Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma

ABSTRACT

Introduction

Relapsed or refractory diffuse large B cell lymphoma (DLBCL) has a poor prognosis. Several novel therapies have gained regulatory approval for treatment of DLBCL, however there is still a need for additional therapies to be added to the armamentarium. Loncastuximab tesirine-lpyl (ADC Therapeutics), an anti-CD19 antibody-drug conjugate (ADC), was recently approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (DLBCL).

Areas covered

We review the design and pharmacologic characteristics of loncastuximab tesirine-lpyl, emphasizing on the significance of CD19 as an effective target as well as pyrrolobenzodiazepine (PBD) as an effective payload. We review the key findings of the phase 1 LOTIS-1 and Phase 2 LOTIS-2 trials of loncastuximab in DLBCL, including efficacy and toxicity profile.

Expert opinion

Key findings in the early-phase trial support the efficacy of Loncastuximab in DLBCL, including in high-risk subgroups. The side effects have been tolerable even in elderly patients (≥75 years). Several ongoing clinical trials are currently evaluating the safety and efficacy of loncastuximab tesirine in a variety of NHL subtypes, as well as the study of combination strategies.

KEYWORDS:

• ADCT-402
• loncastuximab tesirine
• LOTIS-1
• LOTIS-2
• relapsed non-Hodgkin lymphoma
• relapsed refractory diffuse large B cell lymphoma
• antibody drug conjugate (ADC)
• pyrrolobenzodiazepine (PBD)
• cd19 targeting

Article highlights

• Relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) is associated with poor prognosis and many novel agents including antibody-drug conjugates (ADCs), bispecific T cell engager (BiTE) antibodies, monoclonal antibodies, and immune effector cell therapies are being studied in this setting.

• Loncastuximab tesirine (ADCT-402, Zynlonta®) is a novel ADC consisting of a CD19 monoclonal antibody, a linker, and a cytotoxic warhead pyrrolobenzodiazepine (PBD)

• The Phase 1 LOTIS-1 trial was a 2-part study on patients with relapsed/refractory non-Hodgkin lymphoma for whom no other treatment options were available. The overall response rate was 45.6%, with 26.7% CR in this heavily pre-treated population.

• Results of phase II clinical trial in R/R DLBCL (LOTIS-2) demonstrate a median duration of response of 5.7 months for those with partial remission and not reached for those with complete remission.

• Serious adverse event and toxicity profile include hematologic toxicity and non-hematologic toxicity such as liver function test abnormality, rise in γ-glutamyl transferase (GGT).

• FDA approved loncastuximab monotherapy on 4/23/21 in R/R DLBCL after two or more lines of therapy as monotherapy. While there is no direct comparison with other agents, it can be used sequentially with other approved ADCs in this space such as polatuzumab, and in those not eligible for or failed CART therapy

• Future research is focused on combination strategies, frontline therapy in the frail.

Information resources

https://pubmed.ncbi.nlm.nih.gov/33211842/

https://pubmed.ncbi.nlm.nih.gov/33989558/

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf

Declaration of interest

M Hamadami has served in a consultancy role for ADC Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.