Loncastuximab Tesirine Showcases Substantial Antitumor Activity in Heavily Pretreated Relapsed/Refractory DLBCL

Loncastuximab tesirine-lypl (Zynlonta) has demonstrated significant antitumor activity with durable responses and an acceptable toxicity profile, when used as a monotherapy in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to data from the phase 2 LOTIS-2 trial (NCT03589469) recently published in Lancet Oncology.¹

Results showed that in the as-treated population, the antibody-drug conjugate (ADC) elicited an overall response rate of 48.3% (n = 70/145; 95% CI, 39.9%-56.7%). Specifically, 35 of these patients experienced a complete response (CR) and 25 had a partial response (PR) to treatment.

Moreover, the median time to first response was 41.0 days (IQR 38.0-44.0), while the median duration of response (DOR) was 10.3 months (95% CI, 6.9–not estimable [NE]). For patients who achieved a CR, their median DOR was slightly longer, at 13.4 months (10.3-NE), while it was shorter for those who had a PR, at 5.7 months (1.7-NE). The probability of responders maintaining their response for 9 months or longer was 64%.

“In this study, single-agent loncastuximab tesirine produced durable responses, with an ORR of 48.3%, in heavily pretreated patients with relapsed or refractory DLBCL,” the study authors wrote. “In most responding patients, the initial dose led to onset of response by their first disease assessment 6 weeks after treatment start (after 2 cycles). Dose reduction from cycle 3 maintained the same level of steady-state exposure.”

About 40% of patients with DLBCL have refractory disease or relapse after initially responding to frontline treatment with chemoimmunotherapy. Despite recent advances, patients who are not eligible for salvage chemotherapy or autologous hematopoietic stem cell transplant (HSCT) and those who do not respond or relapse following these options continue to have poor outcomes.

Loncastuximab tesirine is an ADC that is comprised of a humanized anti-CD19 antibody that is conjugated to SG3199, a pyrrolobenzodiazepine dimer cytotoxin. The agent was developed to target B-lymphocyte antigen CD19, and it is rapidly internalized by cells that express this target. Notably, the payload causes interstrand DNA crosslinks with minimal DNA distortion, which is hypothesized to contribute to their persistence in cells through the avoidance of DNA repair. Because of the short half-life of the payload, the agent causes limited systemic toxicity.

Previously, data from the dose-escalation phase 1 trial (NCT02669017) indicated that the ADC had an acceptable toxicity profile and promising antitumor efficacy when given to patients with relapsed or refractory B-cell non-Hodgkin lymphoma.^2,3 Here, patients with DLBCL experienced an ORR of 42.3% with loncastuximab tesirine and a short, 6-week median time to first response.

The recommended phase 2 dose for the ADC was established as 150 μg/kg every 3 weeks for 2 cycles, followed by 75 μg/kg every 3 weeks thereafter.

To further examine the safety and antitumor activity of the loncastuximab tesirine in patients with relapsed or refractory DLBCL, investigators launched the open-label, single-arm phase 2 LOTIS-2 trial.

To be eligible for enrollment, patients needed to be at least 18 years of age, have investigator-defined relapsed or refractory DLBCL following 2 or more systemic treatments, have measurable disease, and an ECOG performance status of 0 to 2. Moreover, patients needed to have acceptable organ function.

Notably, those with transformed indolent lymphoma were not excluded from the trial. However, those with bulky disease, Burkitt lymphoma, a history of hypersensitivity to a CD19 antibody, who had prior treatment with the loncastuximab tesirine, or had undergone autologous HSCT within 30 days, were not included.

The ADC was given on an outpatient basis; the agent was administered intravenously, over the course of 30 minutes, once every 3 weeks on day 1 of each 21-day treatment cycle. Loncastuximab tesirine was delivered at a dose of 150 μg/kg for the first 2 cycles, followed by 75 μg/kg thereafter. Treatment was given for up to 1 year or until disease progression, intolerable toxicity, death, major protocol deviation, pregnancy, or decision by either the patient, study investigator, or the trial sponsor.

