Abstract
BackgroundThe EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples.MethodsSeventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles.ResultsThirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p < 0.001). Moreover, there was a significant difference in the maximal tumor shrinkage rate relative to baseline in T790M-positive tumors compared with T790M-negative tumors (42.7% versus 24.0%, p = 0.001). Multivariate analysis demonstrated that the maximum tumor shrinkage rate was a significant predictive factor for the detection of the T790M mutation (p = 0.023, odds ratio 1.03, 95% confidence interval 1.00–1.05).ConclusionsOur retrospective observations suggested that the maximum tumor shrinkage rate with initial EGFR-TKI treatment might be one of the promising predictive biomarkers for emerging refractory tumors with the EGFR-T790M mutation.
Highlights
The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-Tyrosine kinase inhibitor (TKI)) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations
In terms of EGFR mutations at baseline, 26 (66.7%) and 20 (51.3%) patients harbored a deletion in exon 19, while 13 (33.3%) and 18 (46.1%) patients had a L858R missense mutation in exon 21 in the T790M positive and negative groups, respectively (Table 1)
Given that the objective response rate (ORR) to EGFR-TKIs was closely correlated with the emergence of EGFR-T790M-positive disease, we examined the maximal tumor shrinkage (MTS) rate relative to baseline according to exposure to initial EGFR-TKIs
Summary
The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. Non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and the L858R mutation, responds to first and second generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) [1, 2]. Acquired resistance to initial EGFR-TKIs is caused by various mechanisms, such as gatekeeper mutations like the EGFR-T790M second site mutation, activation of bypass signaling, and transformation to small-cell lung cancer. Osimertinib has been approved in several countries, including the U.S.A and Japan, for the treatment of EGFR-T790M-positive NSCLC patients with tumors that are refractory to first or second generation EGFR-TKIs [4]. Osimertinib has been approved in several countries for the first-line treatment of patients with EGFR-mutated NSCLC, based on the results of the FLAURA study [5]
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