Zynlonta (loncastuximab tesirine-lpyl) / Overland ADCT BioPharma, Mitsubishi Tanabe, SOBI - LARVOL DELTA

proPBD-ADCs: optimization of therapeutic potential of ADCs based on capped PBD payload with attenuated potency (AACR 2025) - "In April 2021, the FDA approved the first PBD-based ADC, the CD19 targeting loncastuximab tesirine, for treatment of adult patients with relapsed or refractory large B-cell lymphoma, including DLBCL, after 2 or more lines of therapy...Complemented by a broad choice of payloads with various mode-of-action (toxSYN® platform), these joint technologies have been applied in multiple clinical programs up to phase 3.Our strategy to optimize the therapeutic potential of PBD-ADCs that incorporate GlycoConnect® and HydraSpace® technology further, is two-fold: (a) apply PBD dimer payload with reduced potency versus common clinical structures and (b) incorporate a pro-drug concept (proPBD-ADC) by shielding the PBD payload by a capping structure that is stable in circulation but at the same time conditionally released by tumor-associated proteases or under reducing conditions.Data from efficacy studies with HER2-proPBD-ADCs in CDX tumor bearing mouse models will be..."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • HER-2

Response to Michelerio et al. regarding "Antibody-drug conjugates: A review of cutaneous adverse effects". (PubMed, J Am Acad Dermatol) - No abstract available

Adverse events • Journal • Oncology

Loncastuximab Tesirine for the Treatment of Relapsed or Refractory B-Cell Malignancies (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: University of Washington | Trial completion date: Jul 2026 ➔ Jul 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

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

Response to Saberi SA et al.'s "Antibody-drug conjugates: A review of cutaneous adverse effects". (PubMed, J Am Acad Dermatol) - No abstract available

Adverse events • Journal • Dermatology • Oncology

LORELY: Study of Loncastuximab Tesirine in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) or High-Grade B-Cell Lymphoma (HGBCL) Following CAR-T Therapy Failure (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Istituto Clinico Humanitas

IO biomarker • New P2 trial • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

EPCOR+LONCA: Epcoritamab in Combination With Loncastuximab Tesirine in Relapsed/Refractory Large B-cell Lymphoma (clinicaltrials.gov) - P2 | N=26 | Not yet recruiting | Sponsor: University of Miami

New P2 trial • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Budget impact of introducing glofitamab for treatment of relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy in the United States. (PubMed, J Med Econ) - "Comparators were axicabtagene ciloleucel (Axi-cel), lisocabtagene maraleucel (Liso-cel), tisagenlecleucel (Tisa-cel), loncastuximab tesirine, polatuzumab vedotin + bendamustine + rituximab, rituximab + gemcitabine + oxaliplatin, tafasitamab + lenalidomide, and epcoritamab (Epcor). Across all sensitivity analyses, the inclusion of glofitamab had minimal PMPM budget impact, ranging from -$0.0256 to -$0.0108. With the lowest 3-year total cost per treated patient among the newer therapies, glofitamab being an available option in the 3L + DLBCL market is estimated to save a hypothetical 1,000,000-member health plan $728,697 in cumulative total costs and $0.0202 in PMPM costs over 3 years."

HEOR • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Review of NICE UK Submissions for Antibody-Drug Conjugates in Oncology (ISPOR 2025) - "All of these ADCs were assessed by NICE from inception to 2024 12 FDA-approved ADCs were identified: Trastuzumab emtansine, Trastuzumab deruxtecan, Sacituzumab govitecan, Inotuzumab ozogamicin, Polatuzumab vedotin, Loncastuximab tesirine, Tisotumab vedotin, Enfortumab vedotin, Mirvetuximab soravtansine-gynx, Belantamab mafodotin-blmf, Gemtuzumab ozogamicin, and Brentuximab vedotin. In conclusion, ADCs have revolutionized cancer treatment with their targeted delivery and significant therapeutic benefits. The evolution of ADCs since 2000 highlights their potential in both refractory and early-stage diseases. Continued advancements in ADC design and technology promise even greater therapeutic efficacy."

