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Diffuse large B‐cell lymphoma (DLBCL) is an aggressive subtype of non‐Hodgkin lymphoma with a high rate of disease relapse despite the achievement of clinical responses to frontline chemoimmunotherapy treatments. Loncastuximab tesirine‐lpyl is a novel anti‐CD19 antibody conjugated to an alkylating pyrrolobenzodiazepine agent (SG3199), and it has been approved for relapsed/refractory (r/r) DLBCL. Baseline moderate to severe hepatic impairment has an unclear impact on the safety of loncastuximab tesirine‐lpyl, and there is a lack of clear guidance on dose adjustment from the manufacturer. The authors present two cases of r/r DLBCL safely treated with full‐dose loncastuximab tesirine‐lpyl in the setting of severe hepatic dysfunction. Baseline moderate to severe hepatic impairment has an unclear impact on the safety of loncastuximab tesirine‐lpyl. Two cases of relapsed/refractory diffuse large B‐cell lymphoma safely treated with full‐dose loncastuximab tesirine‐lpyl in the setting of severe hepatic dysfunction are presented. [ABSTRACT FROM AUTHOR]

Currently, a significant percentage of patients with DLBCL are refractory or relapse after a first line of immunochemotherapy. Second relapses after autologous stem cell transplantation or chimeric antigen receptor T-cell therapies present few treatment options and do not yield good results. New molecules have entered the immunotherapy arsenal. Loncastuximab tesirine comprises a humanized anti-CD19 monoclonal conjugated antibody, which consists of an anti-CD19 antibody and cytotoxic alkylating agent, SG3199. Several studies have proven its efficacy in the treatment of refractory cases of DLBCL with a good safety profile, with the main adverse effects being neutropenia, thrombopenia, and liver enzyme involvement. In this review, we explain the mechanism of action of this molecule, the clinical data that have led to its acceptance by the FDA, and the new therapeutic options that are proposed in association with this drug. [ABSTRACT FROM AUTHOR]

The efficacy of loncastuximab tesirine (lonca) following chimeric antigen receptor T-cell therapy (CAR-T) progression/failure is unknown. Hence, we sought to examine real-world use and outcomes of lonca following CAR-T in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the USA. In this retrospective study, we included adults (age ≥ 18 years) with R/R DLBCL who received lonca monotherapy as third- (3 L) or fourth line (4 L) treatment after progressing on second line (2 L) or 3 L CAR-T, respectively. Post-CAR-T lonca outcomes included response rates (overall response rate [ORR] and complete response [CR] rate), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). A total of 118 patients were included in the analysis with 95 receiving lonca following 2 L CAR-T (median age:66 years; 61% male) and 23 following 3 L CAR-T (median age:57 years; 43% male). Patients with 2 L CAR-T/3 L lonca had an ORR of 73% (CR rate of 34%). With a median follow-up of 8.5 months following lonca initiation, median DOR, PFS, and OS were not reached. The DOR, PFS, and OS at 12 months were 68%, 77%, and 84%, respectively. Patients with 3 L CAR-T/4 L lonca had an ORR of 78% (CR rate of 17%). With a median follow-up of 13 months following lonca initiation, the median DOR and PFS were 7.6 and 12.0 months, while median OS was not reached. OS at 12 months was 95%. In this study, we found that lonca monotherapy was an effective treatment option in R/R DLBCL in 3 L and 4 L settings including those who were resistant to or progressed after CAR-T. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin's lymphoma in the United States, with approximately 40% of first-line DLBCL chemoimmunotherapy attempts failing. The FDA approved a new type of antibody–drug conjugate (ADC), Zynlonta (loncastuximab tesirine), once called ADCT-402, on April 23, 2021, for relapsed or refractory (R/R) DLBCL. Loncastuximab tesirine comprises a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Purpose: The purpose of this article is to review the pharmacological properties of loncastuximab tesirine and evaluate its efficacy and safety in the treatment of R/R DLBCL. Methods: In PubMed, Web of Science and CNKI, I searched for relevant literature as of November 2021 through some keywords. Obtained loncastuximab tesirine essential drug and related clinical trial information on https://www.adctherapeutics.com/ and clinicaltrials.gov. Results: Once it binds with cells expressing CD19, loncastuximab tesirine is internalized by the cell and then releases SG3199, which irreversibly binds to the DNA, thereby disrupting the basic DNA metabolism process and ultimately leading to cell death. The results of the main non-comparative clinical trials LOTIS-1, LOTIS-2 and LOTIS-3 were encouraging. In LOTIS-1, the overall response rate (ORR) of R/R DLBCL patients treated with loncastuximab tesirine was 42.3%, and loncastuximab tesirine had excellent stability and acceptable safety profile. The recommended dosage of loncastuximab tesirine is 0.15 mg/kg every three weeks for two cycles, 0.075 mg/kg every three weeks for each subsequent cycle. The pivotal LOTIS-2 showed that loncastuximab tesirine had substantial single-agent antitumour activity in patients with R/R DLBCL: the ORR and complete response rate were 48.3% and 24.1%, respectively, and produced a durable response with acceptable safety and tolerability. The results of the LOTIS-3 phase 1 portion indicated that loncastuximab tesirine 60 µg/kg plus ibrutinib 560 mg had encouraging antitumour activity in R/R DLBCL, with an ORR of 56.7%. Haematological adverse events such as anaemia and neutropenia, non-haematological events such as fatigue and nausea, and biochemical events such as γ-glutamyl transferase increase, and blood alkaline phosphatase increases were common after administration of loncastuximab tesirine. Conclusions: Loncastuximab tesirine is a CD19-targeted ADC that addresses the unmet needs of R/R DLBCL patients who have been heavily pretreated, comprising high-risk populations. [ABSTRACT FROM AUTHOR]

