Loncastuximab Tesirine/Rituximab Elicits Promising Anti-Tumor Activity in Relapsed/Refractory DLBCL

Loncastuximab tesirine-lpyl (Zynlonta) combined with rituximab (Rituxan) demonstrated encouraging antitumor activity and a feasible safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to data from part 1 of the ongoing phase 3 LOTIS-5 trial (NCT04384484) presented at the 10th Annual Meeting of the Society of Hematologic Oncology.¹

At a data cutoff of February 28, 2022, with a median duration of follow-up of 5.83 months (range, 1.9-10.3), the combination led to an objective response rate (ORR) of 75% (n = 15; 95% CI, 50.9%-91.3%). Additionally, 40% (n = 8; 95% CI, 19.1%-63.9%) of patients achieved a complete response, and 35% (n = 7; 95% CI, 15.4%-59.2%) achieved a partial response.

The LOTIS-5 study has now expanded to part 2 of the study following encouraging data from part 1. Part 2 of the study will consist of a 1:1 randomization that commenced in January 2022; recruitment is ongoing.

“Loncastuximab [plus] rituximab demonstrated no new safety signals and showed encouraging antitumor activity in patients with relapsed/refractory DLBCL in a nonrandomized safety run-in period,” lead study author Edwin C. Kingsley, MD, of Comprehensive Cancer Centers of Nevada in Las Vegas, Nevada, stated in a presentation of the data. 

Patients with relapsed or refractory DLBCL tend to have suboptimal outcomes following standard treatment.

Loncastuximab tesirine is a novel antibody-drug conjugate (ADC) composed of an anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin that is approved for the treatment of patients with relapsed/refractory DLBCL following at least 2 prior therapies.

Preclinical data has shown that the addition of rituximab to anti-CD19 ADC therapy may result in prolonged tumor control. This rationale served as the basis for the LOTIS-5 study.

LOTIS-5 is a randomized, 2-part, 2-arm, multi-center study. Part 1 of the trial enrolled 20 patients in a non-randomized, safety run-in period with loncastuximab tesirine plus rituximab to establish the safety of the regimen. In part 2 of the study, approximately 330 patients will be randomly assigned to receive the investigational regimen or standard chemoimmunotherapy consisting of rituximab plus gemcitabine and oxaliplatin.

Eligible patients were 18 years of age or older and had received a pathologic diagnosis of relapsed/refractory DLBCL, including DLBCL transformed from indolent lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. Patients must also have progressed on at least 1 line of prior systemic treatment, be ineligible for stem-cell transplantation, and have measurable disease. Furthermore, patients must have had an ECOG performance status between 0 and 2, adequate organ function, and proven CD19 positivity if previously treated with CD19-directed therapy.

Patients were excluded from the study if they had received previous treatment with loncastuximab tesirine, or rituximab, gemcitabine, and oxaliplatin, or if they had been treated with autologous or allogeneic stem cell transplant within 30 or 60 days before beginning the trial, respectively. Active central nervous system involvement rendered patients ineligible for the study, as did evidence of a chronic HBV infection. Additionally, major surgery radiotherapy, or chemotherapy within 14 days of starting the study drug precluded patients from enrollment.

Patients evaluated in the safety run-in received 0.15 mg/kg of loncastuximab tesirine with 375 mg/m2 of rituximab every 3 weeks for 2 cycles, followed by loncastuximab tesirine at 0.075 mg/kg and 375 mg/m2 for up to 6 additional cycles.

The primary end point of the study is progression-free survival by independent central review. Secondary end points of the phase 3 trial include overall survival, ORR, safety, duration of response, pharmacokinetic parameters, and changes in patient-reported outcomes.

The median age of patients treated on the trial was 74.5 years of age (range, 35-93) and the median number prior systemic therapies was 1 (range, 1-6). Most patients were female (55%; n = 11); 45% were male (n = 9). Enrolled patients had stage II (30%; n = 6), stage III (30%; n = 6), or stage IV (40%; n = 8) disease. A majority (85%; n = 17) of patients presented with DLBCL not otherwise specified, and 15% (n = 3) of patients presented with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.

All patients evaluated did not undergo previous stem cell transplant and most patients had relapsed (90%; n = 18) on their first-line therapy.

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

In terms of safety, 95% (n = 19) of patients had at least 1 treatment-emergent adverse effect (TEAE), and 50% of patients (n = 10) had a grade 3 or higher TEAE.

The most common TEAEs recorded were rash (25%; n = 5), fatigue (20%; n = 4), and increased gamma-glutamyltransferase (20%; n = 4). Grade 3 or greater TEAEs included increased gamma-glutamyltransferase (15%; n = 3), increased alanine aminotransferase (10%; n = 2), and neutropenia (10%; n = 2).

Reference

1. Kingsley E, Grosicki S, Kwiatek M, 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. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology; September 28-October 1, 2022; Houston, TX. Abstract ABCL-320