Results of LOTIS-2, a multicenter, open-label, single-arm Phase II clinical trial evaluating the safety and efficacy of single-agent loncastuximab tesirine-lpyl (Zynlonta™; ADC Therapeutics; previously known as ADCT-402) in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) following two or more systemic treatments, demonstrated substantial single-agent activity, durable responses and an acceptable safety profile in a broad population of difficult-to-treat patients with relapsed or refractory DLBCL.

The results of the study were published online on May 11, 2021, in The Lancet Oncology. [1]

Treatment options
Today, the majority of patients with DLBCL can be treated and cured with standard rituximab (Rituxan®; Genentech/Roche), cyclophosphamide (Cytoxan®; Bristol-Myers Squibb), doxorubicin (Adriamycin®; Pfizer/Pharmacia Oncology), vincristine (Oncovin®; Hospira/Pfizer), and prednisone known as R-CHOP. However, patients who fail R-CHOP generally have poor outcomes. Hence, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. [2]

One of these treatment options is loncastuximab tesirine, a CD19-directed antibody-drug conjugate (ADC). Once bound to a CD19-expressing cell, loncastuximab tesirine is internalized by the cell, where enzymes release and traffic SG3199, a highly cytotoxic DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PDB) dimer payload to lysosomes in CD19-expressing cells. The potent payload binds to DNA minor groove with little distortion, remaining less visible to DNA repair mechanisms. This ultimately results in cell cycle arrest and tumor cell death.[3][4]

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Urgent medical need
“Patients with relapsed or refractory DLBCL who have been heavily pretreated and have difficult-to-treat disease represent an urgent area of medical need that newly approved loncastuximab tesirine is now able to address,” said Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University and lead author of the published study.

“The LOTIS-2 study established that loncastuximab tesirine demonstrated substantial single-agent activity and produced durable responses with an acceptable safety profile in this patient population,” Caimi added.

Study results
LOTIS-2 enrolled 145 patients, aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0-2. This included patients with high-risk characteristics for poor prognoses, such as double-/triple-hit, transformed, and primary refractory DLBCL.

Eligible patients participating in the multicentre trial, conducted in 28 hospital sites in the United States, United Kingdom, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision.

The study’s key findings included an overall response rate (ORR) of 48.3% (70/145 patients), including a 24.1% (35/145 patients) complete response rate and 24.1% (35/145 patients) partial response (PR) rate.  The median time to first response, which was analyzed post-hoc, was 41 days and, as of the data cut off, the median duration of response was 10.3 months.

The study also demonstrated durable responses in high-risk patient groups included 46.2% (6/13 patients) ORR in those who had progression after prior CAR-T therapy with axicabtagene ciloleucel (Yescarta®; Gilead/Kite) or tisagenlecleucel (Kymriah®; Novartis), 33.3% (5/15 patients) ORR in a double or triple hit, and 44.8% (13/29 patients) ORR in transformed DLBCL.  Based on the study results, the authors concluded that loncastuximab tesirine demonstrated an acceptable safety profile.

The most common Grade ≥3 treatment-emergent adverse events were neutropenia (25.5%), thrombocytopenia (17.9%), and increased gamma-glutamyltransferase (16.6%)

The U.S. Food and Drug Administration (FDA) has approved loncastuximab tesirine for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from low-grade lymphoma and also high-grade B-cell lymphoma.

This indication is approved by the FDA under accelerated approval based on the overall response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“We are proud to have the results of our LOTIS-2 trial published in a prestigious peer-reviewed journal,” noted Jay Feingold, MD, Ph.D., Senior Vice President and Chief Medical Officer at ADC Therapeutics.

“On the heels of the FDA approval, this further reinforces the value of loncastuximab tesirine as the first CD19-targeted ADC single-agent treatment for relapsed or refractory DLBCL and the potential for it to become the standard-of-care for 3L+ DLBCL patients in need of new treatment options,” Feingold concluded.

Adverse reactions
In a pooled safety population of 215 patients participating in both the phase I and LOTIS-2 studies, the most common (>20%) observed adverse reactions, including laboratory abnormalities, were thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

Serious adverse responses were observed in 28% of patients participating in the LOTIS-2 study who received loncastuximab tesirine. In these patients, the most common observed adverse reactions of patients occurring in ≥2% of patients receiving loncastuximab tesirine were febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Fatal adverse reactions occurred in 1%, due to infection. The study results also showed the occurrence of serious, Grade 3, cutaneous reactions in 4% which included photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

Overall, the authors of the study article in The Lancet Oncology conclude that loncastuximab tesirine has substantial single-agent antitumor activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL.[1]

Clinical trial
tudy of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL) – NCT02669017
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2) – NCT03589469

Highlights of prescribing information
Loncastuximab Tesirine (Zynlonta™; ADC Therapeutics [Prescribing Information]
Cyclophosphamide (Cytoxan®; Bristol-Myers Squibb) [Prescribing In formation]
Doxorubicin (Adriamycin®; Pfizer/Pharmacia Oncology) [Prescribing Information]
Vincristine (Oncovin®; Hospira/Pfizer) [Prescribing Information]
Prednisone (Generic) [Prescribing Information]
Axicabtagene ciloleucel (Yescarta®; Gilead/Kite)[Prescribing Information]
Tisagenlecleucel (Kymriah®; Novartis) [Prescribing Information]

[1] Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 May 11:S1470-2045(21)00139-X. doi: 10.1016/S1470-2045(21)00139-X. Epub ahead of print. PMID: 33989558.
[2] Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015 Jan 1;125(1):22-32. doi: 10.1182/blood-2014-05-577189. Epub 2014 Dec 11. PMID: 25499448.
[3] Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, Feingold JM, Ardeshna KM, Solh M, Heffner LT, Ungar D, He S, Boni J, Havenith K, O’Connor OA. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Epub 2019 Nov 4. PMID: 31685491.
[4] Zammarchi F, Corbett S, Adams L, Tyrer PC, Kiakos K, Janghra N, Marafioti T, Britten CE, Havenith CEG, Chivers S, D’Hooge F, Williams DG, Tiberghien A, Howard PW, Hartley JA, van Berkel PH. ADCT-402, a PBD dimer-containing antibody-drug conjugate targeting CD19-expressing malignancies. Blood. 2018 Mar 8;131(10):1094-1105. doi: 10.1182/blood-2017-10-813493. Epub 2018 Jan 3. PMID: 29298756.

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