naratuximab emtansine (DEBIO 1562) / Debiopharm, AbbVie - LARVOL DELTA

PI3Kδ activation, IL6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas. (PubMed, Blood Adv) - "Anti-IL6 antibody tocilizumab improved the ADC's cytotoxic activity in CD37+ cells...Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved the cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous anti-tumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or R-CHOP resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3Kδ, and BCL2."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • BCL2 • CD37 • IL6 • MCL1 • MYC • PIK3CD • TP53

CD37 in acute myeloid leukemia: a novel surface target for drug delivery. (PubMed, Blood Adv) - "Our work revealed that the clinically relevant anti-CD37 antibody drug conjugate (ADC) Debio 1562 (αCD37-DM1) is highly cytotoxic to AML blasts, but not normal hematopoietic stem cells. We found that αCD37-DM1 improved clinical outcomes and overall survival in multiple in vivo models of AML. Together, these data demonstrate that targeting CD37 with an ADC such as αCD37-DM1 is a feasible and promising therapeutic option for the treatment of AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD37

[PREPRINT] PI3Kδ activation, IL6 over-expression, and CD37 loss cause resistance to the targeting of CD37-positive lymphomas with the antibody-drug conjugate naratuximab emtansine (bioRxiv) - "The anti-tumor activity of naratuximab emtansine was tested in 54 lymphoma cell lines alongside its free payload. The median IC50 of naratuximab emtansine was 780 pM, and the activity, primarily cytotoxic, was more potent in B than in T cell lymphoma cell lines. In the subgroup of cell lines derived from B cell lymphoma, there was some correlation between sensitivity to DM1 and sensitivity to naratuximab emtansine (r=0.28, P = 0.06). After prolonged exposure to the ADC, one diffuse large B cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the biallelic loss of the CD37 gene. After CD37 loss, we also observed upregulation of IL6 (IL-6) and other transcripts from MYD88/IL6-signaling...In a second model, resistance was sustained by an activating mutation in the PIK3CD gene, associated with increased sensitivity to PI3Kδ inhibition and a switch from functional dependence on the anti-apoptotic protein MCL1 to reliance on BCL2."

Preclinical • Preprint • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Predicting response to naratuximab emtansine, an anti-CD37 antibody-drug conjugate (ADC), in combination with rituximab in diffuse large B-cell lymphoma (DLBCL), by analyzing the spatial arrangement of CD37 and CD20 positive cells using deep learning. (ASCO 2022) - P2 | "DL analysis of the co-expression and spatial arrangement of CD37 and CD20 in pre-treatment biopsies of DLBCL patients could potentially be used as a predictive biomarker for a response to a combination treatment of anti-CD37 and anti-CD20 drugs in DLBCL, and may improve patient stratification for further clinical trials."

Combination therapy • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

Predicting response to naratuximab emtansine, an anti-CD37 antibody-drug conjugate (ADC), in combination with rituximab in Diffuse Large B Cell Lymphoma (DLBCL), by analyzing the spatial arrangement of CD37 and CD20 positive cells using deep learning (AACR-NCI-EORTC 2022) - P2 | "DL analysis of the co-expression and spatial arrangement of CD37 and CD20 positive cells in pre-treatment biopsies of DLBCL patients could potentially be used as a predictive biomarker for a response to a combination treatment of naratuximab emtansine and rituximab in DLBCL, and may improve patient stratification for further clinical trials."

Combination therapy • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

[VIRTUAL] SAFETY AND EFFICACY OF CD37-TARGETING NARATUXIMAB EMTANSINE PLUS RITUXIMAB IN DIFFUSE LARGE B-CELL LYMPHOMA AND OTHER NON-HODGKIN’S B-CELL LYMPHOMAS – A PHASE 2 STUDY (EHA 2021) - P2 | "Conclusion The combination of nara + RTX resulted in good OR and CR rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, nara + RTX could be considered an attractive option for the treatment of R/R DLBCL."

Clinical • Late-breaking abstract • P2 data • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Hepatology • Inflammation • Leukopenia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pain • Thrombocytopenia • Transplantation

B-Cell Targeting Anti-CD37 Humanized Antibodies Engineered for Potent Effector Functions and Extended Plasma Half-Life (ASH 2022) - "Of note, the anti-CD37 antibody-drug conjugates (ADC) naratuximab emtansine and the CD37-targeting radioimmunotherapy (RIT) Betalutin have shown efficacy in NHL patients during clinical testing... The humanized anti-CD37 candidates were characterized in vitro and in vivo and benchmarked against the anti-CD20 antibodies approved for NHL treatment, rituximab and obinutuzumab, and a recombinant version of the bi-paratopic anti-CD37 antibody DuoHexaBody-CD37, currently in Phase I clinical development... Taken together, the humanized and Fc-engineered anti-CD37 antibodies show potent effector functions, favorable pharmacokinetic properties and in vivo therapeutic efficacy. As such, the designed CD37 antibodies should be attractive modalities in targeted treatment of B cell malignancies, such as NHL, including lymphomas non-responding to anti-CD20 treatments, but also potentially for B-cell driven autoimmune disorders."

