Immunotherapy in tyrosine kinase inhibitor-na？ve advanced epidermal growth factor receptor-mutant non-small cell lung cancer—driving down a precarious road in driver-mutated lung cancer

In patients with advanced non-small cell lung cancer (NSCLC) whose tumour harbour a sensitising epidermal growth factor receptor (EGFR) mutation, international guidelines recommend first-line therapy with an EGFR tyrosine kinase inhibitor (TKI) due to longer progression free survival (PFS), higher overall response rate (ORR) and improved quality of life compared to platinum doublet chemotherapy (1,2). Eventually, most patients develop resistance to initial EGFR-TKI therapy. The most common resistance mechanism in approximately 60% of patients is an acquired threonine-to-methionine amino acid substitution at position 790 (T790M) of the EGFR kinase domain in exon 20 resulting in reduced adenosine triphosphate (ATP) competitive TKI-binding that confers loss of drug activity (3). Third-generation EGFR-TKI osimertinib has shown to overcome T790M-induced drug resistance with a significantly improved PFS [10.1 vs. 4.4 months, hazard ratio (HR) 0.3, P<0.001] and ORR [71% vs. 31%, odds ratio (OR) 5.39, P<0.001] compared to platinum-pemetrexed chemotherapy (4). Osimertinib has also been recently approved by the Food and Drug Administration (FDA)—and the European Medicines Agency (EMA)—as first-line therapy for EGFR-mutant (mt) patients due to longer PFS (18.9 vs. 10.2 months, HR 0.46, P<0.001) compared to first-generation EGFR-TKIs (5)