marginal zone lymphoma [n=6], or other [FL Gr 3b, FL unknown, FL ungraded, or Waldenström macroglobulinemia ] [n=6]) were treated with REGN1979 0.03-320 mg and received a median of 9 doses (range 1-24). Pts had a median of 3 prior lines of therapy (range 1-11); 12 pts with prior CAR T therapy were included in the safety analysis of which 6 were included in the efficacy analysis. Twenty-four pts remain on treatment; 18 completed treatment; 54 discontinued early (35 due to progressive disease [PD]). No pts with B-NHL experienced a DLT. The most common treatment-emergent adverse events (AEs) were pyrexia (n=74), CRS (n=55), chills (n=49), infections and infestations (n=47), fatigue (n=36), increased C-reactive protein (n=32), and anemia (n=32). Seven pts experienced Gr 3 CRS. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Most common Gr 3 or 4 AEs were anemia (n=19), decreased lymphocytes/lymphopenia (n=19), infections and infestations (n=18), decreased neutrophils/neutropenia (n=17), and hypophosphatemia/decreased blood phosphorus (n=16). No pts had seizures or grade 4/5 neurologic AEs. Gr 3 neurologic AEs included depressed level of consciousness (unrelated), somnolence, and syncope (n=1 each). Neurological events were transient and none required permanent treatment termination. Five pts discontinued due to AEs: Gr 3 hemolysis; Gr 3 fatigue; Gr 2 and Gr 3 pneumonia; and Gr 3 neck abscess (1 each). Eleven pts died on study: PD (n=6), gastric perforation (n=1), cardiac arrest (n=1), lung infection (n=1), multi-organ failure (n=1), pneumonia (n=1). The Table and Figure show efficacy and duration of response for R/R DLBCL by dose level. Pts who had opportunity for response assessment at Week 12 were included in the analysis of response. Emerging data suggest increasing efficacy with higher doses in R/R DLBCL, with 5 of 8 pts treated at 80/160/320 mg achieving CR; at these doses 2 of 3 pts achieved CR after failure of CAR T therapy. Data also suggest increasing efficacy with increasing doses in R/R FL, but maximum efficacy appears to be achieved at lower doses than in DLBCL; in pts with FL Gr 1-3a treated at ≥5 mg, the ORR was 93% (13/14), and the CR rate was 71.4% (10/14). REGN1979 concentrations in serum increased linearly with dose during the first five weeks. Elevated levels of serum cytokines were observed, mostly in week 1, and no correlation was observed with clinical efficacy. Immunohistological analysis of malignant lymph node tissue demonstrated that pts with high and low CD20 expression achieved clinical response. Relapse among responders was seen with either maintenance or loss of CD20 expression, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions/Summary Tolerability of REGN1979 has been demonstrated at doses up to the final dose level of 320 mg weekly, with no observed DLTs in pts with B-NHL. No pts discontinued due to neurologic AE. Activity was observed broadly in heavily pretreated R/R B-NHL pts treated with REGN1979. With increasing dose, more resistant tumors such as R/R DLBCL are showing benefit, even in pts with prior CAR T therapy failure. Based on these efficacy findings, a global Ph 2 study is underway to evaluate REGN1979 monotherapy in R/R FL Gr 1-3a, R/R DLBCL, and other R/R B-NHL subtypes. Disclosures Bannerji: AbbVie, Inc: Consultancy, travel support; Gilead: Other: travel support; Gilead: Other: travel support; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Celgene: Consultancy; Celgene: Consultancy; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support. Allan:Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Arnason:Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Brown:AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Invectys: Other: other; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Kite: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharma: Research Funding; Janssen: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Regeneron: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment. O'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Martin:I-MAB: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhu:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ibrahim:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Aina:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Deering:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Murphy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinreich:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The data described in the abstract will report on use REGN1979 in a Phase 1 clinical trial of patients with B-NHL.

