Elsevier

The Lancet Oncology

Volume 22, Issue 6, June 2021, Pages 790-800
The Lancet Oncology

Articles
Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial

https://doi.org/10.1016/S1470-2045(21)00139-XGet rights and content

Summary

Background

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody–drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL.

Methods

We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0–2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov, NCT03589469.

Findings

Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9–56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine.

Interpretation

Loncastuximab tesirine has substantial single-agent antitumour 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.

Funding

ADC Therapeutics.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma.1, 2 Approximately 40% of patients with DLBCL have refractory disease or relapse after initially responding to first-line chemoimmunotherapy.3, 4, 5 Outcomes for patients who are unsuitable for salvage chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) and for those who do not respond or who relapse after such treatment remain poor, despite recent approvals of novel therapeutic approaches, including chimeric antigen receptor (CAR) T-cell therapy.6, 7, 8, 9, 10, 11, 12, 13

Loncastuximab tesirine (formerly ADCT-402) is an antibody-drug conjugate comprising a humanised anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin, SG3199.14 It targets B-lymphocyte antigen CD19, a recognised immunotherapeutic target in B-cell non-Hodgkin lymphoma.10, 15 Loncastuximab tesirine is rapidly internalised by CD19-expressing cells, and the pyrrolobenzodiazepine dimer payload causes interstrand DNA crosslinks with minimal DNA distortion, which might contribute to their persistence in cells through evasion of DNA repair.14, 16 Furthermore, the short half-life of the payload limits accumulation, thereby limiting systemic toxicity.16, 17, 18

Research in context

Evidence before this study

Before study commencement in August, 2018, treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) included salvage chemoimmunotherapy followed by autologous haematopoietic stem-cell transplantation (HSCT), and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, which was approved in 2017 for use after the failure of two or more lines of systemic therapy. Many patients with relapsed or refractory DLBCL do not respond to second-line salvage chemoimmunotherapy, and cannot proceed to autologous HSCT. Patients with disease that is refractory to second-line chemoimmunotherapy, and those ineligible for autologous HSCT or relapse early after autologous HSCT, have a poor prognosis and need more effective treatments. The overall response rate with CAR T-cell therapy is high, but durable responses are mainly achieved in patients with complete response. Furthermore, not all patients can receive CAR T-cell therapy because of the time required for manufacture, the need for specialised inpatient care, and the risk of life-threatening complications.

We searched PubMed using the terms “DLBCL”, “CD19”, and “clinical trial” from Jan 1, 2010, to Dec 31, 2017, with no language restrictions, and identified ten publications, seven of which reported on CD19-directed therapies in DLBCL. Four of these seven publications assessed anti-CD19 CAR T-cell therapies. Other CD19 therapies evaluated were a bispecific T-cell engager antibody construct (in two studies), the optimal delivery of which has not been defined in DLBCL, and an antibody-drug conjugate (in one study), which failed to meet the study primary endpoint. Based on this evidence and promising phase 1 study results, we designed this trial to evaluate the CD19-directed antibody-drug conjugate loncastuximab tesirine in relapsed or refractory DLBCL.

Added value of this study

In this trial, with a primary endpoint of overall response rate assessed by central review, we found that the phase 2 dosing regimen of loncastuximab tesirine had a manageable safety profile and had high overall response rate with durable responses in heavily pretreated patients with relapsed or refractory DLBCL. These results are of particular importance because, to our knowledge, this trial included a broader sample of difficult-to-treat patients than did studies of other therapies approved for patients with relapsed or refractory DLBCL. Polatuzumab vedotin combined with bendamustine and rituximab, selinexor, and tafasitamab combined with lenalidomide have been approved for relapsed or refractory DLBCL; however, the trials of these drugs did not consistently include patients with heavily pretreated, transformed, or primary refractory DLBCL, or high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, or with MYC and BCL2 and BCL6 rearrangements.

Implications of all the available evidence

The durable clinical antitumour 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. Loncastuximab tesirine is also being investigated in combination with other therapies.

The first-in-human, phase 1, dose-escalation, and dose-expansion study (NCT02669017) showed loncastuximab tesirine had an acceptable safety profile and encouraging antitumour activity in relapsed or refractory B-cell non-Hodgkin lymphoma.17, 18 Haematological treatment-emergent adverse events occurred most frequently; toxicities considered likely to be related to the pyrrolobenzodiazepine payload included oedema and effusions, liver enzyme elevations, and rash. However, toxicity was generally reversible and manageable by dose delays.18 Patients with DLBCL had an overall response rate of 42·3% and a short median time-to-first-response of 6 weeks.18 Encouraging responses were seen in patients with high-risk characteristics.18 The recommended phase 2 dose was identified as 150 μg/kg once every 3 weeks for two cycles, to optimise the frequency of response, followed by 75 μg/kg once every 3 weeks thereafter, to mitigate the onset of toxicities developing after several treatment cycles.18

We aimed to further evaluate the antitumour activity and safety of single-agent loncastuximab tesirine in patients with relapsed or refractory DLBCL.

Section snippets

Study design and participants

We did an open-label, single-arm, phase 2 trial (LOTIS-2) across 28 hospital sites in the USA, UK, Italy, and Switzerland (appendix p 8). Patients aged 18 years or older with investigator-defined relapsed or refractory DLBCL (2016 WHO classification; including DLBCL not otherwise specified, 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)19 after two or more multiagent systemic treatment

Results

Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine (figure 1). 137 (94%) of 145 patients discontinued treatment during follow-up; the most common reason for treatment discontinuation was disease progression (81 [59%] of 137 patients). Baseline demographic and clinical characteristics are shown in table 1.

In the futility analysis, 24 of 52 patients had complete or partial response

Discussion

In this study, single-agent loncastuximab tesirine produced durable responses, with an overall response rate of 48·3%, in heavily pretreated patients with relapsed or refractory DLBCL. In most responding patients, the initial dose led to onset of response by their first disease assessment 6 weeks after treatment start (after two cycles). Dose reduction from cycle three maintained the same level of steady-state exposure. Futility requirements were met before proceeding to full enrolment.

No new

Data sharing

The study protocol is available in the appendix. Summary data for study are posted at ClinicalTrials.gov as required. Proposals requesting deidentified participant data collected for the study following publication can be sent to [email protected] and will be evaluated on a case-by-case basis.

Declaration of interests

PFC reports grants from ADC Therapeutics, during the conduct of the study; and grants and personal fees from Genentech, personal fees from ADC Therapeutics, Kite Pharmaceuticals, Verastem, Seattle Genetics, Amgen, TG Therapeutics, and Celgene, outside of the submitted work. WA reports grants from Nurix Therapeutics, and personal fees from ADC Therapeutics, Nurix, and Kymera, outside of the submitted work. JPA reports personal fees from ADC Therapeutics, OncLive, and Oncinfo, outside of the

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