The efficacy of Loncastuximab tesirine to treat aggressive B-cell lymphoma

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MUSC Hollings Cancer Center was one of 28 clinical sites around the world that participated in the LOTIS-2 trial to test the efficacy of Loncastuximab tesirine, a promising new treatment for aggressive B-cell lymphoma.

The results of the single-arm, phase 2 trial were published online in May 2021 in Lancet Oncology.

Brian Hess, M.D., a Hollings researcher and lymphoma specialist at MUSC Health, was instrumental in bringing the phase 2 trial to Hollings. The manufacturer of Loncastuximab tesirine, ADC Therapeutics S.A., sponsored the trial.

B-cell non-Hodgkin lymphoma (NHL) is a blood cancer that begins in the lymph nodes, spleen or bone marrow. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive NHL. New treatment options are vital for patients with DLBCL.

While nearly two-thirds of patients have a durable response to frontline therapy, the remaining one-third of patients relapse or are refractory to frontline treatment and typically have a poor prognosis.

The trial was open label, which means the clinician and patient were aware of the treatment that was given, and it was available to patients 18 years or older with relapsed or refractory DLBCL after two or more lines of treatment. This trial is significant because it includes a difficult-to-treat patient population, said Hess.

“Traditional chemotherapy is very unlikely to lead to a sustained response in this patient population. CD19 CAR-T cell therapy is now approved and provides hope for durable response and cure for the majority of these patients; however, not everyone is a candidate for CAR-T cell therapy. In addition, the majority of patients that receive CD19 CAR-T cell therapy eventually relapse and are in need of novel therapies such as loncastuximab,” said Hess.

The LOTIS-2 trial tested the efficacy of Loncastuximab tesirine, an antibody-drug complex that targets CD19—the same molecule targeted on the lymphoma B-cells by CAR-T therapy.

The drug complex works by attaching to CD19, widely expressed on lymphoma B cells, and delivering the drug payload into the cell, thereby minimizing systemic toxicity. Once internalized, the drug damages the DNA of the lymphoma cells, leading to cell death.

“This is a novel mechanism of action that provides potential benefit for patients who otherwise do not have a lot of options,” said Hess. “For patients who are not candidates for, not interested in, or relapse after CAR-T, this is could be a promising therapy option.

Additionally, the drug is delivered intravenously every three weeks, so patient proximity to treatment centers is less critical for this therapy.”

The overall response rate in this clinical trial was 48% (70 out of 145 patients). This means that nearly 50% of relapsed DLBCL patients who had already tried two or more treatments had a complete or partial response to this new therapy.

The phase 2 trial result led to Food and Drug Administration (FDA) approval of Loncastuximab tesirine as a single agent. The next step will be to combine it with other agents to see if this improves efficacy and durability of response. This new trial is expected to be open for enrollment at MUSC in the next six months.

“I am excited that this therapy can now be given to patients who may live two to three hours away from Charleston, South Carolina, and not want or be able to travel to MUSC for treatment.

We look forward to providing education on the potential efficacy and toxicity of this agent to oncology practitioners throughout the state of South Carolina so that patients can receive this therapy locally,” said Hess.

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Chemotherapy represents an essential pillar for the treatment of various forms of hematological malignancies. However, a common theme emerges where these chemotherapy agents are usually associated with nonspecific toxicities and increasing drug resistance, presumably because of their high potency but low tumor selectivity. In this respect, monoclonal antibodies (mAbs) such as rituximab and obinutuzumab designed to specifically bind an antigen on a cancerous cell have been proven to play an essential role in lymphoma treatment [1,2,3,4]. With the development of mAb technologies, antibody–drug conjugates (ADCs), comprising a mAb connected to a small molecule cytotoxic payload via a covalent linker (Fig. 1), have emerged as a novel class of promising immunotherapies in lymphoma.