Loncastuximab tesirine (loncastuximab tesirine-lpyl; ZYNLONTA™) is an antibody-drug conjugate being developed for the treatment of B cell lymphomas by ADC Therapeutics SA. Loncastuximab tesirine consists of a pyrrolobenzodiazepine DNA-alkylating warhead covalently attached via a cleavable linker to an anti-CD19 antibody that binds to B cells. It is currently approved in the US for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL), and is being developed for the treatment of mantle-cell lymphoma, follicular lymphoma and acute lymphoblastic leukaemia. This article summarizes the milestones in the development of loncastuximab tesirine leading to this first approval for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (NOS), DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Relapsed or refractory diffuse large B cell lymphoma (DLBCL) has a poor prognosis. Several novel therapies have gained regulatory approval for treatment of DLBCL, however there is still a need for additional therapies to be added to the armamentarium. Loncastuximab tesirine-lpyl (ADC Therapeutics), an anti-CD19 antibody-drug conjugate (ADC), was recently approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (DLBCL). We review the design and pharmacologic characteristics of loncastuximab tesirine-lpyl, emphasizing on the significance of CD19 as an effective target as well as pyrrolobenzodiazepine (PBD) as an effective payload. We review the key findings of the phase 1 LOTIS-1 and Phase 2 LOTIS-2 trials of loncastuximab in DLBCL, including efficacy and toxicity profile. Key findings in the early-phase trial support the efficacy of Loncastuximab in DLBCL, including in high-risk subgroups. The side effects have been tolerable even in elderly patients (≥75 years). Several ongoing clinical trials are currently evaluating the safety and efficacy of loncastuximab tesirine in a variety of NHL subtypes, as well as the study of combination strategies. [ABSTRACT FROM AUTHOR]

B Introduction: b Patients (pts) with diffuse large B-cell lymphoma (DLBCL) who relapse after stem cell transplant or chimeric antigen receptor therapy or are refractory to second-line therapy have poor prognosis and few treatment options (Chow et al., 2019). LONG-TERM RESPONSES WITH LONCASTUXIMAB TESIRINE: UPDATED RESULTS FROM LOTIS-2, THE PIVOTAL PHASE 2 STUDY IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA Stock ownership: ADC Therapeutics Research funding: ADC Therapeutics B L. Wang b Employment or leadership position: ADC Therapeutics. [Extracted from the article]

We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure–response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan–Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores > 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p < 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p < 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469. [ABSTRACT FROM AUTHOR]

Three new drugs are presented: dostarlimab, loncastuximab tesirine, and aducanumab. Product information, clinical trials, and recommendations are provided. Dostarlimab (Jemperli®) is FDA-indicated for the treatment of adult patients with mismatch repair deficient (dMMR - an abnormality that affects DNA repair) recurrent or advanced endometrial cancer (EC). Loncastuximab tesirine (Zynlonta®) is FDA-indicated 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, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. Aducanumab (Aduhelm®) is FDAindicated for the treatment of Alzheimer’s disease. It is an amyloid beta-directed antibody developed by Biogen of Cambridge, Massachusetts. This indication was approved on June 7, 2021, under the accelerated approval based on the reduction in amyloid beta plaques in patients treated with the drug. [ABSTRACT FROM AUTHOR]

B Methods: b To evaluate the combination of imvotamab and loncastuximab tesirine in vitro, the human B lymphoma Raji cell line that expresses CD19 and CD20 was co-cultured with healthy human peripheral blood mononuclear cells (PBMCs) and subsequently evaluated for T cell activation and T cell-dependent cellular cytotoxicity (TDCC). Additionally, immunohistochemistry (IHC) staining of CD19 and CD20 was conducted on formalin-fixed paraffin-embedded Raji xenograft tumors to confirm target expression in treated animals. We evaluated the combination of imvotamab, an engineered bispecific anti-CD20 IgM antibody T cell engager (TCE) that eliminates CD20+ lymphoma cells by T cell and complement-mediated killing, and loncastuximab tesirine, a FDA and EMA-approved CD19-directed antibody drug conjugate (ADC) in a preclinical model of NHL. [Extracted from the article]

