Loncastuximab Tesirine Continues to Impress in Relapsed/Refractory DLBCL and MCL

Jay Feingold, MD, PhD

Loncastuximab tesirine-lpyl (Zynlonta) continued to demonstrate promising antitumor activity with an acceptable toxicity profile when used in the treatment of select patients with non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), according to updated data from the phase 2 LOTIS-2 trial (NCT03589469) and the phase 1 LOTIS-3 trial (NCT03684694).¹

“The updated results from our pivotal LOTIS-2 clinical trial presented at ICML continue to reinforce the efficacy across difficult-to-treat subgroups and sustained duration of response of commercially-available [loncastuximab tesirine] as a single agent for patients with relapsed or refractory DLBCL,” Jay Feingold, MD, PhD, senior vice president and chief medical officer of ADC Therapeutics SA, stated in a press release. “We’re also pleased that the updated data from the LOTIS-3 clinical trial demonstrate the encouraging antitumor activity and manageable toxicity profile of [loncastuximab tesirine] in patients with relapsed or refractory DLBCL or MCL.”

Updated data from the single-arm, open-label phase 2 LOTIS-2 trial presented during the 16th Annual International Conference on Malignant Lymphoma (ICML) showed that at a data cutoff of March 1, 2020, the antibody-drug conjugate (ADC) elicited an overall response rate (ORR) of 48.3%, with a complete response (CR) rate of 24.8% in patients with relapsed/refractory DLBCL in whom 2 or more established therapies have failed (n = 145).

Moreover, the median duration of response (DOR) was 13.4 months for the 70 responders. For patients who achieved a CR, the median DOR had not yet been reached. The median overall survival (OS) in these patients was 9.5 months.

The trial enrolled patients with relapsed/refractory DLBCL who had received 2 or more prior lines of systemic treatment; all patients received a median of 3 lines of previous therapy.

Patients on the trial received the ADC via a 30-minute infusion at a 150 μg/kg dose once every 3 weeks for the first 2 cycles. In subsequent cycles, the agent was given at a dose of 75 μg/kg. Patients received treatment for 1 year or until progressive disease, intolerable toxicity, or when other discontinuation criteria were met.

Regarding safety, no new signals were observed during the study. Notably, no increase in toxicity was reported in patients aged 65 years or older vs those under the age of 65 years. The most frequent grade 3 or higher treatment-emergent adverse effects (TEAEs) experienced with the ADC included neutropenia (26.2%), thrombocytopenia (17.9%), increased gamma-glutamyltransferase (17.2%), and anemia (10.3%).

Earlier data from the trial supported the FDA’s decision to grant an accelerated approval to loncastuximab tesirine for use in adult patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.²

Updated data from the two-part, open-label, single-arm phase 1/2 LOTIS-3 trial were also shared during the 16th Annual ICML and showed that the combination of loncastuximab tesirine plus ibrutinib (Imbruvica) resulted in an ORR of 62.2%, with a CR rate of 35.1%.

In 24 patients with non-germinal center B-cell (non-GCB) DLBCL, the doublet elicited a slightly ORR of 66.7%. Among 6 patients with GCB DLBCL, the ORR with the combination was 16.7%, and the ORR was highest among the 7 patients with MCL who were on the trial, at 85.7%.

In LOTIS-3, loncastuximab tesirine was given via a 30-minute intravenous infusion using a standard 3+3 dose-escalation design at doses of 60 μg/kg or 90 μg/kg. Participants were given the ADC every 3 weeks for the first 2 doses, with concurrent fixed-dose oral ibrutinib at a daily dose of 560 mg for up to 1 year.³

The doublet was found to have acceptable toxicity, and the most frequent grade 3 or higher TEAEs reported in 5% or more of patients included anemia (10.8%), neutropenia (10.8%), thrombocytopenia (5.4%), and fatigue (5.4%). Pharmacokinetic profiles showed sustained exposure and modest accumulation by cycle 2.

References

1. ADC Therapeutics presents updated ZYNLONTA (loncastuximab tesirine-lpyl) clinical data at 16thAnnual International Conference on Malignant Lymphoma. News release. ADC Therapeutics SA. June 18, 2021. Accessed June 22, 2021. https://bit.ly/3wOsXDe
2. ADC Therapeutics SA (ADCT) announces FDA approval of ZYNLONTA (loncastuximab tesirine-lpyl) in relapsed or refractory diffuse large B-cell lymphoma. News release. ADC Therapeutics. April 23, 2021. Accessed June 22, 2021. https://bit.ly/3tI7330
3. ADC Therapeutics announces maturing data from pivotal phase 2 clinical trial and phase 1/2 combination clinical trial of loncastuximab tesirine (Lonca) in patients with relapsed or refractory diffuse large B-cell lymphoma. News release. June 12, 2020. Accessed June 22, 2021. https://bwnews.pr/2SW7qKc