Loncastuximab Tesirine and Ibrutinib Combination Shows Promise in R/R DLBCL and MCL

Murali Janakiram, MD, MS

The combination of loncastuximab tesirine-lpyl (Zynlonta) and ibrutinib (Imbruvica) displayed encouraging antitumor activity with a manageable safety profile in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), according to updated results from the phase 1/2 LOTIS-3 study (NCT03684694) presented by Murali Janakiram, MD, MS, during the 2021 Pan Pacific Lymphoma Conference.¹

As of the data cutoff date of March 1, 2021, the overall response rate (ORR) among 37 evaluable patients was 62.2%. Specifically, the ORRs for patients with non-germinal center B-cell (GCB) DLBCL (n = 24), GCB DLBCL (n = 6), all DLBCL (n = 30), and MCL (n = 7) were 66.7%, 16.7%, 56.7%, and 85.7%, respectively.

No patients with GCB DLBCL experienced a complete response, compared with 37.5%, 30%, and 57.1% of patients with non-GCB DLBCL, all DLBCL, and MCL, respectively. Partial responses accounted for 29.2% of responses in patients with non-GCB DLBCL, 16.7% of patients with GCB DLBCL, 26.7% of those with DLBCL, and 28.6% of patients with MCL.

Responses are ongoing in 4 patients with non-GCB DLBCL and in 3 patients with MCL. The median duration of response for all patients was 5.55 months (IQR, 2.07-not reached [NR]). Specifically, the median duration of response for patients with non-GCB DLBCL was 4.65 months (IQR, 1.92-NR), 5.55 months (IQR, 2.07-NR) for all patients with DLBCL, and was NR for patients with GBC DLBCL (IQR, NR-NR) and MCL (IQR, 2.17-NR).

“Patients with relapsed or refractory DLBCL and MCL have a poor prognosis, hence effective treatment options are needed,” said Janakiram, an assistant professor of medicine in the Division of Hematology, Oncology, and Transplantation, at the University of Minnesota in Minneapolis. “In the phase 1/2 LOTIS-3 study, we investigated loncastuximab [tesirine] in combination with ibrutinib in this set of patients.”

Loncastuximab tesirine, is an antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In April, the agent was granted accelerated approval by the FDA based on data from the phase 2 LOTIS-2 study (NCT03589469) for the treatment of adult patients with R/R 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

LOTIS-3 is an open-label, single-arm combination study consisting of a dose-escalation phase (phase 1) and a dose-expansion phase (phase 2). Patients received the maximum tolerated dose (MTD) of loncastuximab tesirine in phase 2, determined to be 60 µg/kg in phase 1, intravenously every 3 weeks for 2 cycles and ibrutinib 560 mg orally daily for up to 1 year. After disease assessment at week 14, patients who achieved a partial response or stable disease were eligible to receive 2 additional cycles of loncastuximab tesirine every 4 weeks at cycles 5 and 6.¹

Patients eligible for the study were at least 18 years with R/R DLBCL who intolerant to, or unsuccessful with, standard treatment, and adult patients with R/R MCL who have undergone at least 1 prior therapy.

Patients previously treated with loncastuximab tesirine, ibrutinib, or other Bruton tyrosine kinase inhibitors were excluded from the study. The primary end point was safety, while secondary end points included ORR and determining the pharmacokinetic characteristics of loncastuximab tesirine.

The median age was 72 years (range, 40-91). A majority of the population were patients with stage IV disease (73%); patients with stage II and stage III disease made up 10.8% and 13.5% of the total population, respectively. Most patients had an ECOG performance status of 0 (54.1%), 37.8% had a performance status of 1, and 8.1% registered a performance status of 2.

Patients had a median of 2 (range, 1-6) prior therapies and 22% were those with primary refractory disease. A vast majority of patients included in the trial are males (73%). Concerning prior stem cell transplant, 8.1% received autologous and 2.7% were given allogenic.

Most patients relapsed with their prior first-line systemic therapy (64.9%), while 21.6% were refractory and 13.5% experienced another response. Response to the last line of prior systemic therapy was more evenly distributed between relapse and refraction, with 45.9% of patients relapsing, 48.6% becoming refractory, and 5.4% having another response.

In terms of safety, treatment-emergent adverse effects (TEAEs) were observed in 100% of patients. The most common TEAEs of any grade were thrombocytopenia (32.4%), anemia (24.3%), and diarrhea (24.3%). Fatigue, nausea, and rash of any grade each occurred in 21.6% of patients.

TEAEs of at least grade 3 were reported in 64.9% of patients. The most common grade 3 effects were anemia (10.8%), neutropenia (10.8%), and thrombocytopenia, fatigue, and acute kidney injury (5.4%). TEAEs leading to dose delay, reduction, or interruption were reported in 51.4% of patients and TEAEs that caused treatment discontinuation occurred at a rate of 13.5%.

At the pharmacokinetic data cutoff (August 20, 2020), cycle-related increase in pharmacokinetic exposure was reported and inter-patient exposure was moderate.

“Sustained loncastuximab [tesirine] exposure and modest cycle accumulation was seen by cycle 2,” Janakiram said. In cycle 1, at the MTD, the Cmax in ng/mL was 659 for conjugated antibodies and 1280 ng/mL for the total number of antibodies. In cycle 2, Cmax was 761 ng/mL for conjugated antibodies and 1461 ng/mL for the total number of antibodies.

“The updated safety and efficacy analysis of phase 1 of LOTIS-3 showed that loncastuximab [tesirine] 60 µg/kg plus ibrutinib 560 mg had encouraging antitumor activity in patients with relapsed or refractory DLBCL or MCL,” Janakiram concluded. “Toxicity was manageable at the MTD, and safety data were comparable to that reported in the interim analysis.”

References

1. Janakiram M, Depaus J, Wagner-Johnston N, et al. Clinical activity of loncastuximab tesirine plus ibrutinib in non-hodgkin lymphoma: updated LOTIS-3 phase 1 results. Poster presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021. Fairmont Orchid, HI. Accessed August 11, 2021.
2. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. News release. FDA. April 23, 2021. Accessed August 11, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma