SOHO 2022: Loncastuximab Tesirine Demonstrates Promising Antitumor Activity in Patients with Relapsed/Refractory DLBCL

Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) usually do not respond well
with standard therapy.
Loncastuximab tesirine（Loncastuximab tesirine-lpyl； Lonca) is a novel antibody drug conjugate (ADC) consisting of pyrrolobenzobenzodiazepine (PBD) dimer cytoxin conjugated with an anti-CD19 monoclonal antibody for patients with R/R DLBCL after prior treatment with ≥
2-line systems.
There is preclinical evidence that the addition of rituximab to targeted CD19 ADC therapy may prolong tumor control time
.
Based on this, the investigators conducted the LOTIS-5 trial to evaluate the efficacy
of standard immunotherapy with Lonca+R (Lonca-R) and R+ gemcitabine + oxaliplatin (R-GemOx) in patients with R/R DLBCL 。 Based on data from the ongoing Phase III LOTIS-5 trial (NCT04384484) Part 1, Loncastuximab Tesirine-lpyl (Zynlonta) in combination with rituximab (Rituxan) has demonstrated encouraging antitumor activity and acceptable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), The trial data was presented
at the 10th Annual Meeting of the American Society of Hematology-Oncology (SOHO).

The study was a phase III, randomized, open-label, two-part, two-arm, multicenter study
.
Part 1 is a non-randomized safety lead-in period in which 20 patients are enrolled to determine the safety of
Lonca-R.
In Part 2, approximately 330 patients will be randomized to receive either Lonca-R or R-GemOx in a 1:1 ratio
.
The key inclusion criteria were: (1) age≥ 18 years; (2) Patients diagnosed with DLBCL (including DLBCL converted from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; (3) Have received ≥ first-line systemic therapy in the past; (4) Do not meet the conditions for hematopoietic stem cell transplantation; (5) Diseases
that can be evaluated according to Lugano 2014 criteria.

The primary endpoint was progression-free survival (PFS).

Secondary endpoints were overall survival (OS), overall response rate (ORR), safety, duration of response (DOR), pharmacokinetics, and change in
patient-reported outcomes.

At the cut-off date of 28 February 2022, the median duration of follow-up was 5.
83 months (1.
9 to 10.
3).

The median age of the 20 patients in the safety transition period was 74.
5 years (range 35-93 years), and the median number of previous treatments was 1 (range 1-6).

The baseline characteristics of the patient are shown
in Table 1.

Table 1

As of 28 February 2022, the median number of doses was 5 (range: 1-8) and the median follow-up was 5.
83 months (range: 1.
9-10.
3).

Nineteen (95%) patients developed ≥ 1 adverse event (TEAE) during treatment, and 10 (50%) patients developed grade 3 TEAE
≥.
The most common of all grades of TEAE were rash (5 [25%]), fatigue (4 [20%]), and elevated γ-glutamyltransferase (4 [20%]).

The most common grade 3 TEAE ≥ were elevated γ-glutamyltransferase (3 [15%]), elevated alanine aminotransferase (2 [10%]), and neutropenia (2 [10%]).

The patient's ORR was 15/20 (75%)
.
A total of 8/20 (40%) and 7/20 (35%) achieved a complete and partial response
, respectively.
The efficacy and safety are shown
in Table 2.

Table 2

The objective response rate (ORR) for combination therapy was 75% (n=15; 95% CI: 50.
9% to 91.
3%)
.
In addition, 40% (n=8; 95% CI, 19.
1% to 63.
9%) achieved a complete response and 35% (n=7; 95% CI, 15.
4% to 59.
2%) achieved a partial response
.

Following the encouraging data from Part 1, the LOTIS-5 study has now been extended to Part
2 of the study.
Part 2 of the study will include 1:1 randomization starting in January 2022, with recruitment ongoing
.

"Loncastuximab in combination with rituximab showed no new safety signals and showed encouraging antitumor activity in patients with relapsed/refractory DLBCL during the non-randomized safety lead-in period," principal investigator Edwin C.
Kingsley, PhD, of the Las Vegas Comprehensive Cancer Center in Nevada, said
in the data presentation.

Patients with relapsed or refractory DLBCL who progress after standard therapy tend to have a poor
prognosis.

Loncastuximab tesirine is an antibody-drug conjugate (ADC) conjugated by a humanized monoclonal antibody targeting CD19 with a cytotoxin-pyrrolobenzodiazepine (PBD) dimer, which, once bound to CD19-expressing cells, is able to be internalized by cells and release cytotoxins
.

Preclinical data suggest that the addition of rituximab to anti-CD19 ADC therapy may prolong tumor control time
.
This basis serves as the basis for
the LOTIS-5 study.

LOTIS-5 is a randomized, 2-part, two-arm, multicenter study
.
Part 1 of the trial enrolled 20 patients treated with Loncastuximab Tesirine + rituximab during a nonrandomized, safety lead-in period to determine the safety of
the regimen.
In Part 2 of the study, approximately 330 patients will be randomized to receive either a trial protocol or standard chemoimmunotherapy, including rituximab plus gemcitabine and oxaliplatin
.

Eligible patients ≥ 18 years of age with a pathologic diagnosis of relapsing/refractory DLBCL, including DLBCL
that has transformed from indolent lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement.
Patients must have progressed during at least first-line prior systemic therapy, be unsuitable for stem cell transplantation, and have measurable disease
.
In addition, if CD19-targeted therapy has been previously received, the patient's ECOG performance status must be 0-2, organ function adequate, and be proven CD19 positive
.

Patients who had previously received Loncastuximab Tesirine or rituximab, gemcitabine, and oxaliplatin, or who had received autologous or allogeneic stem cell transplantation within 30 or 60 days prior to trial initiation, were not eligible
for enrollment.
People with active central nervous system involvement or evidence of chronic HBV infection are not eligible
to participate in the study.
In addition, major surgery radiotherapy or chemotherapy in the 14 days prior to initiation of study drug therapy were not eligible
for enrollment.

Patients evaluated during the safety introduction period received 0.
15 mg/kg Loncastuximab Tesirine and 375 mg/m^2 rituximab every 3 weeks for 2 cycles, followed by 0.
075 mg/kg and 375 mg/m^2 Loncastuximab Tesirine for up to 6 additional cycles
.

The primary endpoint of the study was progression-free survival as determined by independent central review
.
Secondary endpoints of phase III trials included overall survival, ORR, safety, duration of response, pharmacokinetic parameters, and change in
patient-reported outcomes.

The median age of patients treated in the trial was 74.
5 years (35-93 years) and the median number of previous systemic treatments was 1 (1-6).

Most patients were female (55%; n=11)； 45% were male (n=9).

The disease stage of enrolled patients was stage II (30%; n=6), phase III (30%; n=6) or stage IV (40%; n=8)
。 Most (85%; n=17) patients developed DLBCL n.
e.
, and 15% (n=3) patients developed high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
.

All patients reviewed had not previously received a stem cell transplant, and most had relapse during first-line treatment (90%; n=18)
。

The median number of doses was 5 (1-8).

In terms of safety, 95% (n=19) of patients developed at least one treatment-in-treatment adverse reaction (TEAE) and 50% (n=10) ≥developed grade 3 TEAE
.

The most common TEAE recorded in the study was a rash (25%; n=5), fatigue (20%; n=4) and γ-glutamyltransferase elevated (20%; n=4)
。 ≥ grade 3 TEAE included an increase in γ-glutamyltransferase (15%; n=3), alanine aminotransferase elevation (10%; n = 2) and neutropenia (10%; n=2)
。

Reference sources

Kingsley E,et al.
Initial Safety Run-In Results of the Phase 3 LOTIS-5 Trial: Novel Combination of Loncastuximab Tesirine With Rituximab (Lonca-R) Versus Immunochemotherapy in Patients With R/ R DLBCL.
2022 SOHO.
ABCL-320.