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

Abstract

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. 1,2 Although such results are significant, resistance to EGFR TKIs inevitably occurs after 10 to 18 months, depending on the TKI compound. 2 To date, efforts to identify the mechanisms of resistance to EGFR TKIs have revealed a predominantly EGFRdependent mechanism in patients receiving first-or second-generation TKIs, who develop the EGFR T790M resistance mutation on exon 20 in 50% to 60% of cases. 3 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. 1 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 4 and in up to 32% of cases in a pilot trial. 5 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 6 showed that among the 91 patients enrolled in the FLAURA study with available pre-and posttreatment blood samples, only 7% developed the C797 mutation. These data are supported by a similar study conducted on patients treated with upfront rociletinib. 7 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. 8,9 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. 10

AZD9291 Resistance Reversal Activity of a pH‐Sensitive Nanocarrier Dual‐Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC

“…[ 5b ] The mechanisms of resistance to AZD9291 are heterogeneous, with a higher proportion of EGFR‐independent pathways than EGFR‐dependent reasons. [ 32 ] Currently, patients have limited options and combinations therapy is commonly used to overcome AZD9291 resistance. For example, AZD9291 was reported to be combined with first‐generation EGFR‐TKI, MEK inhibitors, or RET inhibitors and achieved good efficacy in patients with AZD9291 resistance related to EGFR C797S transmutation, MET amplification, or RET fusion, respectively.…”

Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges

“…Various EGFR mutations have been identified as mechanisms of resistance to third-generation EGFR-TKIs (24,(30)(31)(32). These include EGFR G796R, G796S, and G796D mutations (33,34), S768I mutations (35), L718X and L792X mutations (31), L798I mutation (36), and L858R/T790M/L792H and L858R/T790M/G796R mutations (37), which have been associated with resistance to osimertinib.…”

Immunotherapy plus chemotherapy showed superior clinical benefit to chemotherapy alone in advanced NSCLC patients after progression on osimertinib

“…Cardiopalmus 0 (0) 2 (10) 0 (0) 1 (5) Abbreviations: C, chemotherapy; IO+C, immunotherapy plus chemotherapy.…”

“…Multiple mechanisms are involved in resistance to osimertinib, including EGFR ‐independent mechanisms and EGFR ‐dependent mechanisms, 5 such as tertiary EGFR C797S mutation, bypass (c‐MET, HER2) or downstream activation ( RAS family mutation and amplification), and histological transformation (small‐cell lung cancer transformation and epithelial‐mesenchymal transition) 6 . The resistance mechanism for approximately 50% of patients is unknown 7 .…”