The impact of the tumor shrinkage by initial EGFR inhibitors according to the detection of EGFR-T790M mutation in patients with non-small cell lung cancer harboring 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]. However, it ultimately acquires resistance to EGFR-TKIs after various periods of time. 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. EGFR-T790M, the gatekeeper mutation, is the most common mechanism of acquired resistance and is detectable in approximately 50% of patients who experience acquired resistance to first and second generation EGFR-TKIs [3].

Osimertinib is a third generation EGFR-TKI that inhibits EGFR with activating mutations and/or the T790 M resistance mutation. 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]. In addition, 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].

We usually detect the EGFR-T790M mutation using re-biopsy of tissue, although the procedure is relatively invasive and is not always feasible to perform. Recently, liquid biopsy has received much attention as a non-invasive method to detect EGFR-T790M mutations. However, tissue re-biopsy may still be needed if the liquid biopsy is negative or if other mechanisms of resistance, such as transformation to small cell histology, are being probed. Therefore, elucidation of the clinical profiles underlying the emergence of acquired resistance to initial EGFR-TKIs with the T790M mutation has led us to perform the re-biopsy approach initially.

The goal of this research is to identify a promising clinical biomarker for the detection of the EGFR-T790M mutation using re-biopsy in EGFR-mutated NSCLC patients, based on patient profiles.

Clinically, it is critical to select the population with the EGFR-T790M mutation when we consider obtaining re-biopsy samples from tumors and/or blood to decide on treatment with osimertinib. Previous reports have described various potential factors regarding the emergence of the EGFR-T790M mutation, such as the duration of initial EGFR-TKI treatment, EGFR gene status at baseline, and surgical history [6–8]. Our findings were inconsistent with these factors as predictors of the emergence of the T790 M mutation, while these other predictive factors have showed controversial results for the detection of the T790M mutation [6]. Therefore, a novel powerful biomarker is needed to predict the emergence of the T790M mutation using re-biopsy samples.

Although our observations showed that the ORR to EGFR-TKIs is one of the significant predictive biomarkers, it will be difficult to closely evaluate the response of EGFR-TKI using RECIST categorized into only 4 groups: complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD). To further assess for the response to EGFR-TKIs, we validated the MTS rate as a novel evaluation method. A previous report showed that the MTS rate was not a good prognostic factor in EGFR mutation-positive NSCLC [9]. We have clearly shown here that the increased MTS rate in response to initial EGFR-TKIs was significantly associated with the emergence of the EGFR-T790M mutation among patients with NSCLC tumors with acquired resistance. Further, the optimal cutoff for the MTS rate in relation to the emergency of the EGFR-T790M mutation was 30%, which is the same as the RECIST-PR level. Crucially, multivariate analysis indicated that the MTS rate was an independent predictive factor for the emergence of the T790M mutation using re-biopsy; this showed a greater association than the duration of initial EGFR-TKI treatment, EGFR gene status, and tumor histology, as previously described.

Tumors with the EGFR-T790M mutation showed a relatively low tumor mutation burden (TMB) in next generation sequencing analysis [10], whereas tumors without the EGFR-T790 M mutation with EGFR-TKI acquired resistance showed molecular heterogeneity [11]. In fact, TMB was reported to be a promising predictor of the detection of the EGFR-T790M mutation [12]. These observations suggest that the original de novo tumors that ultimately acquire resistance with the T790M mutation are more likely to retain EGFR signal directivity than those without the T790M mutation. Similarly, our retrospective findings showed that de novo EGFR mutated tumors with good responses to initial EGFR-TKIs have a higher dependency on EGFR signaling in cases of acquired T790M mutation than those without the T790M mutation, suggesting that the MTS rate with initial EGFR-TKIs may be a useful predictor of the emergence of the T790M mutation using re-biopsy.

This study has several limitations. Firstly, it comprised a small retrospective sample. However, previous retrospective observations have used similar sample sizes, with occasional exceptions [6–8]. Second, we only considered a Japanese cohort. Third, there may have been bias considering when EGFR-TKI was started, even though treatment was administered in multiple centers, and in the timing of evaluation using CT scanning, even though it was performed every 1–3 months after treatment. Therefore, a further prospective study is warranted to identify the role of the MTS rate for detecting the emergence of the EGFR-T790 mutation in NSCLC following initial EGFR-TKI treatment.

Our retrospective observations suggested that the MTS rate in response to initial EGFR-TKI treatment might be one of the promising predictors for the emergence of refractory tumors with the EGFR-T790M mutation. Further experiments are needed to validate this.