Small Molecules in Oncology

Osimertinib

Small Molecules in Oncology

Recent results in cancer research Fortschritte der Krebsforschung Progrès dans les recherches sur le cancer, January 2018

30069773

978-3-31-991441-1, 978-3-31-991442-8

Umberto Malapelle, Biagio Ricciuti, Sara Baglivo, Francesco Pepe, Pasquale Pisapia, Paola Anastasi, Marco Tazza, Angelo Sidoni, Anna M. Liberati, Guido Bellezza, Rita Chiari, Giulio Metro, Malapelle, Umberto, Ricciuti, Biagio, Baglivo, Sara, Pepe, Francesco, Pisapia, Pasquale, Anastasi, Paola, Tazza, Marco, Sidoni, Angelo, Liberati, Anna M., Bellezza, Guido, Chiari, Rita, Metro, Giulio

Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI). First-generation or reversible EGFR-TKIs include gefitinib and erlotinib, while, more recently, second-generation or irreversible EGFR-TKIs have been developed, namely afatinib and dacomitinib, with the aim of overcoming/delaying acquired resistance to treatment. Nevertheless, clinical trials have shown that resistance eventually emerges after a median time of slightly less than one year, regardless of whether first- or second-generation EGFR-TKIs are used. In this context, a secondary EGFR mutation in exon 20, namely T790M, has been found to be responsible for approximately 60% of cases of acquired resistance. Alternatively, T790M resistance mutation can be found de novo, in which case it limits the antitumor activity of both first- or second-generation EGFR-TKIs. Osimertinb is an orally bioavailable, third-generation EGFR-TKI that acts by irreversibly binding both EGFR activating mutations and T790M, while sparing wild-type EGFR. On this basis, osimertinib has proven more efficacious than platinum-based chemotherapy in the setting of EGFR T790M-positive NSCLCs pretreated with a first- or second-generation EGFR-TKI. More recently, in another phase 3 trial, osimertinib outperformed gefitinib or erlotinib as first-line treatment of EGFR-mutated (ex19del or L858R) advanced NSCLCs, thus emerging as a new standard of care in this setting. In the present review, we will discuss the preclinical and clinical development of osimertinib, briefly touching upon its activity in special populations and biomarkers of sensitivity to treatment.