Loncastuximab Tesirine Elicits Responses in R/R Marginal Zone Lymphoma

Izidore Lossos, MD

The antibody-drug conjugate (ADC) loncastuximab tesirine-lpyl (Zynlonta) elicited a high response rate with acceptable tolerability in patients with relapsed or refractory marginal zone lymphoma, according to initial data from a phase 2 trial (NCT05296070).¹

At a data cutoff date of March 30, 2024, 13 of 15 evaluable patients achieved complete responses (CRs) with the ADC, and 1 patient experienced a partial response (PR). All responses were maintained at the time of data cutoff. Moreover, loncastuximab tesirine was also found to have an acceptable toxicity profile, with only 2 treatment discontinuations. One patient discontinued after cycle 2 and continued to be in CR at 10 months, and the other patient discontinued after cycle 4 and continued to be in CR at 6 months.

“Achievement of CR to treatment represents the strongest predictor of positive outcomes in MZL, so these initial results are encouraging,” Izidore Lossos, MD, lead trial investigator as well as professor and director of the Lymphoma Program at the Sylvester Comprehensive Cancer Center, University of Miami, in Florida, stated in a press release. “We are now expanding the number of sites to accelerate enrollment in this trial.”

The investigator-initiated trial enrolled patients aged 18 years or older with histologically confirmed MZL, including those with extranodal, nodal, and splenic subtypes.² Patients needed to have received at least one prior line of systemic treatment, including at least one anti-CD20 antibody. After their most recently received treatment, they must have not achieved a CR or PR or experienced disease progression. They also needed to have lymphadenopathy that was radiographically measurable or an extranodal lymphoid malignancy, an ECOG performance status of 0 to 2, a life expectancy of longer than 3 months, and acceptable hematologic, hepatic, and renal function.

If patients had diffuse large B-cell lymphoma (DLBCL) transformation, a history of central nervous system lymphoma or leptomeningeal disease, were concurrently receiving other anticancer treatment, had active graft-vs-host disease, or did not sufficiently recover from adverse effects (AEs) or complications from a major surgery or treatment before the initiation of study treatment, they were excluded.

Study participants (n = 50) received loncastuximab tesirine at 150 µg/kg given for six cycles across 18 weeks.¹

The primary end points of the study were CR rates at 6 months and 12 months.² Secondary end points included 6- and 12-month PR, 6- and 12-month overall response rate, progression-free survival, overall survival, duration of response, and treatment-related AEs.

“Relapsed/refractory MZL can be difficult to manage, making this an indication of high unmet medical need,” Mohamed Zaki, MD, PhD, chief medical officer of ADC Therapeutics, stated in the press release.1 “As this investigator-initiated trial progresses, assuming the results continue to be positive, we plan to potentially pursue a regulatory pathway and compendia in parallel as soon as sufficient data are available.”

In April 2021, the FDA granted accelerated approval to loncastuximab tesirine for use in adult patients with relapsed or 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.³ The decision was based on data from the phase 2 LOTIS-2 study (NCT03589469) in which the ADC induced an ORR of 48.3% in patients with relapsed/refractory DLBCL who had previously received at least 2 lines of systemic therapy. The ADC was also approved by the European Medicines Agency for the same indication.

References

1. ADC Therapeutics announces initial data from investigator-initiated phase 2 clinical trial of Zynlonta in patients with relapsed/refractory marginal zone lymphoma. News release. ADC Therapeutics SA. May 6, 2024. Accessed May 6, 2024. https://ir.adctherapeutics.com/press-releases/press-release-details/2024/ADC-Therapeutics-Announces-Initial-Data-from-Investigator-Initiated-Phase-2-Clinical-Trial-of-ZYNLONTA-in-Patients-with-RelapsedRefractory-Marginal-Zone-Lymphoma/default.aspx
2. Study to evaluate the efficacy and safety of loncastuximab tesirine in patients with relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2). ClinicalTrials.gov. Updated August 29, 2023. Accessed May 6, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03589469
3. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. FDA. April 23, 2021. Accessed May 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma