Loncastuximab tesirine in relapsed or refractory DLBCL: Results from a phase II trial

The CD19-targeted antibody–drug conjugate, loncastuximab tesirine, was recently added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the treatment of B-cell lymphomas. The approval of loncastuximab tesirine by the U.S. Food and Drug Administration (FDA) was based on the results of the phase II LOTIS-2 trial (NCT03589469), as previously reported on the Lymphoma Hub. The drug can be used as a treatment option for patients with diffuse large B-cell lymphoma (DLBCL) who have relapsed following ≥2 lines of systemic therapy.

The phase II LOTIS-2 trial results have now been published in The Lancet Oncology by Caimi et al,¹ and the Lymphoma Hub is pleased to provide a summary of the study.

Study design

A single-arm, multicenter trial in patients aged ≥18 years with relapsed/refractory (R/R) DLBCL who received ≥2 prior lines of systemic therapy and had an Eastern Cooperative Oncology Group (ECOG) performance status 0–2. Loncastuximab tesirine was given to eligible patients (N = 145) intravenously on Day 1 of each 21-day cycle (150 µg/kg for two cycles, followed by 75 µg/kg per cycle for up to 1 year).

• The primary endpoint was overall response rate (ORR), defined according to 2014 Lugano classification as the proportion of patients with best overall response (complete response [CR] or partial response [PR]).
• Secondary endpoints included duration of response, CR rate, relapse-free, progression-free, and overall survival, and the frequency and severity of adverse events (AEs). 

Results

The primary analyses of anti-tumor activity and safety were based on all patients who received at least one dose of loncastuximab tesirine (as-treated population, N = 145). Of these, 137 (94%) discontinued treatment during follow-up, the most common reason for this being disease progression, which occurred in more than half of the patients (59%). The baseline characteristics are presented in Table 1.

Table 1. Baseline characteristics*

ABC, activated B-cell; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; HGBCL, high-grade B-cell lymphoma; HSCT, hematopoietic stem cell transplant; IQR, interquartile range; NE, not evaluable; PMBCL, primary mediastinal B-cell lymphoma. *Data from Caimi et al.1 †Investigator reported without independent testing. ‡Previous HSCT is included; for patients who received an autologous transplant, the mobilization regimen was considered a line of therapy if it was chemotherapy-based and distinct from the other previous lines of treatment.
Characteristic	As-treated population (N = 145)
Male/female sex, %	59/41
Median age, years (IQR)	66 (56–71)
Histology, %
DLBCL, NOS	88
HGBCL	8
PMBCL	5
GCB or ABC DLBCL,† %
GCB	33
ABC	16
Unknown	51
Disease stage at enrolment, %
I-II	23
III-IV	77
Previous systemic therapies,‡ %
2 lines	43
3 lines	24
>3 lines	32
Response to first-line systemic therapy, %
Relapse	68
Refractory	20
Unknown/NE/missing	12
Response to most recent line systemic therapy, %
Relapse	30
Refractory	58
Unknown/NE/missing	12
Refractory to all previous therapies, %
Yes	17
No	79
Unknown/NE/missing	3
Relapse within 3 months of first-line therapy, %	24
Relapse within 6 months of first-line therapy, %	39

Response and survival outcomes

• ORR was 48% (95% CI, 39.9–56.7), and patients achieving a CR and PR were equivalent (Table 2).
• The median time to first response (CR or PR) was 41 days (IQR, 38–44) and the median duration of response was 10.3 months (95% CI, 6.9–not estimable); 13.4 months for patients with CR and 5.7 months for patients with PR.
• Of the responders, 64% maintained responses for ≥9 months.
• Median progression-free, overall, and relapse-free survival were 4.9 months (95% CI, 2.9–8.3), 9.9 months (95% CI, 6.7–11.5), and 13.4 months (95% CI, 10.3–not estimable), respectively.
• Sixty-eight of 145 patients received subsequent therapy; 15 received CD19-directed chimeric antigen receptor (CAR) T-cell therapy. The ORR and CR rates to CAR T-cell therapy for these 15 patients were 47% and 40%, respectively.
• The median duration of treatment was 45 days (IQR, 22–113). The median average weight-adjusted dose per cycle was 113.5 µg/kg, and there was a median of 3 treatment cycles (IQR, 2–5).

Table 2. Response to loncastuximab tesirine in patients with R/R DLBCL assessed by central independent review*

Response, %	As-treated population (N = 145)
CI, confidence interval. *Data from Caimi et al.1 †Patients without PET-CT scan or whose scan was determined to be not evaluable by the independent reviewer.
Overall response rate	48.3 (95% CI, 39.9–56.7)
Complete response rate	24.1 (95% CI, 17.4–31.9)
Complete response	24
Partial response	24
Stable disease	15
Progressive disease	21
Not evaluable†	16

Adverse events

• Almost all patients (99%) reported at least one treatment-emergent AE (TEAE), the most common being neutropenia (26%), thrombocytopenia (18%), and increased gamma-glutamyl transferase (17%).
• At least one serious TEAE was reported in 39% of patients, with 15% considered to be related to loncastuximab tesirine. The most common of these were febrile neutropenia (4%), pleural effusion (1%), non-cardiac chest pain (1%), and pericardial effusion (1%).
• TEAEs related to pyrrolobenzodiazepine payload included edema or effusion (31%), skin or nail AEs (43%), and liver enzyme abnormalities (51%) and were mostly mild to moderate in severity and reversible.
• Dose modification or treatment discontinuation due to TEAEs was required in 62% of patients. Dose delays were the most common modifications, seen in more than half of patients (51%).
• More than half of patients died (53%); most deaths (78%) were due to disease progression. Fatal TEAEs were seen in only 6% of patients and these were not considered to be related to loncastuximab tesirine.

Conclusion

The study shows that loncastuximab tesirine produces durable responses in heavily pretreated patients with R/R DLBCL, including patients who had maintained CD19 expression after prior CD19-directed CAR T-cell therapy. Response to subsequent consolidation with HSCT or CAR T-cell therapy in some patients who had received loncastuximab tesirine highlights the potential for loncastuximab tesirine as a bridge to other therapies. A study evaluating loncastuximab tesirine plus ibrutinib (NCT03684694) is currently underway and has shown promising initial results.