Strategien zur Überwindung der erworbenen EGFR-TKI-Resistenz durch T790M spezifische Substanzen am Beispiel von Osimertinib

Zusammenfassung

Die Resistenzbildung gegenüber der 1. und 2. Generation von Tyrosinkinase-Inhibitoren (TKIs) des epidermalen Wachstumsfaktors (EGFR) stellt bei der Behandlung von Patienten mit nicht kleinzelligem Lungenkarzinom, die eine aktivierende Mutation im EGFR aufweisen, ein großes Problem dar. Drittgenerations-EGFR-TKIs richten sich sowohl gegen aktivierende als auch gegen die Resistenz-vermittelnde T790M-Mutation. EGFR-TKIs der 3. Generation zeigen in klinischen Studien bei T790M-positiven Patienten relevante Wirksamkeit bei meist milden bis moderaten klassenspezifischen Nebenwirkungen. Molekularpathologischen Analysen kommt bei der Entscheidung zur Therapie mit Drittgenerations-EGFR-TKIs eine bedeutsame Rolle zu. In dieser Übersichtsarbeit wird der aktuelle Entwicklungsstand von Drittgenerations-EGFR-TKIs dargestellt mit einem Schwerpunkt auf Osimertinib, dem ersten und bislang einzigen in Deutschland zugelassenen Wirkstoff dieser Klasse. Zudem wird die Relevanz einer molekularen Diagnostik an Tumorgewebe bzw. an zirkulierender Tumor-DNA diskutiert.

Abstract

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed.

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