ASH 2024 Promising response to loncastuximab tesirine in lymphoma

medwireNews: The antibody–drug conjugate (ADC) loncastuximab tesirine has shown encouraging results for the treatment of high-risk follicular lymphoma (FL) and marginal zone lymphoma (MZL) in two trials presented at the 66th ASH Annual Meeting & Exposition. Speaking to the audience in San Diego, California, USA, the presenter of the first trial explained that loncastuximab tesirine consists of an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin and is currently approved for the second- or later-line treatment of relapsed or refractory large B-cell lymphoma. The current trials investigated the agent for the treatment of relapsed or refractory FL and relapsed or refractory MZL, settings for which there is no standardized therapeutic approach. Phase 2 trial in FL This single-arm trial was conducted at the Sylvester Comprehensive Cancer Center in Miami, Florida, USA, and investigated the ADC in combination with rituximab. The investigators enrolled 39 adults (median age 68 years) with relapsed or refractory FL (grade 1–3A) who had received at least one prior line of therapy and had need for treatment based on presenting with progression of disease within 24 months (POD24) after first-line therapy, one or more Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria, or second relapse. The participants received intravenous loncastuximab tesirine on day 1 of each 21-day cycle at a dose of 150 µg/kg for two cycles and 75 µg/kg thereafter. Rituximab was given at a dose of 375 mg/m2 for four once-weekly doses, followed by one dose every 8 weeks for cycles 5, 6, and 7. Patients with a complete response at week 21 discontinued loncastuximab and received two more doses of rituximab, while those with a partial response continued both agents for a further 18 weeks. The primary endpoint of the study was complete response at week 12 by the Lugano criteria and this was achieved by 66.7% of patients, which was higher than the target rate of 50.0%. A further 30.7% achieved a partial response, giving an overall response rate (ORR) of 97.4%. Presenter Juan Alderuccio, from the Sylvester Comprehensive Cancer Center, pointed out the majority of complete responses occurred by week 12 but there were four patients with a partial response at this timepoint and a complete response by week 21, which gave a best complete response rate of 76.9%. The progression-free survival (PFS) rate at 6 and 12 months was an identical 94.6%, while the respective overall survival (OS) rates were 97.1% and 94.1%. Alderuccio reported that “the safety profile in [FL] was consistent with prior studies in large B-cell lymphoma with no new safety signals,” adding that “most AEs [adverse events] were of grade 1 or 2, including hyperglycemia, increase in liver enzymes, fatigue, and rash.” The most common AEs of grade 3 were lymphopenia and neutropenia, occurring in 12.8% and 10.3% of patients, respectively, with grade 4 events in 7.7% and 2.6%. There were no treatment-related deaths during the course of the trial. “This study suggests that a fixed-duration program of loncastuximab with rituximab is a promising combination in second-line and later [FL],” concluded the presenter, informing the audience that the findings were published simultaneously in The Lancet Haematology. Phase 2 trial in MZL For this multicenter trial, reported in a poster, Izidore Lossos (Sylvester Comprehensive Cancer Center) and colleagues recruited 23 adults (median age 65 years) who had previously received one or more lines of therapy and required treatment based on symptoms, predefined criteria by MZL subtype, or POD24. They were given loncastuximab 150 µg/kg every 3 weeks for two cycles followed by the lower dose of 75 µg/kg for four cycles. The complete response rate after six cycles – the primary endpoint – was 70%, with partial response in 21%, equating to an ORR of 91%. The study authors noted that all but one of the complete responses were maintained at the time of analysis, “with the longest follow-up being 27 months from the start of treatment.” A total of 60.6% of participants had an ongoing overall response at 18 months and 66.7% had an ongoing complete response. The estimated PFS rate at 12 months was 91.7% and the OS rate was 100%. “Generally, [loncastuximab] was well tolerated, and the observed safety was consistent with the known profile,” said Lossos and team. Neutropenia and increased alkaline phosphatase were the most frequently observed AEs of grade 3, experienced by 13% of patients each, followed by increased alanine aminotransferase, in 8.7%. There was only one grade 4 event, a case of neutropenia. Three participants required a dose reduction and one stopped treatment after the fourth cycle due to cholestatic hepatitis, with full recovery and normalization in liver function tests after discontinuation. The investigators summarized that the ADC demonstrated “clinically meaningful activity with a robust [complete response] rate” in this patient population in the ongoing study. But they added that although complete responses appeared durable, “longer follow-up is needed.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group ASH Annual Meeting & Exposition 2024; San Diego, California, USA: 7–10 December (abstract 337) Lancet Haematol 2024; doi:10.1016/S2352-3026(24)00345-4 ASH Annual Meeting & Exposition 2024; San Diego, California, USA: 7–10 December (abstract 3032)

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ASH 2024 Promising response to loncastuximab tesirine in lymphoma

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