Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3–4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359.

Purpose We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. Patients and methods Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression‐free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). Results About 1227 patients were included. The 7‐year OS was 84.3% (95% CI 80.8‐87.2) for ABVD vs 87.7% (95% CI 84.5‐90.2) for BEACOPP. Two follow‐up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP = 1.59; 95% CI 1.09‐2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7‐year PFS was 71.1% (95% CI 67.1‐74.6) for ABVD vs 81.1% (95% CI 77.5‐84.2) for BEACOPP (P < .001). After ABVD, 25 secondary cancers (4.0%) were reported with no myelodysplasia (MDS)/acute myeloid leukemia (AML) compared to 36 (6.5%) after BEACOPP, which included 13 patients with MDS/AML. Following ABVD, 86 patients (13.8%) received ASCT vs 39 (6.4%) for BEACOPP. Conclusions This analysis showed a slight improvement in OS for BEACOPP and confirmed a PFS benefit. Frontline use of BEACOPP instead of ABVD increased secondary leukemia incidence but halved the requirement for ASCT.

Introduction: Treatment options are limited in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Combined therapy using agents with different mechanisms of action, such as an antibody-drug conjugate (ADC) with an inhibitor of Bruton's tyrosine kinase (BTK), may improve therapeutic outcomes. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an ADC comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, approved for the treatment of patients with R/R DLBCL after ≥2 lines of prior systemic therapy. Ibrutinib, a small-molecule inhibitor of BTK, has shown antitumor activity - particularly as a combination treatment - in patients with R/R DLBCL (Depaus et al, abstract 2099, ASH Dec 5-8, 2020). Here, we present the results of a planned interim analysis in patients with DLBCL (irrespective of cell of origin), non-germinal center B-cell-like DLBCL (non-GCB DLBCL), and GCB DLBCL. Methods: In this ongoing, Phase 2, open-label, single-arm study, patients aged ≥18 years with R/R DLBCL, measurable disease (per 2014 Lugano classification), and ECOG performance status 0-2 were enrolled. Patients were treated with Lonca 60 μg/kg once every 3 weeks for 2 cycles (patients who had a complete response [CR], partial response [PR], or stable disease were permitted to have an additional Lonca dose at Day 1 of Cycles 5, 6, 9, and 10), plus ibrutinib 560 mg/day taken orally for up to 1 year. The primary objective of the study was to evaluate the complete response rate (CRR) achieved with Lonca plus ibrutinib in patients with R/R non-GCB DLBCL (cell of origin, as determined by the investigator), assessed by central review. A Simon's 2-stage design was used in this study with a planned interim analysis conducted when the 22nd patient in the non-GCB DLBCL cohort had 2 tumor assessments. The objective of this planned interim analysis was to determine if CRR in the non-GCB DLBCL cohort warranted continuation of patient enrollment for study completion; if ≥6 patients achieved a CR the study was planned to proceed to the next stage. Thirteen patients with GCB DLBCL who met the defined cut-off for the interim analysis were also included in the dataset. Results: As of April 21, 2021, 35, 22, and 13 patients with DLBCL overall, non-GCB DLBCL, and GCB DLBCL, respectively, were included in the planned interim analysis. In the overall DLBCL cohort, patients had a median age of 72 years (range 19-82) and had received a median of 3 prior therapies (range 1-6), including stem cell transplant. Patients in the overall DLBCL cohort received a median of 2 (range 1-6) cycles of Lonca and 4 (range 1-10) cycles of ibrutinib. CRRs among the planned interim analysis population were 34.3% (12/35; 95% CI: 19.1-52.2), 27.3% (6/22; 95% CI: 10.7-50.2), and 46.2% (6/13; 95% CI: 19.2-74.9) in the overall DLBCL cohort, non-GCB DLBCL cohort, and GCB DLBCL cohort, respectively. ORR (CR + PR) was 57.1% (20/35; 95% CI: 39.4-73.7) in the overall DLBCL cohort, and 45.5% (10/22; 95% CI: 24.4-67.8) and 76.9% (10/13; 95% CI: 46.2-95.0) in the non-GCB DLBCL and GCB DLBCL cohorts, respectively (Figure 1). Median (95% CI) duration of response in the overall DLBCL cohort was 5.49 (5.49-not reached) months and was not reached in the non-GCB DLBCL or GCB DLBCL cohorts. In the overall DLBCL cohort, non-GCB DLBCL cohort, and GCB DLBCL cohort, 32 (91.4%), 21 (95.5%), and 11 (84.6%) patients, respectively, had at least 1 treatment-emergent adverse event (TEAE). In total, 16 (45.7%) patients in the overall DLBCL cohort (15 [68.2%] with non-GCB DLBCL; 1 [7.7%] with GCB DLBCL) had Grade ≥3 TEAEs; the most common (≥10%) were neutropenia in 7 (20%) patients and thrombocytopenia in 4 (11.4%) patients. Overall, 17 (48.6%) patients had TEAEs leading to dose reduction, delay, or interruption. TEAEs leading to treatment discontinuation occurred in 8 (22.9%) patients. Conclusions: At the doses tested, treatment with Lonca plus ibrutinib showed encouraging anti-tumor activity and a manageable safety profile in patients with R/R DLBCL. The study protocol will be amended to investigate whether Lonca given at each cycle in combination with ibrutinib improves efficacy outcomes in patients with R/R DLBCL. Funding: ADC Therapeutics SA (NCT03684694). Figure 1 Figure 1. Disclosures Carlo-Stella: AstraZeneca: Honoraria; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Janakiram: FATE Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Kyowa Kirin Therapeutics: Honoraria; ADC Therapeutics: Research Funding. Dia: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company. He: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company; State University of New York Research Foundation: Current Employment. Ervin-Haynes: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company. Depaus: Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Ibrutinib is not approved for DLBCL.

