New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong?

Abstract

Nele Van Der Steen,1,* Chiara Caparello,2,* Christian Rolfo,3 Patrick Pauwels,4 Godefridus J Peters,1 Elisa Giovannetti5 1Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands; 2Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 3Phase I – Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Edegem, 4Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium; 5Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy *These authors contributed equally to this work Abstract: Recently, the development of the third-generation epidermal growth factor receptor-small molecule inhibitor (EGFR-TKI) rociletinib had failed. In this review, the wide-ranging aspects of the evolution of EGFR-TKIs were collected, with a special focus on rociletinib. The influence of different oncogenic mutations on EGFR activity was also discussed. Resistance to the first (erlotinib, gefitinib)- and second (afatinib)-generation EGFR-TKIs provided the rationale behind the development of the third-generation inhibitors (rociletinib, osimertinib). On the basis of these data, a comparison of their efficacy on the different mutated EGFRs and the respective resistance mechanisms is further reported. Moreover, the evolution and results of the clinical trials of rociletinib (TIGER trials) are compared with the trials on osimertinib, another third-generation EGFR-TKI that now has been granted US Food and Drug Administration approval. The reasons behind the arrest in the further development of rociletinib are put in the perspective of future drug development. Keywords: rociletinib, EGFR, EGFR-TKI, NSCLC, targeted therapies

Keywords

• Rociletinib
• EGFR
• EGFR-TKI
• NSCLC
• targeted therapies