Original StudyClinical 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
Graphical abstract
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.
References (60)
- et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Lancet Oncol
(2010) - et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
Lancet Oncol
(2011) - et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Lancet Oncol
(2012) - et al.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
Lancet Oncol
(2014) - et al.
Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial
Lancet Oncol
(2016) - et al.
Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study
Lancet Oncol
(2016) - et al.
Application of plasma genotyping technologies in non–small cell lung cancer: a practical review
J Thorac Oncol
(2017) - et al.
Liquid biopsy for advanced non-small cell lung cancer (NSCLC): a statement paper from the IASLC
J Thorac Oncol
(2018) - et al.
Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2018) - et al.
The APPLE trial: feasibility and activity of AZD9291 (osimertinib) treatment on positive plasma T790M in EGFR-mutant NSCLC patients. EORTC 1613
Clin Lung Cancer
(2017)
Re-biopsy status among non-small cell lung cancer patients in Japan: a retrospective study
Lung Cancer
Association between EGFR T790M status and progression patterns during initial EGFR-TKI treatment in patients harboring EGFR mutation
Clin Lung Cancer
A higher proportion of the EGFR T790M mutation may contribute to the better survival of patients with exon 19 deletions compared with those with L858R
J Thorac Oncol
Clinical characteristics of T790M-positive lung adenocarcinoma after resistance to epidermal growth factor receptor-tyrosine kinase inhibitors with an emphasis on brain metastasis and survival
Lung Cancer
Clinical factors predicting detection of T790M mutation in rebiopsy for EGFR-mutant non–small-cell lung cancer
Clin Lung Cancer
T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients
Lung Cancer
Spatiotemporal T790M heterogeneity in individual patients with EGFR-mutant non–small-cell lung cancer after acquired resistance to EGFR-TKI
J Thorac Oncol
Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors
Lung Cancer
Epidermal growth factor receptor (EGFR) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non-small cell lung cancer progression during first-generation tyrosine kinase inhibitor therapy: a prospective observational study
Cancer Commun (Lond)
Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients
Lung Cancer
Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC)
Clin Lung Cancer
Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer
Ann Oncol
First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study
Br J Cancer
Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non–small-cell lung cancer in Asia (IPASS)
J Clin Oncol
Screening for epidermal growth factor receptor mutations in lung cancer
N Engl J Med
Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma
N Engl J Med
Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers
J Natl Cancer Inst
Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR
N Engl J Med
Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations
J Clin Oncol
Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer
J Clin Oncol
Cited by (19)
A Pan-Canadian Validation Study for the Detection of EGFR T790M Mutation Using Circulating Tumor DNA From Peripheral Blood
2021, JTO Clinical and Research ReportsCitation Excerpt :The variable detection rates may be owing to the low patient numbers at some centers, and the variable clinical progression patterns after first or second-generation TKIs. For example, in some patients, acquired T790M variant could be detected in ctDNA before radiological progression.24 Eligibility for this validation study required stage IIIB or IV advanced EGFR-mutant NSCLC and along with clinical signs of progression.
Analysis of circulating tumour DNA to identify patients with epidermal growth factor receptor–positive non-small cell lung cancer who might benefit from sequential tyrosine kinase inhibitor treatment
2021, European Journal of CancerCitation Excerpt :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.
ErbB in NSCLC as a molecular target: Current evidences and future directions
2020, ESMO OpenCitation Excerpt :A study on 93 osimertinib-resistant NSCLC patients showed the coexistence of C797S with novel tertiary EGFR C797G in 24% of cases73; and besides C797X, other mutations such as those in the G796, L792, L718, G719 and G724 residue have been showed to sterically interfere with the osimertinib-EGFR interaction.74–78 T790M loss is another common mechanism demonstrated in about 50%–60% of patients at osimertinib progression.79–81 Acquired EGFR mutations (C797S, 14%) was observed in 21% of cases while 49% of patients showed the T790M loss at progression in ctDNA.
EGFR T790M testing through repeated liquid biopsy over time: a real-world multicentric retrospective experience
2022, Journal of Thoracic Disease
A.D.M. and M.L. contributed equally to this article as first authors.