Antibody-drug conjugates: can the payload improve activity in HER2 expressing cancers?
Mené au Japon sur 24 patientes atteintes d'une tumeur mammaire, gastrique ou gastro-œsophagienne réfractaire de stade avancé, cet essai de phase I évalue les caractéristiques pharmacocinétiques, l'activité antitumorale, la dose maximale tolérée et la toxicité du trastuzumab déruxtécan, un conjugué anticorps-médicament ciblant HER2 et dispensé par voie intraveineuse
Antibody–drug conjugates represent a relatively new class of drugs in oncology and carry a great hope of using the exquisite sensitivity of the ligand–antibody complex to deliver a cytotoxic payload directly and specifically to malignant cells—a cancer treatment smart bomb. The seeds of this concept take us back over 110 years, when Paul Ehrlich first promoted his side-chain theory, postulating that specific receptors are associated with cells or can be distributed in the blood stream in response to a stimulus, or antigen.1 Key drug design criteria to consider in the development of a successful antibody–drug conjugate include the antibody used to target malignancy (eg, delivery system), the cytotoxic drug being delivered (eg, payload), and the linker that allows for a stable drug in plasma as well as intracellular disassociation and optimal delivery of the payload within the cell. In The Lancet Oncology, Toshihiko Doi and colleagues2 present the results of a phase 1 dose-escalation study of a novel antibody–drug conjugate, DS-8201, which links a potent topoisomerase I inhibitor (exatecan derivative) to a humanised anti-HER2 antibody. What makes this drug novel and exciting is that the enzymatically cleavable peptide-linker used allows for greater cargo and better delivery.3 Specifically, DS-8201 has a drug-to-antibody ratio of 7–8 (eg, 7–8 molecules of the cytotoxic drug per antibody), whereas most antibody–drug conjugates have a drug-to-antibody ratio of 2–4, allowing greater and potentially more focused delivery of the cytotoxic drug. A comparator drug, T-DM1, also uses HER2 as the target, but uses a non-reducible thioether linker and a microtubule inhibitor DM1 (derivative of maytansine) as the payload and has a drug-to-antibody ratio of 3·5.4 T-DM1 is quite effective, already approved for breast cancer on the basis of positive results seen in patients with breast cancer who had received one previous HER2-directed therapy in the EMILIA study,5 and in patients who had received at least two previous HER2-targeted therapies in the TH3RESA study.6, 7 However, T-DM1 was not effective in the second-line setting in HER2-positive gastric cancer when compared with taxane chemotherapy. (...)
The Lancet Oncology , commentaire en libre accès, 2016