Loncastuximab Tesirine Shows Synergistic Activity With Ibrutinib in DLBCL, MCL

The combination of the antibody­-drug conjugate (ADC) loncastuximab tesirine (ADCT-402) and ibrutinib (Imbruvica) showed early clinical activity with manageable toxicity in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), according to interim results from a phase 1 dose-escalation and -expansion trial (NCT03684694) that were virtually presented during the 2020 European Hematologic Association Annual Congress.

Among 18 evaluable patients with relapsed/refractory DLBCL (n = 17) and MCL (n = 1), the combination elicited an overall response rate (ORR) of 66.7%, including 9 complete responses, and 3 partial responses (PRs).

“Patients with relapsed/refractory DLBCL or MCL have a poor prognosis and limited salvage treatment options,” said lead study author, Julien Depaus, MD, of the Université Catholique de Louvain in Belgium, during the presentation. “Combinations of drugs with different mechanisms of action may provide better outcomes. Preclinically, the combination of loncastuximab tesirine and ibrutinib has shown synergy.”

As of April 2020, 23 patients with DLBCL and 2 patients with MCL were enrolled in the phase 1 trial. In the dose-escalation portion of the study, patients received a median of 2 cycles of the ADC at a dose of 60 µg/kg (n = 19) or 90 µg/kg (n = 6) for a median duration of 42 days (range, 1-379).

Both regimens were administered intravenously in 30-minute infusions using the standard 3+3 dose-escalation design. Patients received loncastuximab tesirine every 3 weeks for the first 2 doses, followed by concurrent administration with 560 mg of daily ibrutinib for up to 1 year.

At the 14-week assessment, patients who derived a PR or had stable disease received an additional 2 doses of loncastuximab tesirine every 4 weeks.

In order to be eligible for enrollment, patients had to be 18 years of age or older and have a pathologically confirmed diagnosis of relapsed/refractory DLBCL or MCL.

Baseline characteristics showed that the majority of patients were male (76%) and had a median age of 69 years. More than half (56%) of patients had an ECOG performance status (PS) of 0, while 32% had a PS of 1 and 12% had a PS of 2. According to the Ann Arbor criteria, 12% of patients had stage II disease, 12% had stage III disease, and 76% had stage IV disease.

Additionally, 92% of all patients had non-germinal center B-cell DLBCL. Of these patients, 1 had double-hit DLBCL, 3 were double expressors, and 2 had transformed marginal zone B-cell lymphoma.

The median number of prior systemic therapies patients had received was 2 (range, 1-5). The majority of patients (n = 18) relapsed on their first-line regimen, in which 5 were refractory and 2 had unknown, not evaluable, or missing information.

Additionally, 44% had relapsed on and 48% were refractory to their last line of prior systemic therapy. Two patients were not evaluable or were missing information in this regard. 

One patient had prior autologous stem cell transplantation and 2 patients had prior allogeneic stem cell transplant.

The maximum-tolerated dose of loncastuximab tesirine was 60 µg/kg with 560 mg/day of ibrutinib. At this dose level, an ORR of 75% and CR rate of 58.3% was observed. More specifically, 63.6% (n = 7) and 9.1% (n = 1) of 11 patients with DLBCL achieved a CR and PR, respectively. One patient with MCL who received this dose had a PR. 

The most common treatment-emergent adverse effects (TEAEs) of any grade across dose levels were thrombocytopenia (48%), anemia (32%), fatigue (24%), rash (24%), alanine aminotransferase increase (20%), diarrhea (20%), and nausea (20%).

Although all patients experienced a TRAE, the toxicities leading to treatment discontinuation occurred in 16% (n = 4) of patients.

Regarding safety, dose-limiting toxicities (DLTs) were reported in 2 patients who received the 90 µg/kg dose of the combination. Of these DLTs, one patient died as a result of a cardiac event potentially related to ibrutinib, and one patient experienced grade 3 thrombocytopenia and anemia, both of which were considered to be related to the combination.

“Good exposure to loncastuximab tesirine was demonstrated throughout the dosing interval, and the study is continuing to enroll patients to further evaluate this combination,” concluded Depaus. 

Reference

Depaus J, Ervin-Haynes A, Carlo-Stella C, et al. Interim results of a phase 1/2 study of loncastuximab tesirine (lonca) combined with ibrutinib in advanced diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP1284.