Structure and properties of an antibody-drug conjugate. MMAE: monomethyl auristatin E; MMAF: monomethyl auristatin F; DM1: N20-deacetyl-N20-(3-mercapto-1-oxopropyl)-maytansine; DM4: N20-deacetyl-N20-(4-mercapto-4-methyl-1-oxopentyl)-maytansine; MC: maleimidocaproyl; SMCC: succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate; PBD: pyrrolobenzodiazepines

Once attached to the corresponding cell-surface antigen of cancer cells, the ADC is internalized, and the cytotoxic payload is released, causing cell cycle termination and cell apoptosis. The drug can also diffuse into adjacent cells even if the cells are target-negative, resulting in cell death termed “bystander killing” (Fig. 2). This effect is generally believed to occur following the process of surface antigen targeting and internalization, but it was recently suggested to occur independently of internalization [5]. Despite the relatively straightforward molecular platform of ADCs, their application in clinical practice is hampered by multiple factors, including the narrow therapeutic index, the selection of the corresponding antibodies, the stability of the linkers, and the internalization rate of the payloads [6]. Hence, the generation of an efficacious and highly stable ADC is dependent on the proper arrangement of all sections.

ADC mechanisms of action. Once bound to the corresponding cell-surface antigen of cancer cells, the ADC is internalized, and the cytotoxic payload is released, resulting in cell apoptosis. The drug can also diffuse into adjacent cells regardless of antigen positivity, resulting in cell death, termed “bystander killing”

At present, three ADCs, brentuximab vedotin (BV), polatuzumab vedotin (Pola), and loncastuximab tesirine, have been approved by the Food and Drug Administration (FDA) for various types of lymphoma, and these agents exert favorable effects in clinical applications [7,8,9,10]. Furthermore, additional ADCs are presently in clinical trials to evaluate whether they can be efficacious treatment options for patients in diverse clinical settings. The topics discussed here involve the fundamental components of ADC strategies and focus on exploring opportunities for previously incurable subjects and summarizing the ADCs currently in clinical use and development (Table 1).

Loncastuximab tesirine

CD19 is a 95 kDa glycoprotein that is critically involved in the processes of B cell proliferation, differentiation, activation, and antibody production, and it can also promote BCR signal transduction. As a biomarker, CD19 is prevalently expressed in B cell malignancies and is thought to be the most reliable surface biomarker for B cells [75].

Loncastuximab tesirine (ADCT-402), which was recently approved for use in patients with R/R large B cell lymphoma, comprises a humanized mAb specifically directed to CD19, a PBD dimer, and a cleavable disulfide-bond linker. The results of 183 patients with R/R NHL who received loncastuximab tesirine in the phase I dose-expansion study (NCT02669017) reported an ORR of 46% and a CR rate of 27% with a median DOR of 5.4 months [76]. Among patients in the DLBCL, MCL, and FL subgroups, the ORRs were 42%, 47%, and 79%, respectively.

Notably, the ORR was 56% in the subgroup of elderly patients (≥ 75 years old) with DLBCL, indicating encouraging efficacy. The patients tolerated the therapy well because the treatment-related toxicities were largely hematologic and generally manageable with dose delays, followed by fatigue, nausea, edema, and hepatotoxicity, while dose-limiting toxicities (DLTs) were reported in only 4 patients.

The rapid onset of response also supported the further development of loncastuximab tesirine when compared with the new combination therapy of tafasitamab plus Len in patients with R/R DLBCL (1.5 vs. 2.0 months) [77]. Given the small number of patients in the FL subgroup (n = 14), larger randomized studies are needed for validation.

The updated analysis of data from a phase II trial (NCT03589469) reported an ORR of 48%, a CR rate of 24% and a median DOR of 10.3 months in 145 evaluable patients with R/R DLBCL with a 26% frequency of severe neutropenia and a 17% frequency of grade 3 to 4 glutamyltransferase (GGT) increase [78]. T

he data also revealed an ORR of 46% among patients who failed prior CD19-directed chimeric antigen receptor T cell (CAR-T) therapy, indicating that these immunotargeted agents may be used consequentially in high-risk patients.

 A survival advantage was also noted in patients with double- or triple-hit DLBCL, with an ORR of 33% (notably all CRs) and a median DOR of 13.4 months. Other phase I trials have explored loncastuximab tesirine as part of immunochemotherapy, such as with rituximab (NCT04384484) or ibrutinib.

Reference link : https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01097-z

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More information: Paolo F Caimi et al, Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial, The Lancet Oncology (2021). DOI: 10.1016/S1470-2045(21)00139-X

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