Antibody-Drug Conjugate Shows Early Promise in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

PHILADELPHIA – ADCT-402, an investigational antibody-drug conjugate, showed signs of clinical activity in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, according to results from a phase I study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

An aggressive subtype called diffuse large B-cell lymphoma (DLBCL) accounts for roughly one-third of all new non-Hodgkin lymphoma cases. Approximately 30 to 40 percent of patients with DLBCL relapse after first-line treatment. 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,” said 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 and colleagues tested the safety and clinical activity of an antibody-drug conjugate called loncastuximab tesirine, or ADCT-402, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. ADCT-402 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, said Kahl, who sees patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

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 percent had a complete response, and 18.8 percent had a partial response. Of the 51 evaluable patients with DLBCL treated at a dose of 120 µg/kg or higher, 37.3 percent had a complete response, and 17.6 percent 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.

“With most of the established treatments, we typically see response rates around 30 percent for DLBCL patients,” said Kahl. “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 ADCT-402 will ultimately prove to be a good addition for this patient population.”

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, said Kahl.

This study was funded by ADC Therapeutics. Kahl has received support from ADC Therapeutics and has consulted for Seattle Genetics and Genentech.