The Latest Research and Development into the Antibody–Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy

Abstract

A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular targeted drugs, such as specific kinase inhibitors and monoclonal antibodies, is a possible solution to overcome this limitation and has achieved clinical success so far. Use of an antibody-drug conjugate (ADC) is a rational strategy for improving efficacy and reducing systemic adverse events. ADCs use antibodies selectively to deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. Lessons learned from clinical failure of early ADCs during the 1980s to 90s have recently led to improvements in ADC technology, and resulted in the approval of four novel ADCs. Nonetheless, further advances in ADC technology are still required to streamline their clinical efficacy and reduce toxicity. [fam-] Trastuzumab deruxtecan (DS-8201a) is a next-generation ADC that satisfies these requirements based on currently available evidence. DS-8201a has several innovative features; a highly potent novel payload with a high drug-to-antibody ratio, good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo; the released cytotoxic payload could exert a bystander effect. With respect to its preclinical profiles, DS-8201a could provide a valuable therapy with a great potential against HER2expressing cancers in clinical settings. In a phase I trial, DS-8201a showed acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

“…PBD dimers are the most potent class of cytotoxic drugs among commonly used ADC payloads, followed by maytansinoids, auristatins, and calicheamicin showing comparable potency to one another [122]. However, cytotoxicity is not the only criterion for the selection of the payload for ADC construction, as exemplified by the clinical success of trastuzumab deruxtecan whose exatecan payload arguably has a weaker cytotoxicity than maytansinoids but which as an ADC is more potent than trastuzumab emtansine [122], or the employment of MMAF in some auristatin-based ADCs despite its lower in vitro potency than MMAE (see above). Along with other ADC components, including the conjugation chemistry and the linker structure, the chemical and biological properties of the payload may also influence the clinical outcome of ADC therapies.…”

Update Breast Cancer 2020 Part 2 – Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics

“…Trastuzumab-deruxtecan (DS-8201a, T-Dxd) is a newly developed substance from the class of antibody-drug conjugates (ADC) [8] which is already known in our field through T-DM1. The new substance is composed of the monoclonal antibody trastuzumab and the cytostatically active DXd which are chemically bound through a linker [9].…”

Update Mammakarzinom 2020 Teil 2 – fortgeschrittenes Mammakarzinom: neue Substanzen und Einzug diagnostikabhängiger Therapien

“…Trastuzumab-Deruxtecan (DS-8201a, T-Dxd) ist eine neuentwickelte Substanz aus der Klasse der Medikamenten-Antikörper-Konjugate ("Antibody-Drug-Conjugates", ADC) [8], die in unserem Fachgebiet bereits durch T-DM1 bekannt ist. Die neue Substanz setzt sich aus dem monoklonalen Antikörper Trastuzumab und dem zytostatisch wirkenden Dxd zusammen, die über einen Linker chemisch gebunden sind [9].…”

“…In einer kürzlich publizierten Phase-II-Studie mit 184 auswertbaren Patientinnen nach Vorbehandlung mit T-DM1 und im Median 6 Vortherapien zeigte sich eine beeindruckende Ansprechrate von 60,9 % (95 %-Konfidenzintervall (KI) 53,4-68) und ein Anteil von Patientinnen ohne Progress nach 6 Monaten von 76,1 % (95 %-KI 69,3-82,1). Das progressionsfreie Überleben (PFS) betrug 14,8 Monate (95 %- KI 13,[8][9][10][11][12][13][14][15][16]9). Die häufigste Nebenwirkung war Übelkeit, meist Grad I und II.…”