Elsevier

Clinical Lung Cancer

Volume 21, Issue 1, January 2020, Pages 1-14.e3
Clinical Lung Cancer

Original Study
Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non–small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy

https://doi.org/10.1016/j.cllc.2019.07.009Get rights and content

Abstract

Background

Clinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non–small-cell lung cancer (NSCLC) progressing after first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate.

Patients and Methods

This is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases.

Results

A total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity.

Conclusion

This study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.

Introduction

Activating epidermal growth factor receptor (EGFR) mutations are found in 10% to 15% of Caucasian patients with advanced non–small cell lung cancer (NSCLC) and in up to 50% of Asian patients with NSCLC. EGFR mutations are more common in never or light smokers, women, and adenocarcinomas.1, 2, 3, 4 Exon 19 deletions and exon 21 L858R point mutation account for up to 90% of EGFR mutations.5

First-generation EGFR tyrosine kinase inhibitors (TKIs), including erlotinib and gefitinib, are reversible EGFR inhibitors, whereas second-generation TKIs, including afatinib, are irreversible pan-human epidermal growth factor receptor inhibitors that covalently bind to EGFR. Multiple phase III trials have shown higher response rates and a statistically significant improved progression-free survival (PFS) in EGFR-mutant tumors treated with first- and second-generation EGFR TKIs compared with platinum-based first-line chemotherapy; consequently, erlotinib, gefitinib, and afatinib are first-line standard of care in EGFR-mutant NSCLC.4, 6, 7, 8, 9, 10, 11

Acquired resistance to EGFR TKIs leads to disease progression,12 occurring after a median of 9 to 15 months of TKI therapy.6, 7, 8, 9, 10, 11, 13

Several mechanisms of acquired resistance have been reported. The substitution of threonine to methionine at amino acid position 790 (T790M) in exon 20 of the EGFR gene reduces first- and second-generation EGFR TKIs binding by enhancing the ATP binding affinity of EGFR-mutant receptor kinase domain and occurs in about 50% of resistant cases.14, 15, 16 Other less common mechanisms are MET amplification (up to 20% of cases) and histologic transformation to small-cell lung cancer (10%-15% of cases).17, 18

The third-generation EGFR TKI osimertinib is active against exon 19 deletion and exon 21 mutation as well as against the T790M mutation,19, 20, 21, 22 displaying prolonged PFS (10.1 vs. 4.4 months; hazard ratio, 0.30) and response rate (71% vs. 31%) when compared with platinum-based second-line chemotherapy in the phase III AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) trial.23 More recently, the phase III AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA) trial showed longer PFS (18.9 vs. 10.2 months; hazard ratio, 0.46) with osimertinib compared with gefitinib or erlotinib in previously untreated patients.24

Based on these results, osimertinib received United States Food and Drug Administration and European Medicines Agency approval for metastatic EGFR-mutant and acquired EGFR T790M mutation-positive (T790M+) patients with NSCLC progressing on or after first- or second-generation TKI, or as first-line in patients with sensitizing EGFR mutations. The introduction of osimertinib in clinical practice led to the optimization of liquid biopsy and EGFR T790M status detection in circulating tumor (ct)-DNA. Liquid biopsy is a non-invasive, repeatable, quicker, less expensive technique, and accounts for heterogeneity compared with tissue biopsy.25, 26 Liquid biopsy is used as the initial test for detection of T790M mutation in patients with evidence of TKI resistance. However, owing to about 50% to 90% sensitivity of liquid biopsy depending on the mutational analysis methods used, when a negative result is obtained, tissue biopsy is encouraged.26, 27

In some patients, acquired T790M mutation could be detected in liquid biopsy before radiologic progression,28, 29 but it is currently unknown whether switching to osimertinib before radiologic progression could impact outcomes.30 After disease progression, the best time point for T790M mutation detection is currently undefined on the basis of type (ie, systemic disease spread or oligoprogression) or site (intracranic or extracranic) of progression.

To date, mostly retrospective31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 2 prospective46, 47 Asian case series investigated clinical-pathologic characteristics of T790M mutant lung cancer. Only a few data are available in Caucasian patients, and none of these studies investigated clinical progression patterns related to T790M in detail.48, 49, 50

In this study, we compared clinical features in acquired T790M+ compared with T790M mutation-negative (T790M) cases, progressing after first- or second-generation EGFR TKIs. Secondarily, we assessed different progression patterns between the 2 groups. Finally, we explored the progression pattern at the time of liquid biopsy negativity and subsequent positivity, in a subgroup of patients receiving serial liquid biopsies.

Section snippets

Study Design and Patient Population

This is an observational retrospective study at 7 Italian Centers enrolling patients with EGFR-mutant NSCLC progressing after first or second-generation EGFR TKIs, between 2014 and 2018 (Figure 1).

The inclusion criteria were histologically confirmed diagnosis of advanced NSCLC, presence of an EGFR exon 18 to 21 mutation at diagnosis, progression to front-line systemic treatment with first- or second-generation EGFR TKIs (erlotinib, gefitinib, or afatinib) and presence of at least one liquid

Study Population

Two hundred and thirty-five patients were included across 7 oncologic centers in Italy. Most patients were females with EGFR mutant stage IV lung adenocarcinoma, older than 65 years, and without smoking history. The main patient features are summarized in Table 1.

First-line treatment was gefitinib in 126 (53%), erlotinib in 51 (22%), and afatinib in 58 (25%) patients. Among patients who received erlotinib, 9 were included in a clinical trial where EGFR TKI was combined with an anti-vascular

Discussion

At the time of this paper submission, OS data from AURA3 and FLAURA studies were not available, thus the choice between first-line osimertinib versus old-new generation sequence is currently a matter of debate.

Evidence about clinical features of patients with EGFR mutations potentially predicting the acquisition of T790M mutation is currently limited and mostly available on Asian patients.31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50

This clinical scenario would

Conclusions

This study on a wide Caucasian NSCLC population reports a typical phenotype of patients with EGFR mutations harboring acquired T790M mutation at the time of disease progression to first- or second-generation TKIs. Age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.

Disclosure

The authors have stated that they have no conflicts of interest.

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      The resistance mutation was only detected in one of the diagnostic samples versus 52.3% of samples taken at progression. Other groups have also reported a T790M detection rate at progression of 50% [30]. As expected, the percentage of T790M detection in our study increased over time, with 3.2% of samples being positive at 3 months and 14.8% of samples being positive at 6 months.

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    A.D.M. and M.L. contributed equally to this article as first authors.

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