As reported in The Lancet Oncology by Caimi et al, the phase II LOTIS-2 trial has shown that the CD19-directed antibody–alkylating drug conjugate loncastuximab tesirine-lpyl produced durable responses in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The study supported the April 2021 accelerated approval of the agent for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL–not otherwise specified (NOS), DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

Study Details

In the trial, 145 patients with relapsed or refractory DLBCL after two or more multiagent systemic treatments and measurable disease were enrolled at sites in the United States, United Kingdom, Italy, and Switzerland between August 2018 and September 2019. DLBCL was defined according to the 2016 World Health Organization classification and included DLBCL-NOS, high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements or with MYC and BCL2 and BCL6 rearrangements, and primary mediastinal B-cell lymphoma. Patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle at 150 μg/kg for two cycles and at 75 μg/kg thereafter for up to 1 year or until disease relapse/progression or unacceptable toxicity. Histology consisted of DLBCL-NOS in 88% of patients, high-grade B-cell lymphoma in 8%, and primary mediastinal B-cell lymphoma in 5%. Patients included those with high-risk characteristics, including double-hit, triple-hit, transformed, or primary refractory DLBCL.

The primary endpoint was overall response rate assessed by central review. Primary antitumor activity and safety analyses were performed when all responding patients had at least 6 months of follow-up after initial documented response.

Responses

Objective response was observed in 70 patients (48.3%, 95% confidence interval [CI] = 39.9%–56.7%), with complete response observed in 35 (24.1%, 95% CI = 17.4%–31.9%). An additional 22 patients (15%) had stable disease. Median time to response was 41.0 days (interquartile range = 38.0–44.0 days). Median duration of response was 10.3 months (95% CI = 6.9 months–not estimable), including 13.4 months (95% CI = 10.3 months–not estimable) among those with complete response and 5.7 months (95% CI = 1.7 months–not estimable) among those with partial response. The probability of responders maintaining responses for ≥ 9 months was 64%. Among the 35 patients with complete response, 20 (57%) had ongoing complete response at data cutoff (April 2020). Median progression-free survival was 4.9 months (95% CI = 2.9–8.3 months).

Adverse Events

The most common grade ≥ 3 adverse events were neutropenia (26%), thrombocytopenia (18%), and increased gamma-glutamyltransferase (17%). Serious adverse events were reported in 39% of patients and were considered treatment-related in 15%, with the most common treatment-related events consisting of febrile neutropenia (3%), anemia (1%), pleural effusion (1%), noncardiac chest pain (1%), and pericardial effusion (1%).  Adverse events led to discontinuation of treatment in 23% of patients, most commonly due to increased gamma-glutamyl transferase (10%), peripheral edema (3%), localized edema (2%), and pleural effusion (2%). Adverse events led to death in eight patients (6%), with none of the deaths considered related to treatment.

The investigators concluded, “Loncastuximab tesirine has substantial single-agent antitumor activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL.”

Paolo F. Caimi, MD, of University Hospitals Cleveland Medical Center, Case Western Reserve University, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by ADC Therapeutics. For full disclosures of the study authors, visit thelancet.com.