Abstract Introduction: REGN1979 is a hinge-stabilized CD20xCD3bispecific full-length antibody (Ab) based on an IgG4isotype modified to reduce Fc binding. It is designed to bind T cells (via CD3) and CD20-expressing cells. Cross-linking results in specific, local T cell activation and engagement ofcytolytic functions, independent of T cell receptor mediated recognition. This mechanism of action (MOA) is distinct from approved anti-CD20 Abs, and may provide additional therapeutic benefit. This report describes safety and clinical outcomes in 25 patients (pts) treated with REGN1979. Methods: The study uses a 3+3 design to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and activity of REGN1979 inpts with NHL and CLL, in separate dose escalation cohorts. REGN1979 is administered IV over 1-4 hours, weekly (QW) for 4 doses followed by every 4 weeks (Q4W) for 5 doses. Each dose level (DL) consists of an initial starting dose followed by a higher (step-up) dose.Pts with either progressive disease (PD) after initial response or suboptimal initial response could be retreated. Results: As of clinical cut-off, 25pts had been enrolled and treated with REGN1979 at flat doses ranging from 0.03 - 3.0 mg: 20pts with NHLand 5pts with CLL. NHL subtypes included DLBCL (n=12), FL (n=6), and MCL (n=2). Allpts hada medianof3 (range 1-7) prior regimens, and received a median of 5 (range 2-9) doses of REGN1979. Sixpts remained on initial treatment, 3pts completed treatment, and 16pts discontinued treatment (14 for PD; 2 subject decision). Of 4pts who entered retreatment, 2pts remained ongoing. The most common treatment-related treatment-emergent AEs (TR-TEAEs) were pyrexia (56%), infusionrelated reaction (IRR) (40%), chills (36%), cytokine release syndrome (CRS) (28%), fatigue (24%), tachycardia (24%), hypomagnesaemia (20%) and hypotension (20%). Grade >= 3 TR-TEAEs occurred in 8 pts(32%): IRR (12%), CRS (8%), hypotension (8%), and pyrexia, tachycardia, dyspnea, anemia, hypoxia, hypertension, tachypnea, transaminases increased, and tumor pain each in 1 pt(4%). All were grade 3 with the exception of 1 ptwith grade 4 hypotension. There were no protocol-defined DLTs, nor grade 5 TEAE. No ptsdiscontinued REGN1979 due to TR-TEAE. IRR and CRS events were most commonly reported with the first administration of both initial and step-up dose with incidence and severity decreasing with increasing exposure. Tenptsreported at least one TR-SAE: CRS (24%), IRR (20%), and increased AST and tumor pain, each in 1pt(4%). Threeptswith aggressive lymphoma who discontinued REGN1979 due to PD died of their disease within 30 days of their last dose. Notably, modifications to pre-medication(s) and drug administration instructions have improved tolerability (fewer and less severe IRR/CRS). No clinically significant CNS TEAEs have been observed. CT-based (Cheson, 2007) anti-tumor activity was observed in 11 ptswith NHL: PR [n=4,median duration of 50d];SD [n=7, median duration of >196d]. The overall response rate (ORR) in NHL ptsacross DLs was 20%. In 2 highest dose levels, ORR was 27% (Fig 1). Of the 14pts evaluated by PET, 4pts had a partial metabolic response, withmedian duration of 244d perLugano Criteria. Twopts with CLL attained SD as best overall response. PK: REGN1979 concentrations in serum increased with increasing DL and were variable across pts. Variability was less at higher DLs and also decreased over time during therapy. At DLs tested, REGN1979 concentrations did not notably increase over time during treatment. PD/Cytokines: At the lowest dose tested, 0.03 mg, transient B-cell depletion was observed inpts with measurable circulating B cells.Samples from 12pts were available for cytokine analysis. Interim analysis indicates REGN1979 induces cytokine release as expected based on MOA. An increase in IL-6, IL-10 and to lesser extent IFN-γ was observed. The magnitude of cytokine response generally correlated with symptomatic IRR/CRS. Conclusion: REGN1979 demonstrated an acceptable safety profile at flat doses of 0.03 - 3.0 mg (< 1% of rituximab dose) inpts with NHL and CLL. Most TEAEs were associated with IRR/CRS, and were managed with supportive therapy and modification to REGN1979 administration. No clinically significant neurological toxicity was observed. Preliminary antitumor activity demonstrates increased activity at higher doses. Dose escalation and treatment schedule optimization continue. Disclosures Brown: Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy. Arnason:Gilead: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Chavez:Janssen: Speakers Bureau. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy; Pfizer: Consultancy, Other: Travel. Adriaens:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Kostic:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Paccaly:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Gao:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Trail:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Brownstein:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership.