NICE • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • Breast Cancer • Cervical Cancer • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

ADC Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Operational Update (PRNewswire) - "Product Revenues: ZYNLONTA reached commercial brand profitability in 2024, generating net product revenues of $16.4 million for the fourth quarter ended December 31, 2024, and $69.3 million for the full year of 2024 as compared to $16.6 million and $69.1 million for the same periods in 2023....Research and Development (R&D) Expense: R&D expense was $27.1 million and $109.6 million for the fourth quarter and full year ended December 31, 2024, respectively. This compares to R&D expense of $30.3 million and $127.1 million for the same periods in 2023."

Commercial • Sales • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Non-Hodgkin’s Lymphoma

Loncastuximab Tesirine Versus Polatuzumab Vedotin Plus Bendamustine and Rituximab in Relapsed/Refractory DLBCL After ≥ 2 Lines of Therapy: Matching-Adjusted Indirect Comparison. (PubMed, Adv Ther) - "These results suggest no evidence of a difference in efficacy between the two treatments and potentially more favorable safety profile for Lonca compared with Pola + BR in patients with R/R DLBCL after two or more lines of treatment."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases

ADC Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Operational Update (PRNewswire) - "Enrollment for the Phase 3 confirmatory trial evaluating ZYNLONTA in combination with rituximab in patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) was completed in December 2024. The Company expects to provide updated data before the end of 2025, once the pre-specified number of progression-free survival (PFS) events is reached....The Company reported positive initial data in December 2024 from the LOTIS-7 Phase 1b open-label clinical trial evaluating the safety and efficacy of ZYNLONTA in combination with the bispecific antibody glofitamab (COLUMVI™) in patients with r/r non-Hodgkin Lymphoma (NHL)....Enrollment of 40 patients in the dose expansion is expected to be completed in the second quarter of 2025. We expect to share data on a subset of patients in the second quarter of 2025 with a fuller, more mature data update anticipated during the second half of 2025."

Enrollment status • P1 data • P3 data • Diffuse Large B Cell Lymphoma • Non-Hodgkin’s Lymphoma

Zynlonta: "12/13 CRs remain in CR as of the data cut-off; Most responses observed at initial assessment, 5 patients converted from SD/PR to CR over time"; Diffuse Large B Cell Lymphoma (ADC Therapeutics) - Guggenheim Securities SMID Cap Biotech Conference

P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Oncology

Sylvester Study Leads to Updated National Guidelines for Follicular Lymphoma Treatment (University of Miami) - "The guidelines were released Feb. 10 by the National Comprehensive Cancer Network (NCCN), a nonprofit alliance of cancer centers. The new guidelines greenlight a combination of two drugs, rituximab and loncastuximab tesirine (Zynlonta), for third-line and subsequent therapy in patients with classic follicular lymphoma....After 12 weeks, the treatment yielded an overall response rate of 97% and a complete response rate of 67%. Some patients continued to improve, leading to a complete response rate of 76.9% at 21 weeks....Based on these data and newer findings from the study, the NCCN listed loncastuximab plus rituximab as an option for patients with follicular lymphoma who have failed two or more lines of previous therapy."

NCCN guideline • Follicular Lymphoma

LOTIS 7: A Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination With Other Anti-cancer Agents in Participants With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS-7) (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: ADC Therapeutics S.A. | Trial completion date: Feb 2026 ➔ Dec 2026 | Trial primary completion date: Feb 2025 ➔ Dec 2025

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

Real-World Effectiveness of Chemoimmunotherapy and Novel Therapies for Patients With Relapsed/Refractory Aggressive Large B-Cell Lymphoma. (PubMed, Clin Lymphoma Myeloma Leuk) - "Patients with r/r LBCL have unfavorable outcomes and need more effective treatment alternatives."

