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

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.

<p>The European Medicines Agency Clinical Data Website Enables Insights Into Clinical Development Timelines And Strategy</p>

“…However, additional development costs and risks (eg, withdrawal from the market) remain. 36 High-level timelines have been previously published for USA marketing approvals, 4 and were found to be in line with the findings of the present analysis. Prior to this, it was reported that an average of 12 years was necessary for an experimental drug to progress from bench to market.…”

Cancer drug resistance: a new perspective

“…Small molecule inhibitors of EGFR such as erlotinib and gefitinib, are only active in adenocarcinoma of non-small cell lung cancer when the tumor has activating mutations, making the tumor cell dependent on (or addicted to) EGFR signaling. Additional mutations (e.g., T790M) lead to resistance, but these cells are sensitive to the 3rd generation of EGFR inhibitors [13] . From these data it should be noted, that dependent on the target a high expression (or mutated enzyme) can lead to either resistance or increased sensitivity.…”

Subcellular localization of several structurally different tyrosine kinase inhibitors

“…A decreased uptake or increased efflux may limit the cellular drug accumulation, and the efficacy of these drugs [5]. Moreover, inhibition may be reversible or irreversible; especially novel third or fourth generation TKIs display irreversible enzyme inhibition [6]. Recently we demonstrated that sunitinib, an inhibitor of the Vascular endothelial growth factor receptor (VEGFR) accumulates in lysosomes [7], while preliminary experiments demonstrated a similar distribution for crizotinib, an ALK-EML4 and cMET inhibitor [5].…”