What is known and objective: Targeted small molecule EGFR Tyrosine Kinase Inhibitors (TKI's) and the Anaplastic Lymphoma Kinase (ALK) inhibitors have been promising tools for advanced non-small-cell lung cancers (NSCLCs). However, tumours tend to develop subsequent mutations, rendering them drug-resistant. Hence, alternative pathways of therapy need to be explored.
Comment: Gefitinib, erlotinib and afatinib, once considered as alternatives to platinum-based cytotoxic chemotherapy, have been rendered ineffective in patients with NSCLCs harbouring T790M mutation. Osimertinib is effective in T790M-mutant cancers, but not against those exhibiting the subsequent C797S mutation. ALK gene alterations have rendered tumours insensitive to crizotinib. However, lorlatinib and brigatinib are effective in tumours showing ALK+ mutations. Drugs acting through alternative pathways like the PD-1 pathway, BRAF, VEGFR, EGFR antibodies and NTRK inhibition have been showing promising results.
What is new and conclusions: Osimertinib, brigatinib and allosteric C797S EGFR inhibitors like AI1045, BRAF inhibitors like LXH254 under trials and entrictinib, a recently approved NTRK inhibitor, have all shown improved progression-free survival compared with earlier generations of small molecule inhibitors for NSCLCs.
Keywords: ALK inhibitor; EGFR inhibitor; NSCLC; resistant cancer; targeted therapy.
© 2020 John Wiley & Sons Ltd.