The antibody-drug conjugate (ADC) loncastuximab tesirine (loncastuximab tesirine-lpyl, Zynlonta®), is a useful option for third-line and subsequent treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Loncastuximab tesirine comprises a humanized anti-CD19 antibody linked to a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent. It is the first CD19-targeted ADC approved for third-line and subsequent treatment of relapsed or refractory large B-cell lymphoma, DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. In the pivotal phase II LOTIS-2 trial, loncastuximab tesirine as monotherapy produced an overall response rate (ORR) of 48% in heavily pre-treated patients with relapsed or refractory DLBCL, some of whom had previously received chimeric antigen receptor (CAR)-T cell therapy or hematopoietic stem cell transplantation (HSCT). The adverse event profile of loncastuximab was consistent with that seen with other PBD-based treatments, characterized by fluid overload and elevated γ-glutamyl transferase levels. Plain Language Summary: Loncastuximab tesirine (Zynlonta®) is a novel anticancer therapy that uses a humanized antibody to deliver a toxic drug payload directly to cancer cells. The antibody component of loncastuximab tesirine targets a cell surface protein called CD19 that is unique to B lymphocytes, a type of white blood cell. Upon binding to CD19 on the cell surface, the antibody-drug conjugate is drawn inside, whereupon the toxic payload is released. Loncastuximab tesirine is approved in the USA for third-line and subsequent treatment of adult patients with relapsed or refractory large B-cell lymphoma including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. In the pivotal clinical trial that led to this approval, loncastuximab tesirine monotherapy produced an overall response rate of 48% in heavily pre-treated patients with relapsed or refractory DLBCL, and had an adverse event profile consistent with that seen with other treatments that use the same toxic payload. On this basis, monotherapy with loncastuximab tesirine can be considered as a useful option for third-line and subsequent treatment of DLBCL. [ABSTRACT FROM AUTHOR]

LOTIS-5, AN ONGOING PHASE 3 RANDOMIZED STUDY OF LONCASTUXIMAB TESIRINE WITH RITUXIMAB (LONCA-R) VERSUS IMMUNOCHEMOTHERAPY IN PATIENTS WITH R/R DLBCL Rituximab (R), an anti-CD20 monoclonal antibody, is part of standard immunotherapy for DLBCL, both as frontline therapy and in subsequent treatments. B Introduction: b Patients with relapsed or refractory ( I R i / I R i ) diffuse large B-cell lymphoma (DLBCL) typically have poor outcomes following standard treatment. [Extracted from the article]

B Introduction: b Combining agents with different mechanisms of action may enhance treatment (Tx) efficacy in patients (pts) with relapsed/refractory ( I R i / I R i ) B-cell non-Hodgkin lymphoma (B-NHL). The safety and activity of Lonca combined with other agents in pts with I R i / I R i B-NHL will be evaluated in LOTIS-7. PHASE 1B OPEN-LABEL STUDY OF LONCASTUXIMAB TESIRINE IN COMBINATION WITH OTHER ANTICANCER AGENTS IN PATIENTS WITH RELAPSED/REFRACTORY B-CELL NON-HODGKIN LYMPHOMA (LOTIS-7). [Extracted from the article]

Objective: This article summarizes the background, clinical trials, and place in therapy for the first two anti-CD19 monoclonal antibodies that have been recently FDA approved for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Summary: Treatment options are limited for patients that have relapsed after or are ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T-cell therapy. Recent novel therapy approvals have started to change management strategies and outcomes for these patients. Two examples of recent FDA approvals are tafasitamab and loncastuximab tesirine, which represent the first anti-CD19 targeting monoclonal antibodies for patients with R/R DLBCL. Tafasitamab was granted accelerated approval in combination with lenalidomide for adult patients with R/R DLBCL after one or more lines of therapy based on the phase 2, L-MIND trial. Loncastuximab tesirine was granted accelerated approval for adult patients with R/R DLBCL after two or more lines of therapy based on the phase 2, LOTIS-2 trial. The place in therapy and sequencing of these agents can present a challenge to prescribers especially in regards to patients being evaluated for CD19 targeting CAR T-cell therapy. Conclusion: Tafasitamab and loncastuximab tesirine are options for use in patients with R/R DLBCL and are welcome additions to the limited therapy options for these patients. Further data is needed to elucidate sequencing and the impact these agents may have on CAR T-cell therapy. Ongoing clinical trials are studying these agents in the upfront setting in combination with other chemoimmunotherapy agents which may further expand treatment options for patients with B-cell lymphomas. [ABSTRACT FROM AUTHOR]

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