A biologics license application has been submitted to the FDA for loncastuximab tesirine for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma.
A biologics license application (BLA) has been submitted to the FDA for loncastuximab tesirine (Lonca) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to an announcement from ADC Therapeutics SA, the product developer.1
The BLA was based on findings from the phase 2 LOTIS 2 trial, in which the antibody-drug conjugate (ADC) elicited an overall response rate (ORR) of 48.3% and a complete response (CR) rate of 24.1% in patients with relapsed/refractory DLBCL who had received 2 or more prior lines of systemic therapy.2
“A critical unmet need remains for heavily pretreated patients with relapsed or refractory DLBCL, including those with poor prognosis, those who never responded to prior therapy, and those who received prior stem cell transplant,” Jay Feingold, MD, PhD, senior vice president and chief medical officer of ADC Therapeutics, said in a press release. “Based on the antitumor activity, durability, and generally manageable tolerability [loncastuximab tesirine] has demonstrated in LOTIS 2, we believe [the agent] has the potential to fill this need.”
Loncastuximab tesirine is comprised of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to the pyrrolobenzodiazepine dimer cytotoxin, according to ADC Therapeutics SA.
When it binds to the CD19-expressing cell, the agent was developed to be internalized by the cell. Once that happens, the warhead, which is designed to irreversibly bind to DNA, is released; this creates highly potent inter-strand crosslinks that prevent DNA strand separation. By blocking this separation, it inhibits DNA metabolic processes that are involved in replication and cell death.
In the phase 2, multicenter, open-label, single-arm LOTIS 2 trial, investigators set out to examine the safety and efficacy of the ADC in patients with relapsed/refractory DLBCL who received 2 or more prior lines of systemic treatment. Patients had received a median of 3 prior lines of treatment.
In the trial, participants were given a 30-minute intravenous (IV) infusion of loncastuximab tesirine at a dose of 150 μg/kg once every 3 weeks for the first 2 treatment cycles; this was followed by 75 μg/kg for subsequent treatment cycles. Treatment was continued for up to 1 year, or until progressive disease, intolerable toxicity, or when other discontinuation criteria were met.
At a data cutoff of April 6, 2020, a total of 145 patients were enrolled on the trial and they had received a mean of 4.3 cycles of the ADC (range, 1-15). Additional results presented during the 2020 European Hematology Association (EHA) Congress showed that ADC elicited an ORR of 37.9% in patients refractory to first-line prior therapy, and 36.9% in those refractory to last-line prior treatment. Moreover, the median duration of response was 10.25 months.
With regard to safety, loncastuximab tesirine was found to be tolerable, with no new safety concerns reported. The most commonly experienced treatment-emergent adverse effects that were grade 3 or higher and occurred in 10% or more of participants included neutropenia (25.5%) with low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), increased gamma-glutamyl transferase (16.6%), and anemia (10.3).
“The completion of our first BLA submission to the FDA is a significant milestone for ADC Therapeutics and takes us one step further in our evolution toward becoming a commercial-stage organization,” Chris Martin, chief executive officer of ADC Therapeutics, added in the release. “We are grateful to the trial participants and investigators and to all our employers for their commitment to this clinical program, and we look forward to working with the FDA to bring [loncastuximab tesirine] to patients as quickly as possible.”
Loncastuximab tesirine is also under examination in combination with ibrutinib (Imbruvica) in patients with relapsed/refractory DLBCL or mantle cell lymphoma (MCL). In the phase 1/2 trial, the ADC was given in 30-minute IV infusions using the standard 3+3 dose-escalation design at doses of 60 μg/kg or 90 μg/kg. Participants were given loncastuximab tesirine every 3 weeks for the first 2 doses, with concurrent fixed-dose oral ibrutinib at 560 mg/day for up to 1 year.
At a data cutoff of April 6, 2020, 25 participants had been enrolled to the trial; the majority, or 23, had DLBCL and 2 patients had MCL. A total of 18 patients were determined to be evaluable for antitumor activity. Interim data from the phase 1 portion of the trial, also presented during the 2020 EHA Congress, showed that across the dose levels, the combination elicited an ORR of 66.7% with a CR rate of 50.0%. Moreover, at the recommended phase 2 dose of 60 μg/kg, the combination showed an ORR of 75.0% with a CR rate of 58.3%.
The phase 3 confirmatory LOTIS 5 trial (NCT04384484), has also been initiated, according to ADC Therapeutics. In this trial, investigators will examine loncastuximab tesirine in combination with rituximab (Rituxan) versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.3 Results from this trial are intended to support a supplemental BLA for the agent for use in the second-line treatment of patients with relapsed/refractory DLBCL.