Overcoming resistance to osimertinib in non–small cell lung cancer: Hopes, doubts, and in‐between

The treatment of non–small cell lung cancer (NSCLC) harboring sensitive EGFR mutations has changed dramatically in the last 15 years, simultaneously improving our clinical and biological knowledge and changing our attitude toward the EGFR-positive disease; furthermore, the use of highly effective tyrosine kinase inhibitors (TKIs) has improved survival, reaching 38.6 months of median overall survival with first-line osimertinib. Although such results are significant, resistance to EGFR TKIs inevitably occurs after 10 to 18 months, depending on the TKI compound. To date, efforts to identify the mechanisms of resistance to EGFR TKIs have revealed a predominantly EGFRdependent mechanism in patients receiving firstor second-generation TKIs, who develop the EGFR T790M resistance mutation on exon 20 in 50% to 60% of cases. Treatment with osimertinib significantly improved survival in resistant T790M-positive disease and has recently moved to a front-line setting based on the results of FLAURA trial. Data about osimertinib in both a pretreatment and naïve setting have been encouraging considering its high efficacy and low toxicity. However, despite its promise as a potential new way forward, some clinicians may be hesitant to return to a chemotherapeutic regimen in response to the identification and characterization of resistance alterations rather than clinical trial data. The mechanisms of resistance to third-generation drugs are more heterogeneous, including a higher proportion of EGFR-independent mechanisms compared with EGFR-dependent mechanisms. The “in cis” coexisting C797S point mutation has emerged as the main EGFR-dependent mechanism of resistance to osimertinib across all studies, with a variable rate of incidence. Indeed, among 83 EGFR TKI–pretreated patients expressing a positive EGFR mutation in blood at baseline, C797S mutation was found in 15% of cases at osimertinib resistance in the AURA3 trial and in up to 32% of cases in a pilot trial. Intriguingly, the incidence of C797S resistance mutation is much lower in patients progressing after first-line osimertinib therapy; a recent study by Ramalingam et al showed that among the 91 patients enrolled in the FLAURA study with available preand posttreatment blood samples, only 7% developed the C797 mutation. These data are supported by a similar study conducted on patients treated with upfront rociletinib. However, the EGFRindependent mechanisms include a wide and heterogeneous landscape of other receptor tyrosine kinase pathways, such as MET and HER2 amplifications, BRAF and PIK3CA mutations, and gene fusions. Presently, the greatest therapeutic progress is focusing precisely on this cluster, highlighting MET as a potential new target for acquired resistance after third-generation EGFR TKIs. Most data on the genomic landscape of EGFR mutant tumors at progression to third-generation EGFR TKIs derive from blood-based next-generation sequencing (NGS) studies of patients receiving osimertinib in clinical trials. So far, few experiences have been conducted on tissue samples to evaluate resistance mechanisms to third-generation EGFR TKIs. The largest tissue series have included patients receiving osimertinib in any treatment line, both first-line therapy and after previous treatment with EGFR TKIs; other series have observed only a post-osimertinib genomic landscape or genetic alterations with different and thus not properly comparable techniques. The study by Lee et al in this issue of Cancer is one of the larger series evaluating the mechanisms of resistance to third-generation EGFR TKI osimertinib and olmutinib in an EGFR TKI–pretreated setting on tissue samples from rebiopsy of progressing sites, including 36 posttreatment samples and 15 paired samples. From a technical perspective, Lee et al performed a mutational analysis on DNA derived from formalin-fixed, paraffin-embedded or fresh tissue of NSCLC patients treated with osimertinib or olmutinib using a previously validated