IO biomarker • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Safety and Efficacy of CD37-Targeting Naratuximab Emtansine PLUS Rituximab in Diffuse Large B-Cell Lymphoma and Other NON-Hodgkin’S B-Cell Lymphomas – a Phase 2 Study (ASH 2021) - P2 | "The combination of nara + RTX resulted in good OR and CR rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, nara + RTX could be considered an attractive option for the treatment of R/R B-NHL. The treatment was well tolerated and contributed to the pts’ well-being, as demonstrated by the QoL results."

Clinical • P2 data • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukopenia • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • Transplantation

Nucleai to Publish Pathology-based Data at ASCO 2022 for Phase 2 Research of the Most Common Type of Non-Hodgkin’s Lymphoma (Businesswire) - P2 | N=100 | NCT02564744 | Sponsor: Debiopharm International SA | "Nucleai...today announced that it will share new data at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting in an online publication on an exploratory analysis of a phase 2 study to find new pathology-based predictive biomarkers for DLBCL, the most common type of Non-Hodgkin’s lymphoma....Up to 40% of patients with DLBCL, which accounts for 30-40% of cases, have relapsed and/or refractory (R/R) disease, despite recent improvements in response and survival with standard of care treatment."

P2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] Safety and Efficacy of CD37-Targeting Naratuximab Emtansine plus Rituximab in Diffuse Large B-cell Lymphoma and other Non-Hodgkin’s B-cell Lymphomas – a Phase 2 Study (ICML 2021) - P2 | "The combination of nara with RTX was well tolerated, with a manageable safety profile of expected, mainly hematological AEs. A preliminary analysis shows promising efficacy. Final data, regimen comparison, and related analyses will be available in the FP."

Clinical • P2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Debio 1562-201: Study to Evaluate the Efficacy and Tolerability Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=101; Completed; Sponsor: Debiopharm International SA; Active, not recruiting ➔ Completed

Trial completion • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Debiopharm's CD37 Antibody Drug Conjugate Shows Promising Phase II Results for the Treatment of B-Cell Malignancies (PRNewswire) - P2, N=101; NCT02564744; Sponsor: Debiopharm International SA; "Debiopharm...announced the phase II results assessing naratuximab emtansine...for the treatment of DLBCL and other B-cell malignancies. EHA late breaking abstract results presented on June 12th, revealed meaningful efficacy and high complete response rates (CRR), especially in heavily pre-treated patients with ≥2 prior lines of treatment, in combination with rituximab. Objective Response Rate (ORR) in all efficacy-evaluable patients (N=76) was 44.7%, CRR was 31.6%. In patients with ≥2 prior therapies, non-primary refractory (N=28) ORR was 46.4% and CRR was 32.1%."

Late-breaking abstract • P2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

Study to Evaluate the Efficacy and Tolerability Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=101; Active, not recruiting; Sponsor: Debiopharm International SA; Trial completion date: Jan 2021 ➔ Jun 2021

Clinical • Combination therapy • Trial completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Development of novel preclinical models of secondary resistance to the anti-CD37 antibody drug conjugate (ADC) IMGN529/DEBIO1562 in diffuse large B-cell lymphoma (DLBCL) (AACR 2018) - "We presented two novel DLBCL models of secondary resistance to the anti-CD37 ADC IMGN529/DEBIO1562. These models, apparently driven by different biologic processes, will help in clarifying mechanisms of resistance to the drug and developing combination therapeutic approaches."

