Loncastuximab Tesirine Yields Durable Responses in Patients With Relapsed/Refractory MCL and Other B-Cell NHL Subtypes

The antibody-drug conjugate loncastuximab tesirine-lpyl (Zynlonta) as single-agent therapy elicited durable tumor responses in patients with relapsed/refractory mantle cell lymphoma (MCL) and other subtypes of B-cell non-Hodgkin lymphoma (B-NHL), according to the final results of a phase 1 study (NCT02669017).¹

Findings from the trial identified an overall response rate of 46.7% in patients with MCL (n = 15), which consisted of a complete response (CR) rate of 33.3% and a partial response (PR) rate of 13.3%. The median duration of response (DOR) for patients with MCL was not reached. Additionally, patients achieved a median progression-free survival (PFS) of 4.8 months (95% CI, 1.1-7.8 months). With up to 25 months of data, the median overall survival (OS) that was not yet reached due to a low number of events.

Loncastuximab tesirine consists of a humanized anti-CD29 monoclonal antibody that is stochastically conjugated through a cathepsin-cleavable valine-alanine linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer toxin.² Investigators consider CD19 to be a valuable target for immunotherapy agents in patients with B-NHL, as it is commonly expressed throughout B-cell development following B-lineage commitment.^3,4

The first-in-human, dose-escalation trial, which aimed to assess that safety and activity of single-agent loncastuximab tesirine, enrolled patients who were aged 18 or older with histologically-confirmed relapsed/refractory B-NHL who could not tolerate or progressed on available therapies. Part 1 of the 2-part trial took place in 11 centers across 3 countries, including the United States, the United Kingdom, and Italy.

Loncastuximab tesirine was given via intravenous infusion over 60 minutes once every 3 weeks on day 1 of each 21-day cycle. The first part of the study utilized a 3+3 dose escalation design that started patients with a dose of 15 μg/kg every 3 weeks. Patients included in the second half of the trial were assigned to the recommended dose level and regimen that was identified in the first part of the study.

In total, 183 patients were treated with loncastuximab tesirine, with 88 patients having received doses ranging from 15 μg/kg up to 200 μg/kg every 3 weeks. The cumulative toxicity observed at the 200 μg/kg dose resulted in a protocol amendment, with 22 patients having received said dose every 6 weeks. Investigators selected 120 μg/kg (n = 42) and 150 μg/kg (n = 88) every 3 weeks to be studied in the second part of the trial, although some patients who were given the 150 μg/kg dose were reduced to 75 μg/kg every 3 weeks following 3 cycles of treatment.

The primary objectives in part 1 of the study was to evaluate the agent’s safety and tolerability and determine the maximum-tolerated dose(s) and recommend dose(s) for the expansion portion of the study. In the second half of the study, primary objectives included evaluating safety and tolerability of loncastuximab tesirine at the recommended dose. Key secondary end points included the evaluation of antitumor activity; characterization of exposure to the total antibody, PBS antibody, and free warhead at different doses and cycles through pharmacokinetic parameters; and evaluating induction of antidrug antibody to the agent.

The majority of patients enrolled on the study had diffuse large B-cell lymphoma (DLBCL; 76.0%; n = 139) while others had MCL (8.2%; n = 15), follicular lymphoma (7.7%; n = 14), or other B-NHL histologies (8.2%; n = 15). Patients had a median of 3 prior lines of systemic therapy (range, 1-13), 23% had received prior hematopoietic cell transplantation, and 1.6% had underwent CAR T-cell therapy. The majority of patients were refractory to their most recent systemic therapy (59.6%) and 23.5% were primary refractory.

The most common reason for treatment discontinuation was progressive disease (45.4%) and the most common reason for study discontinuation was death (60.7%).

Additional data indicated that the overall study population had an ORR of 45.6% (95% CI, 38.1%-53.1%), including a CR rate of 26.7% and a PR rate of 18.9%. When examining ORR by histology, those with DLBCL had an ORR of 42.3% (95% CI, 33.9%-51.1%) and those with follicular lymphoma had a rate of 78.6% (95% CI, 49.2%-95.3%). The median time to response for responders within the total patient population was 43.0 days (range, 31-323).

The median DOR for the total patient population was 5.4 months (95% CI, 4.0–not reached), including 4.5 months in the DLBCL cohort (95% CI, 3.9-9.5). The median DOR was not reached in patients with follicular lymphoma The median PFS for the total patient population was 3.1 months (95% CI, 2.7-4.2), including 2.8 months in the DLBCL cohort (95% CI, 1.1-7.8). The median PFS was not reached in the follicular lymphoma cohort due to a low number of events. Additionally, the median OS for the overall population was 8.3 months (95% CI, 6.7-10.7), including 7.5 months in the DLBCL cohort (95% CI, 6.0-9.8). The median OS was not reached in the follicular lymphoma cohort due to a low number of events

Dose-limiting toxicities occurred in 4 patients and included grade 4 thrombocytopenia (n = 1; 120 μg/kg), grade 3 febrile neutropenia (n = 1; 150 μg/kg), and grade 4 thrombocytopenia (n = 2; 200 μg/kg). Hematologic any-grade treatment-emergent adverse effects (TEAEs) occurred commonly across all arms and included platelet count decrease (71.1%), neutrophil count decrease (59.2%), and anemia (32.8%). Additionally, common nonhematologic TEAEs in all cohorts included fatigue (42.6%), nausea (32.2%), and peripheral edema (31.7%). Common grade 3 or higher TEAEs included neutrophil count decrease (39.7%), platelet count decrease (26.7%), and gamma-glutamyl transferase increase (21.3%).

Loncastuximab tesirine was approved by the FDA in April 2021 for patients with relapsed/refractor large B-cell lymphoma, including DLBCL, following progression on 2 or more prior lines of therapy.⁵ The decision was based on findings from the phase 2 LOTIS-2 clinical trial (NCT03589469), which examined the agent in patients with relapsed/refractory DLBCL who had progressed after 2 or more lines of therapy. Findings from the study indicated that the agent yielded an ORR of 48.3%, including a CR rate of 24.1%.

References

1. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512
2. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131(10):1094-1105). doi:10.1182/blood-2017-10-813493
3. Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma. 1195;18(5-6):385-397. doi:10.3109/10428199509059636
4. Hammer O. CD19 as an attractive target for antibody-based therapy. MAbs. 2012;4(5):571-577. doi:10.4161/mabs.21338
5. ADC Therapeutics announces FDA approval of ZYNLONTA™ (loncastuximab tesirine-lpyl) in relapsed or refractory diffuse large B-cell lymphoma. News release. ADC Therapeutics SA. April 23, 2021. Accessed July 13, 2021. https://bit.ly/3eoY1l7