Loncastuximab Tesirine Produces Significant Antitumor Response in Relapsed/Refractory DLBCL

Phase 2 data supporting the use of loncastuximab tesirine in patients with diffuse large B-cell lymphoma published in The Lancet Oncology show the agent inducing a response in about half of patients with pretreated disease.

Loncastuximab tesirine (Zynlonta) produced significant, durable antitumor activity and showed promise as a therapy for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to findings from the recent phase 2 LOTIS-2 trial (NCT03589469).1

Data to come out of this trial served to support the accelerated approval of the agent in April 2021 as treatment of 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.2

“The durable clinical antitumor activity of single-agent loncastuximab tesirine compared with recently approved therapies, including activity in difficult-to-treat subgroups, suggest it could change practice as a potential treatment option for patients with relapsed or refractory DLBCL who have received two or more previous systemic therapies,” Paolo F. Caimi, MD, of University Hospitals Cleveland Medical Center and Case Western Reserve University in Cleveland, and colleagues wrote. “Loncastuximab tesirine is also being investigated in combination with other therapies.”

The investigators conducted the open-label, single-arm trial of loncastuximab tesirine therapy in 145 patients with DLBCL. The cohort included patients with indicators of poor prognosis, including patients with primary refractory disease, as well as double-hit, triple-hit, or transformed disease. All patients had previously received at least 2 multiagent systemic therapies and were treated at 28 different centers in the United States, the United Kingdom, Switzerland, and Italy. Caimi and colleagues administered intravenous loncastuximab tesirine at a dose of 150 μg/kg on the first day of 2 21-day cycles, followed by 75 μg/kg. Treatment continued until progression, relapse, or death; decision by the patient, sponsor, or investigator to stop treatment; major protocol deviation or pregnancy; or the 1-year mark. The main outcome was overall response rate.

A total of 70 patients demonstrated a response, for an objective response rate (ORR) of 48.3% (95% CI, 39.9%-56.7%). Half of these (n = 35) achieved a complete response, whereas the other half demonstrated a partial response.

The most common adverse events of grade 3 or higher were increased gamma-glutamyltransferase (n = 24; 17%), thrombocytopenia (n = 26; 18%), and neutropenia (n = 37; 26%). Fifty-seven patients (39%) experienced serious adverse events. Eight patients (6%) died of treatment-emergent adverse events. The investigators reported that none of these deaths were related to loncastuximab tesirine, however.

“No new safety concerns regarding loncastuximab tesirine were identified and no increase in toxicity was observed in patients aged 65 years or older,” wrote Caimi and colleagues. “Frequencies of pyrrolobenzodiazepine-related adverse events, such as rash, liver enzyme elevations, and oedema or effusion were similar or less than that in the phase 1 study.”

Investigators added that despite significant occurrences of “grade 3 or higher adverse events, most of these events reflected laboratory abnormalities rather than clinical symptoms.”

Prior evidence suggests, “a substantial unmet need for patients with relapsed or refractory

DLBCL, particularly those unsuitable for, or progressing after, autologous HSCT,” the investigators wrote. Although chimeric antigen receptor T-cell treatments remain important therapies, they can be logistically difficult and sometimes cost-prohibitive, leaving patients who have a poor prognosis and rapidly progressing illness in need. In this study, however, patients who received prior CD19-directed CAR T-cell therapy demonstrated a similar response rate to that of the general patient population.

Caimi and colleagues wrote that there were limitations to the study, including the fact “progression-free survival and overall survival data with loncastuximab tesirine continue to mature,” and that many patients in the trial were still in follow-up by the time of publication. Further, the investigators acknowledged that subgroups of patients were small, which limited subgroup analyses in terms of statistical comparison.

A study evaluating loncastuximab tesirine plus ibrutinib (NCT03684694) has shown encouraging preliminary results, and a randomised phase 3 study of loncastuximab tesirine plus rituximab compared with standard immunochemotherapy has been initiated (NCT04384484),” Caimi and colleagues wrote.

References

1. Caim PF, AI W, 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. May 11, 2021. doi: 10.1016/S1470-2045(21)00139-X

2. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. News release. FDA. April 23, 2021. Accessed May 24, 2021. https://bit.ly/2QL6E1w