The primary end point of the trial was ORR, while secondary end points comprised DOR, CR rate, relapse-free survival (RFS), progression-free survival (PFS), and overall survival (OS). Safety end points were also evaluated, along with pharmacokinetic parameters and health-related quality of life.

A total of 184 patients were evaluated for eligibility between August 1, 2018 and September 24, 2019; 79% of these patients (n = 145) were enrolled to the trial and were given at least 1 dose of the ADC.

The median age of the study participants was 66 years (IQR, 56-71), with 45% of patients under the age of 65 years. More than half, or 59%, of patients were male, and 88% had a histology of DLBCL or not otherwise specified. Additionally, 10% of patients had double- or triple-hit DLBCL, while 14% had double- or triple-expressor DLBCL. Ninety-four percent of patients did not have bulky disease, but 20% had transformed DLBCL.

The median number of prior lines of systemic treatment was 3.0 (IQR, 2.0-4.0), with 43% having received 2 prior lines, 24% having received 3 prior lines, and 32% having received more than 3 lines. The majority, or 68%, of patients relapsed on their frontline systemic treatment, while 20% proved to be refractory and 12% had a different response. Fifty-eight percent of patients were refractory to their most recent line of systemic therapy. Most patients did not receive prior CAR T-cell therapy.

Additional data showed that the median PFS with the ADC was 4.9 months (95% CI, 2.9-8.3), while the median OS was 9.9 months (95% CI, 6.7-11.5). Moreover, the median RFS with loncastuximab tesirine was 13.4 months (95% CI, 10.3-NE).

Forty-seven percent of patients (n = 68) went on to receive another therapy after the ADC; 6% (n = 9) underwent autologous HSCT and 10% (n = 15) received CD19-directed CAR T-cell therapy. Notably, the ORR to CAR T-cell therapy following the ADC was 47% per investigator assessment (n = 7/15) with 40% (n = 6) achieving a CR.

Findings from subgroup analyses of antitumor activity parameters demonstrated antitumor activity across the prespecified subsets examined in the trial, including those with high-risk characteristics.

Ninety-four percent of patients (n = 137) discontinued treatment during follow-up and the most frequent reason for doing so was progressive disease.

Regarding safety, 99% of patients (n = 143) experienced at least 1 treatment-emergent toxicity with the ADC. The most commonly experienced grade 3 or higher adverse effects (AEs) included neutropenia (26%), thrombocytopenia (18%), and increased gamma-glutamyl transferase (17%).

Thirty-nine percent of patients (n = 57) reported at least 1 serious treatment-emergent AE (TEAE), and 15% (n = 22) experienced serious AEs that were thought to potentially be related to the study treatment. The most common of these effects were febrile neutropenia (3%), anemia (1%), pleural effusion (1%), non-cardiac chest pain (1%), and pericardial effusion (1%).

Fifty-three percent of participants (n = 77) died during the study period and more than half (78%; n = 60) were because of progressive disease, while 6% (n = 5) were because of fatal TEAEs; 16% of patients (n = 12) died following the AE reporting period. The 5 patients who had fatal toxicities experienced sepsis, small intestinal perforation, septic shock, pneumonia, and acute kidney injury—all of which were not determined to be related to the ADC.

Sixty-two percent of patients (n = 90) experienced TEAEs that resulted in dose modifications or treatment discontinuation; 23% of these patients (n = 34) discontinued treatment, 51% (n = 74) required dose delays, 8% (n = 11) needed dose reductions, and 1% (n = 1) experienced infusion interruption. For the most part, dose delays were short and allowed for patients to continue treatment with loncastuximab tesirine.

Based on data from this phase 2 trial, the FDA granted loncastuximab tesirine accelerated approval in April 2021 for the treatment of adult patients with relapsed or refractory large B-

cell lymphoma following 2 or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

References

1. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. Published online May 11, 2021. doi:10.1016/S1470-2045(21)00139-X
2. Kahl BS, Hamadani M, Radford J, et al. A phase I study of ADCT-402 (loncastuximab tesirine), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2019;25(23):6986-6994. doi:10.1158/1078-0432.CCR-19-0711
3. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512