Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer

• 3rd generation EGFR TKIs are T790M selective with minimal inhibition in WT EGFR.
• The 3rd generation EGFR TKIs are highly active and are well tolerated.
• Acquired resistance to 3rd generation EGFR TKIs include EGFR C797S mutation.
• A new class of EGFR TKI has increased CNS penetration with promising CNS activity.

Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9–13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. A novel class of “third generation” EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed to penetrate blood brain barrier to treat brain metastases and leptomeningeal disease and has showed promising responses in patients with brain metastases. Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.