Discontinuation of LOTIS-9 Trial: Zynlonta in Unfit DLBCL Patients

ADC Therapeutics Halts LOTIS-9 Trial of Zynlonta for DLBCL Patients

Source – ADC Therapeutics

On July 20, 2023,  ADC Therapeutics announced its decision to discontinue the Phase II LOTIS-9 clinical trial, which was evaluating the combination of Zynlonta (loncastuximab tesirine-lpyl) and rituximab (Lonca-R) in unfit or frail patients with previously untreated diffuse large B-cell lymphoma (DLBCL). The company has encountered challenges in defining the addressable segment of the difficult-to-treat unfit or frail DLBCL patient population, particularly due to the presence of significant active underlying comorbidities. As a result, the benefit-risk profile does not support the continuation of the LOTUS-9 trial.

Following a recent meeting, the US Food and Drug Administration (FDA) has placed a partial clinical hold on the trial for new patient enrollment. However, patients who are already on therapy and experiencing clinical benefit will be allowed to continue treatment after reconsenting. Once these reconsenting patients have completed their treatment, ADC Therapeutics will proceed with the necessary steps to conclude the trial. The company does not intend to pursue further study of this regimen in the unfit or frail previously untreated DLBCL patient population.

Zynlonta (loncastuximab tesirine-lpyl) has already received approval from the US FDA and the European Medicines Agency for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy. This includes DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. The trial encompassed a diverse group of heavily pre-treated patients, many with challenging-to-treat disease, such as those who did not respond to first-line therapy, patients refractory to all prior lines of therapy, and patients with specific genetic characteristics like double/triple hit genetics. Additionally, patients who had undergone stem cell transplant and CAR-T therapy prior to treatment with Zynlonta were included. 

Following a meeting with the FDA, ADC Therapeutics has decided to discontinue the Phase II LOTIS-9 Clinical Trial of Zynlonta (loncastuximab tesirine-lpyl) and Rituximab in unfit or frail patients with previously untreated DLBCL. The FDA had placed a partial hold on enrolling new patients in the trial, but patients already receiving the drug and experiencing clinical benefits can continue in the study after reconsenting. Once these patients have completed their treatment, ADC will take the necessary steps to conclude the trial.

During the study, 12 respiratory-related, treatment-emergent adverse events were observed, but 11 of them were previously deemed “unrelated” or unlikely to be associated with Zynlonta treatment. Additionally, all seven patients who passed away were aged 80 or older and had at least one significant comorbidity at the time the trial was originally paused.

In 2021, Zynlonta received clearance from the FDA through the accelerated pathway as a standalone treatment for adults with relapsed or refractory DLBCL after undergoing two previous lines of therapy. Notably, it became the first CD19-targeted antibody-drug conjugate to be approved as a single-agent following an impressive overall response rate of 48.3% observed in a Phase II trial. It is essential to mention that Zynlonta represents the sole approved product from ADC Therapeutics.

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