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.