Journal • Real-world evidence • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

LOTIS-9: A Study of Loncastuximab Tesirine and Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Participants With Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - P2 | N=41 | Terminated | Sponsor: ADC Therapeutics S.A. | Completed ➔ Terminated; The benefit-risk profile does not support continuation of the LOTIS-9 trial.

Trial termination • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Loncastuximab Tesirine and Mosunetuzumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P2 | N=36 | Recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Dec 2024 ➔ Apr 2025 | Trial primary completion date: Dec 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma • CD20

Orphan Drug Designations and Approvals (FDA) - Generic Name: loncastuximab tesirine-lpyl, rade Name: Zynlonta, Date Designated: 06/08/2017, Orphan Designation: Treatment of diffuse large B-cell lymphoma, Orphan Designation Status: Designated/Approved

Orphan drug • Diffuse Large B Cell Lymphoma

Understanding how CD19 expression levels impact the response to loncastuximab tesirine: a plain language summary. (PubMed, Future Oncol) - "While Lonca uses the CD19 target to find and destroy cancer cells, Lonca does not require a large amount of CD19 to kill tumor cells. These results mean that Lonca may be an effective treatment for patients with DLBCL, even if CD19 expression in tumors is undetectable by immunohistochemistry."

Biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

LOTIS 5: Study to Evaluate Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P3 | N=440 | Active, not recruiting | Sponsor: ADC Therapeutics S.A. | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

Loncastuximab Tesirine and Rituximab as Bridging Therapy Prior to Standard-of-care CD19 CAR T-cell Therapy in Patients With Large B-cell Lymphoma (clinicaltrials.gov) - P2 | N=29 | Not yet recruiting | Sponsor: University of Utah

New P2 trial • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Loncastuximab Tesirine and Rituximab Following Stereotactic Radiosurgery (SRS) in Patients With Primary and Secondary Central Nervous System Lymphomas (Lonca-R After SRS in CNSL) (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: University of Utah | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Secondary Central Nervous System Lymphoma

Real-World Treatment Patterns of Large B-Cell Lymphoma Patients over Time in a Post-CAR T Approval Era (TCT-ASTCT-CIBMTR 2025) - "Other common regimens in the 2L setting included other chemoimmunotherapy (n = 33; 25.8%), novel therapies (n = 31; 25.0%, including polatuzumab, loncastuximab, tafasitimab, or bispecific-based therapy), and R-ICE/R-DHAP (n = 12; 9.4%). This study suggests a large proportion of potentially eligible CAR T patients are not receiving CAR T, particularly in 2L. Despite the NCCN category 1 recommendation for CAR T use in 2L based on randomized trials, our study shows that non-curative intent treatments are being utilized instead. As data mature, future research could examine differences in outcomes in these populations."

Clinical • HEOR • Real-world • Real-world evidence • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

The potential of antibody-drug conjugates for effective therapy in diffuse large B-cell lymphoma. (PubMed, Expert Opin Biol Ther) - "Both polatuzumab vedotin and loncastuximab tesirine are established as useful therapeutics options, with polatuzumab vedotin currently approved in first line and relapsed/refractory setting, while loncastuximab tesirine is approved in relapsed setting. ADCs are effective with tolerable safety profile and currently many more ADCs are undergoing clinical trials."

Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Synthesis of novel pyrrolobenzodiazepine (PBD) C1-substituted monomers and dimers with DNA-binding activity and cytotoxicity. (PubMed, Bioorg Med Chem Lett) - "The pyrrolobenzodiazepines (PBDs) represent a major class of sequence-selective DNA-alkylating molecules, one example of which, in its dimeric DNA-cross-linking form, is employed as the payload in the anticancer Antibody Drug Conjugate (ADC) loncastuximab tesirine-lpyl. To date, PBD analogues have been produced with substituents at every position of the tricyclic skeleton except the C1-position. We report here the first synthesis of a C1-subsitituted PBD monomer and dimer, both of which possess DNA-binding activity and cytotoxicity in a cancer cell line."

Journal • Oncology