Abstract Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. We report updated promising efficacy results of a Phase 1 trial of REGN1979 in patients (pts) with relapsed/refactory (R/R) B-NHL previously treated with anti-CD20 Abs. Methods The primary objectives of the study are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives include assessment of preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R NHL must have received at least 1 prior CD20-directed therapy. Treatment consists of 12 weekly doses of REGN1979 followed by every 2 week dosing for 12 doses for a total of 36 weeks. Guidelines are provided for management of cytokine release syndrome (CRS) and include steroids and/or tocilizumab at investigator discretion. Results As of June 1, 2018, 54 pts with B-NHL were treated with REGN1979 monotherapy: DLBCL (pt number [n]=30), FL (n=16), MCL (n=5), MZL (n=2), and WM (n=1). The median number of prior regimens was 3 (range, 1-11); 41 pts were refractory to their last prior systemic therapy, 18 had bulky disease, and 6 had prior HSCT. Pts were treated with REGN1979 0.03-27 mg and received a median of 7 (range, 1-24) doses. Eight pts remain on treatment, 13 completed treatment, and 33 discontinued therapy prior to the planned 36 wks (majority [n=22] due to progressive disease [PD]). There have been no DLTs to date. The most common treatment-related treatment-emergent adverse events (TR-TEAEs) included infusion-related reactions (IRR) or CRS; 26 pts experienced CRS (Grade 1-2, n=23; Grade 3, n=3) with a median duration of CRS of 2 (range 1-15) days. Six pts received tocilizumab. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Other common Grade ≥3 TR-TEAEs were lymphocytopenia/ decreased lymphocyte count (n=8); neutropenia/ decreased neutrophil count (n=7); and thrombocytopenia/ decreased platelet count, hypotension, hypophosphatemia, and anemia (each n=3). Seventeen pts experienced a nervous system event including headache, dizziness, paraesthesia, dysgeusia, and peripheral neuropathy with no Grade ≥3 events; no neurologic event required termination of study drug. Seven pts died on study: PD (n=5), gastric perforation (n=1), and cardiac arrest (n=1). TEAEs leading to premature discontinuation of REGN1979 were Grade 3 fatigue (n=1), Grade 3 hemolysis (n=1), and Grade 2 pyrexia/Grade 2 tachycardia (n=1). Among 27 pts treated with REGN1979 ≥5 mg (dose associated with tumor killing in pre-clinical data), the overall response rate (ORR) was 55.6% (5 complete response [CR] and 10 partial response [PR]; Table/Figure). Responses were seen in 7/7 FL Grade 1-3a pts (5 CR, 2 PR), 6/15 DLBCL pts (all PR), 2/2 MCL pts (all PR). At 18 mg and 27 mg of REGN1979, 4 of 4 pts with DLBCL had best response of PR. Post data cut-off, 1 pt with a DLBCL best response of PR converted to CR. PK and pharmacodynamic assessments suggest that for pts treated with REGN1979 5-18 mg, best exposures in the first 3 weeks appear to linearly increase with dose. In pts treated with up to REGN1979 18 mg, a maximum mean Ctrough of 1.6 mcg/mL was observed in the first 3 weeks of weekly dosing. Studies of peripheral blood biomarkers demonstrated depletion of peripheral B lymphocytes, transient margination of circulating T-cells, and elevated circulating cytokines following REGN1979 dosing. Increased peak cytokine levels (IL-6, IL-10, and TNF-alpha) were observed in pts with CRS. Immunohistological analysis of malignant lymph node tissue demonstrated a decrease of CD20 expression in responding pts; among the responders, subsequent relapse was associated with either maintenance of CD20 expression or further CD20 loss, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions REGN1979 displays efficacy and an acceptable safety profile in pts with R/R B-NHL. Most TR-TEAEs were IRR/CRS and have been well managed with supportive care. No significant neurological toxicity has been observed. At doses of 5-27 mg of REGN1979, the preliminary ORR was 100% in pts with FL Grade 1-3a and 40.0% in pts with DLBCL. This promising efficacy warrants further clinical investigation. Disclosures Bannerji: Regeneron Pharmaceuticals, Inc.: Consultancy; AbbVie, Inc.: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Millenium: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Kura: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role. Brown:Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Abbvie: Consultancy; Gilead: Consultancy, Research Funding; Sun Pharmaceutical Industries: Research Funding; Sunesis: Consultancy; Loxo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Invectys: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Boehringer: Consultancy. Allan:Genentech: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. O'Brien:Kite Pharma: Research Funding; Aptose Biosciences Inc.: Consultancy; Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Sunesis: Consultancy, Research Funding; Alexion: Consultancy; Amgen: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Chavez:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen: Consultancy. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Navarro:Regeneron Pharmaceuticals, Inc.: Employment. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding.