Loncastuximab tesirine, also known as ADCT-402, an investigational antibody-drug conjugate being developed by ADC Therapeutics, showed signs of clinical activity in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

This is the conclusion based on results from a phase I study published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR)

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma that develops from the B-cells in the lymphatic system. Accounting for 30% – 40% of all cases, DLBCL is the most common subtype of this disease.

Approximately 30%-40% of patients with DLBCL relapse after first-line treatment.

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Unmet medical need
While some patients with relapsed disease benefit from autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy, a subset of patients do not respond to these treatments or are ineligible.

“There is a large unmet need for patients with relapsed/refractory DLBCL, particularly for patients who don’t respond to stem cell transplant or CAR-T,” explained Brad S. Kahl, MD, a medical oncologist at Washington University School of Medicine in St. Louis.

“There are really no attractive options currently available for those patients,” Kahl added.

Antibody-drug conjugate
Kahl and colleagues tested the safety and clinical activity of an antibody-drug conjugate called loncastuximab tesirine in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Loncastuximab tesirine combines a potent DNA-damaging agent called pyrrolobenzodiazepine (PBD) with a monoclonal antibody directed against CD19.

“CD19 is expressed on the surface of virtually all B-cell lymphomas,” explained Kahl. “Employing an antibody-drug conjugate that targets CD19 is an effective way to target a cytotoxic agent to malignant B cells.”

PBD is more potent than traditional cytotoxic agents, and unlike some other cytotoxic agents, it is not associated with peripheral neuropathy. These are important features for patients with relapsed/refractory disease who may have developed resistance to other cytotoxic agents, or who may have existing peripheral neuropathy from previous treatments, Kahl said, who sees patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

Study design
The study enrolled 88 patients, 18 years of age or older, with relapsed/refractory B-cell non-Hodgkin lymphoma who did not respond to or were ineligible for established therapies. Of these patients, 63 had DLBCL.

Patients received one of several test doses of ADCT-402, administered intravenously, every three weeks. Patients were treated until disease progression or patient withdrawal.

The greatest responses were observed in patients treated at a dose of 120 µg/kg or higher. Of these patients, 40.6% had a complete response, and 18.8% had a partial response. Of the 51 evaluable patients with DLBCL treated at a dose of 120 µg/kg or higher, 37.3% had a complete response, and 17.6% had a partial response. Among patients with complete responses, the median duration of response was not reached after a median follow-up of 7.5 months.

Response rates
“With most of the established treatments, we typically see response rates around 30% for DLBCL patients,” Kahl noted.

“To have a therapy with a higher response rate and some durability would be a great advancement for the field and for these patients. We’re hopeful that loncastuximab tesirine will ultimately prove to be a good addition for this patient population,” he added.

Adverse events
Eighty-seven of the 88 enrolled patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs were low blood cell counts, fatigue, liver-test abnormalities, nausea, rash, shortness of breath, and tissue swelling. Sixty-five of the 88 patients experienced a TEAE of grade 3 or higher, including low blood cell counts, liver test abnormalities, fatigue, and shortness of breath. Seven patients had a TEAE with a fatal outcome due to disease progression, according to Kahl.

Based on the results of this phase I study, a dose of 150 µg/kg was selected for an ongoing phase II trial, which recently completed enrollment. In an attempt to mitigate some of the TEAEs, patients in the phase II study will receive fewer doses and will be pre-medicated with a low-dose steroid to reduce inflammation, explained Kahl.

A limitation to the phase I study was that each dose cohort contained a relatively small number of patients, Kahl, concluded.

Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, Feingold JM, Ardeshna KM, et al. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2019 Nov 4. doi: 10.1158/1078-0432.CCR-19-0711. [Pubmed][Article]

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