Using the novel antibody-drug conjugate, loncastuximab tesirine to treat patients with R/R diffuse large B-cell lymphoma

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Published: 26 Jun 2020
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Prof Carmelo Carlo-Stella - Humanitas Cancer Center, Milan, Italy

Prof Carmelo Carlo-Stella speaks to ecancer in an online interview for the virtual EHA 2020 meeting.

He gives an overview of this phase II trial, which assessed the efficacy of loncastuximab tesirine for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma.

Prof Carlo-Stella presents the promising initial findings from this study, which could offer a new treatment option for heavily-pretreated patients, who have failed prior therapies.

 

Good morning, I am Carmelo Carlo-Stella. I am a Professor of Haematology at Humanitas University in Milan and I am chief of the lymphoma unit at Humanitas Clinical and Research Centre which is, again, located in Milan. In the next few minutes I will share with you the initial results of our phase II study using loncastuximab tesirine, since known as Lonca, which is an oral PBD-based antibody-drug conjugate that has been used in patients with relapsed and refractory diffuse large B-cell lymphoma.

Let’s start with a short background of this study. The diffuse large B-cell lymphoma is an aggressive form of non-Hodgkin’s lymphoma accounting, essentially, for 30% of all lymphoma subtypes. Patients with newly diagnosed diffuse large B-cell lymphoma have a high cure rate ranging from 50-60% upon receiving first line chemotherapy, which is represented by R-CHOP. In a striking contrast, patients with refractory or relapsed diffuse large B-cell lymphoma have a poor prognosis. Indeed, this treatment of relapsed and refractory DLBCL represent an unmet medical need, urgently requiring novel therapies.

Over the past decade several different therapeutic targets have been explored in this field and among the different therapeutic targets CD19 antigen represents and emerges as an attractive therapeutic target. Essentially, due to the high expression and diffuse expression of CD19 among the B-cell malignancies – almost all B-cell malignancies do express CD19 – and this is our first reason. The second reason for the success of the CD19 antigen as a therapeutic target is represented by the stable expression that this antigen has. Several approaches are currently being developed for targeting CD19 and these different approaches include CAR T-cells as well as a variety of different monoclonal antibodies, including naked antibodies, bispecific antibodies and antibody-drug conjugates.

Lonca, indeed and in fact, is an antibody-drug conjugate comprising a humanised anti-CD19 antibody conjugated to a potent PBD-dimer. PBD-dimer is highly cytotoxic and it’s credible for the mechanism of action of the antibody. The mechanism of action of Lonca has several steps starting from the binding of Lonca to CD19. This is followed by internalisation of the antibody and cleavage of the PDB-dimer which migrates to the locus where the PDB-dimer DNA and this results in the DNA replication which in turn results in apoptotic cell death.

Lonca has already been explored and investigated for toxicity in a large phase I study which was recently published in Clinical Cancer Research. The results I will show you are the initial results of a large phase II study which is overall 145 patients and has an endpoint represented by the overall response rate. This is the primary endpoint of the study.
Injection of Lonca is performed IV. For the first two cycles Lonca is injected at 150μg/kg of body weight. Starting from the third cycle and for a maximum figure of one year, Lonca is injected every two weeks at 75μg/kg of body weight. The median age of the 145 patients enrolled in the study was 66 years. By histology 88% of the patients had diffuse large B-cell lymphoma and a minority of the patients had a primary mediastinal B-cell lymphoma or high grade B-cell lymphoma. 20% of the diffuse large B-cell lymphoma had a DLBCL crossover from a follicular lymphoma. Nearly 80% of the patients had an advanced stage disease. These patients were highly pre-treated, in fact they had received a median of three prior lines of therapy before being included in the study. 20% of the patients were primary refractory and 58% were refractory to the last systemic therapy they had received.

What about the results? The overall response rate, which is the primary endpoint of the study, for the entire population was 48% including 24% of complete remission and 24% of partial remission. Primary refractory patients, which accounted for 20% of the global population enrolled in the study, had an overall response rate of 38% whereas patients which were refractory to their last therapy, this accounted for 58% of the global population, these patients experienced a 37% overall response rate. The median duration of response was 10.2 months. This value is remarkable since it has been obtained with a monotherapy, in fact Lonca was used as a single agent. These results of 10 months median duration of response was achieved in patients who had received a median of three lines of previous therapy, thus these patients were highly pre-treated. It has been obtained in a patient population including 58% of refractory patients, refractory to the last systemic therapy prior to study entry.

The safety profile was good. Toxicity of Lonca was, in fact, manageable and essentially limited to haematological toxicity including anaemia, neutropenia and thrombocytopenia. All these adverse events were manageable and arrestable. The extra-haematological toxicity included 15% of patients experiencing grade 3 GGT increase. GGT increase was related more to a biochemical event rather than being associated with histological changes and abnormalities in the liver.
So, in conlusion, based on the efficacy data and safety data we can say that Lonca has a substantial single agent anti-tumour activity in highly pre-treated patients with relapsed and refractory diffuse large B-cell lymphoma. Therefore, Lonca has the potential to fill a physical unmet medical need for the treatment for relapsed and refractory DLBCL.
The next steps of this trial will be represented by, first, collect the data with a more mature stage and then obviously publish this data. But in the meantime we are preparing next future trials, randomised trials, to explore the activity of Lonca at an earlier stage of disease.

The interesting activity of Lonca is represented by the significant percentage of refractory patients, including both primary refractory and secondary refractory patients who responded to Lonca. This was represented by around 37% of refractory patients who responded. This is an interesting property related to the mechanism of action of Lonca. This property can be [??] to be explored specifically in refractory patients by combining Lonca with chemotherapy. When I speak to refractory patients I’m referring to high risk patients including lymphoma patients and patients with deletion or mutation of p53 who, by definition, are refractory patients.