Preclinical • Diffuse Large B Cell Lymphoma

Study to Evaluate the Efficacy and Tolerability Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=101; Active, not recruiting; Sponsor: Debiopharm International SA; N=75 ➔ 101; Trial completion date: Apr 2022 ➔ Jan 2021; Trial primary completion date: Oct 2020 ➔ Jan 2021

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Study to Evaluate the Efficacy and Tolerability Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=75; Active, not recruiting; Sponsor: Debiopharm International SA; Trial primary completion date: Jun 2020 ➔ Oct 2020

Clinical • Combination therapy • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

ImmunoGen reports second quarter fiscal year 2016 financial results and provides corporate update (Immunogen Press Release) - "[Immunogen]...intends to present initial biomarker data from [the 20-patient Phase 1 expansion cohort for mirvetuximab soravtansine] at a medical meeting in 2Q2016 in addition to reporting mature data from the 40-patient Phase 1 cohort in this disease at the meeting....Patient enrollment in a Phase 2 trial assessing IMGN529 in combination with rituximab is expected to begin early this year. Enrollment in a Phase 2 trial assessing coltuximab ravtansine in a different combination regimen is expected to begin in 2H2016....ImmunoGen is preparing to initiate Phase 1 testing of IMGN779 for the treatment of acute myeloid leukemia in 1H2016."

Anticipated conference • Anticipated enrollment status • Anticipated new P1 trial • Anticipated P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

ImmunoGen, Inc. announces 2015 outlook for product pipeline (Immunogen Press Release) - "Expected 2015 events [for IMGN529] include selection of recommended P2 dose in 1H 2015, start of initial efficacy testing, including as a treatment for relapsed/refractory DLBCL and for CLL in 2Q/3Q 2015 and presentation of updated clinical data in 2H 2015....2015 expectations [for IMGN289 include initiation of a] dose-finding P1 clinical testing for the treatment of EGFR-positive solid tumors....[Anticipated] Submission of Investigational New Drug Application (IND) [for IMGN779] 2H 2015."

Anticipated clinical data • Anticipated IND • Anticipated new P1 trial • Pipeline update • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

ImmunoGen, Inc. reports second quarter fiscal year 2012 financial results and provides quarterly update (Immunogen) - Phase II trials are now in process that evaluate SAR3419 as a single agent for DLBCL; in combination with Rituxan for DLBCL & as a single agent for B-ALL; Clinical data are expected to be reported at a mid-year medical conference from the Phase I trial establishing the optimized dosing schedule being used in Phase II

Anticipated P1 data • P2 trial update • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

ImmunoGen, Inc. earns milestone with start of SAR3419 phase II testing (Market Watch) - Immunogen has started P2 testing for SAR3419; Sanofi's Phase 2 testing will focus on treatment for diffuse large B-cell lymphoma and for B-cell acute lymphoblastic lymphoma

P2 trial update • Hematological Malignancies

IMGN529 in Combination With Rituximab in Patients With RR DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=75; Not yet recruiting; Sponsor: ImmunoGen, Inc.

New P2 trial • Biosimilar

Preliminary findings from a phase I, multicenter, open-label study of the anti-CD37 antibody-drug conjugate (ADC), IMGN529, in adult patients with relapsed or refractory non-Hodgkin lymphoma (NHL) (ASCO 2014) - Presentation time: Friday, May 30; 1:00 PM - 4:00 PM; Abstract #8526; P1, N=46; NCT01534715; Sponsor: ImmunoGen; "The protocol was amended to provide peri-infusional steroids as a prophylactic regimen and dose re-escalation is ongoing; 3 patients treated at 0.4 mg/kg have completed C 1 with no DLTs. Clinical trial enrollment is ongoing with additional data expected. Preclinical studies to investigate the mechanism of the transient neutropenia are underway."

P1 data • Non-Hodgkin’s Lymphoma • Oncology

ImmunoGen announces recent product program advancements and anticipated 2016 events in advance of J.P. Morgan Healthcare Conference (Immunogen Press Release) - "Events anticipated in 2016: [1] Advancing Phase 2 combination trial and potentially other program updates for IMGN529; [2] Disclosure of combination regimen to be assessed in 1H2016 and initiation of Phase 2 combination study midyear for coltuximab ravtansine; [3] Initiation of Phase 1 testing [of IMGN779] for the treatment of AML in 1H2016."

Anticipated new P1 trial • Anticipated new P2 trial • Acute Myelogenous Leukemia • Oncology

Study to Evaluate the Efficacy and Tolerability Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=75; Recruiting; Sponsor: Debiopharm International SA; Trial primary completion date: Dec 2017 ➔ Mar 2019

Trial primary completion date • Biosimilar • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Study to Evaluate the Efficacy and Tolerability Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory DLBCL and Other Forms of NHL (clinicaltrials.gov) - P2; N=75; Active, not recruiting; Sponsor: Debiopharm International SA; Recruiting ➔ Active, not recruiting; Trial primary completion date: Feb 2020 ➔ Jun 2020

Clinical • Combination therapy • Enrollment closed • Trial primary completion date