The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) remains an area of unmet need. Combination therapy using agents with different mechanisms of action may improve upon therapeutic outcomes. We investigated the combination of loncastuximab tesirine (Lonca; an antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin) with ibrutinib (a small-molecule inhibitor of Bruton's tyrosine kinase). Here we present updated safety and efficacy data from the Phase 1 portion of a Phase 1/2 study (NCT03684694). Methods: The protocol is a dose escalation and dose expansion, open label, single-arm, combination study in patients (≥18 years) with R/R DLBCL or R/R MCL. The primary objectives of Phase 1 are to characterize the safety and tolerability of Lonca plus ibrutinib, and identify the recommended Phase 2 dose and schedule. Secondary objectives include evaluation of antitumor effects. The maximum tolerated dose SUPPLEMENT ABSTRACTS -325 (MTD) was determined during the dose escalation part as Lonca 60 µg/ kg IV every 3 weeks (Q3W) for 2 cycles and oral ibrutinib 560 mg/day po for up to 1 year. After disease assessment at Week 14, patients with partial response or stable disease may receive 2 additional cycles of Lonca every 4 weeks at Cycles 5 and 6. Results: At data cut-off (January 4, 2021), 30 patients with DLBCL (24 with non-germinal center B-cell [non-GCB] DLBCL and 6 with GCB DLBCL) and 7 patients with MCL had received the MTD. Median patient age was 72 years (range 40-91) and 28 (75.7%) had Stage 4 disease. Patients received a median of 2 (range 1-6) prior therapies. Eight (21.6%) patients were primary refractory and 18 (48.6%) were refractory to their last-line of therapy; 24 (64.9%) and 17 (45.9%) had relapsed with first-line and last-line therapy, respectively. Patients received a median of 2 Lonca cycles (range 1-4) and 4 (range 1-14) ibrutinib cycles. Median treatment duration was 105 days (range 18-379). Treatment-emergent adverse events (TEAEs) were reported in 37/37 (100%) patients; most common (≥20%) were thrombocytopenia (11 [29.7%]), anemia (9 [24.3%]), fatigue, diarrhea, and rash (all 8 [21.6%]). Grade ≥3 TEAEs were reported in 24/37 (64.9%) patients; most common (≥5%) were anemia (4 [10.8%]), neutropenia (4 [10.8%]), thrombocytopenia (2 [5.4%]), and fatigue (2 [5.4%]). TEAEs leading to treatment discontinuation occurred in 3 (8.1%) patients.Overall response rate (ORR; in 36 evaluable patients) was 63.9% (36.1% and 27.8% for complete and partial response, respectively).

Complete response rate (CRR; primary endpoint) per 2014Lugano Classification, by central review, will be tested for the intent-to-treat population between treatment arms using the Cochran-Mantel-Haenszel method adjusted for stratification factors from the randomization list. The trial is 99% powered for the primary endpoint assuming a 55% CRR to Lonca and a 15% CRR to idelalisib; the sample size for enrollment (∼150 pts) allows for a robust safety data set. Secondary endpoints include overall response rate (key secondary endpoint); progression-free survival; overall survival; duration of response; incidence and severity of adverse events (AEs) and serious AEs; change from baseline in laboratory values, vital signs, 12-lead electrocardiogram, and Eastern Cooperative Oncology Group performance status; concentration and pharmacokinetic parameters of Lonca total and PBD-conjugated Ab, and unconjugated warhead (SG3199); antidrug Ab titers; and pt-reported outcome (PRO) measures of change from baseline in PROs (by EuroQol-5 Dimensions-5 Levels and Functional Assessment of Cancer Therapy-Lymphoma) and, incidence, severity, and interference of specific symptomatic AEs from the PROs version of the Common Terminology Criteria for AEs.EA -previously submitted to EHA 2021.