Results for Phase I/IIa study confirms that indatuximab ravtansine, also known as BT-062, an antibody-drug conjugate being developed by Biotets, offers good tolerability and signs of efficacy in the treatment of solid tumors and, in pre-clinical studies, very good effectiveness when combined with a chemotherapeutic agent for the treatment of difficult to treat triple-negative breast cancer.
Indatuximab ravtansine is an antibody drug conjugate consisting of a monoclonal antibody and a highly potent cytotoxic maytansine derivative (DM4; N2′- Deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine) using an ADC-technology developed by ImmunoGen.
First isolated in 1972 from the bark of the African shrub Maytenus ovatus, maytansinoids represent a class of microtubulin polymerization inhibitors derived from the naturally occurring maytansine, a benzoansamacrolide.[a] Similar to vinca alkaloids, they bind to tubulin at the vinca-binding site, depolymerizing tubulin and, as a result, inducing mitotic block and cell death.
The first and maytansinoid-based ADC, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), was approved in 2013 for HER2-positive metastatic breast cancer.
The antibody of the investigational drug binds specifically to the cell surface heparan sulphate proteoglycan CD138 (syndecan-1), a transmembrane protein receptor for the extracellular matrix (ECM) that mediates cell-cell adhesion via interactions with heparan-binding molecules.
CD138, which is over-expressed on multiple myeloma cells and a variety of solid tumors.
Once the conjugate has been internalized into the target cell, the cytotoxic agent DM4 is released from the targeting molecule by lysosomal degradation. As a result, the conjugation of DM4 to the antibody keeps the cytotoxic moiety inactive until it is released within the CD138-expressing target cell. This combination of high efficacy and specificity with low systemic toxicity sets indatuximab ravtansine apart from most therapies currently used to treat malignancies.
Triple-negative breast cancer
In a phase I/IIa trial, funded by the Cluster for Individualized ImmunIntervention (Ci3) Mainz, Germany, researchers examined the safety and anti-tumor activity of indatuximab ravtansine as a monotherapy in patients with triple-negative metastatic breast cancer, a type of cancer in which the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are not expressed, and patients with metastatic bladder cancer.
Both types of tumor are bearing the receptor CD138 on their surface.
To qualify for enrollment in this trial, patients with breast cancer had to have failed at least two treatment regimens. Patients with urinary bladder cancer had to have failed at least one prior treatment regimen. In the phase I part of the trial, the maximum tolerated dose (MTD) of indatuximab ravtansine in solid tumor indications was determined. In the Phase IIa part, indatuximab ravtansine was administered at this dose to further assess its safety and efficacy in the mentioned indications.
The study confirmed a good safety profile of indatuximab ravtansine and showed initial encouraging signs of efficacy in these critically ill patients for whom options for further treatment are largely exhausted.
Furthermore, indatuximab ravtansine in combination with chemotherapy showed very good efficacy in a tumor model for triple-negative breast cancer, a type of tumor that is particularly difficult to treat.
In mice loaded with human tumors, very good efficacy was already shown at low doses of indatuximab ravtansine monotherapy and was further improved when indatuximab ravtansine was given in combination with the cytostatic drug docetaxel.
Preclinical data on the mode of action of indatuximab ravtansine have been published in two full papers.
Underlining the potential
The clinical and preclinical results presented here underline the promising potential and support further development of indatuximab ravtansine as combination therapy for CD138-positive solid tumors.
The combination therapy approach is supported by evidence obtained with
indatuximab ravtansine in the treatment of multiple myeloma, a malignant disease of the bone marrow also involving CD138-positive cells. In this indication a combination of BT-062 with appropriate agents lead to a considerable increase in efficacy:
Safety and efficacy
Safety and early signs of efficacy of indatuximab ravtansine monotherapy were reported in two other clinical trials in patients with relapsed/recurrent or refractory multiple myeloma.
Data from a clinical phase I/IIa trial combining indatuximab ravtansine with lenalidomide or pomalidomide and dexamethasone in multiple myeloma are now available over a period of almost six years. This data show that in this patient population, treatment with indatuximab ravtansine in combination with lenalidomide or pomalidomide and dexamethasone can lead to partial or complete response. The study continues as some patients have been benefitting from the combination treatment for over four years.
These results support that combination therapy with appropriate chemotherapeutic or immune-oncological drugs may further enhance efficacy of indatuximab ravtansine in the solid tumors studied, similar to the effects observed in multiple myeloma.
New business model
Because Biotest is going to focus on the development of plasma products in the future, the company plans to sell off or further develop their portfolio of promising antibody-based drug candidates in a separate company.
[a] – A 19-membered ring ansamacrolide.