An 81-year-old Chinese male never-smoker with a medical history of hypertension and hyperlipidemia presented with a productive cough and a 5-lb weight loss over 3 months.
The Case: An 81-year-old Chinese male never-smoker with a medical history of hypertension and hyperlipidemia presented with a productive cough and a 5-lb weight loss over 3 months. A chest x-ray revealed a mass in the right lower lobe of the lung, which was confirmed by CT of the chest. A positron emission tomography (PET)/CT scan showed a right lower lobe mass with a standardized uptake value of 9.1 and revealed additional bilateral lung nodules and bulky, bilateral mediastinal lymphadenopathy. A transbronchial biopsy revealed poorly differentiated adenocarcinoma, with immunostaining positive for TTF1 and negative for P40. Epidermal growth factor receptor (EGFR) testing by direct Sanger sequencing identified two separate EGFR mutations: an L858R mutation in exon 21 and a de novo T790M mutation in exon 20 (Figure 1). Based on the activating mutation in exon 21, erlotinib, 150 mg PO daily, was initiated. Although the patient tolerated the drug without any adverse events, a PET/CT scan 8 weeks later revealed increased burden of intrapulmonary metastatic disease, a worsening pleural effusion, and new destructive bony lesions in the posterior T5 and L1 vertebral bodies (Figure 2). The patient was offered systemic chemotherapy and instructed to discontinue erlotinib. Despite this recommendation he declined any further therapy and eventually enrolled in an outpatient hospice program. He died approximately 1 year after diagnosis.
A new era in lung cancer treatment was ushered in with the identification of driver mutations and the subsequent development of targeted agents. In patients with advanced-stage disease, activating EGFR mutations in exons 19 and 21 are predictive of sensitivity to tyrosine kinase inhibitor (TKI) therapy. EGFR mutations are identified in roughly 15% to 20% of adenocarcinomas of the lung in non-Asian populations and in up to 50% of Asian patients.[1-3] Eight randomized studies have all demonstrated improved response rates and progression-free survival (PFS) for treatment-naive, advanced-stage adenocarcinoma patients with sensitizing EGFR mutations treated with TKI therapy, as compared with chemotherapy, with several of these studies also demonstrating improved quality of life.[3-11] Despite improved outcomes with TKI therapy, all advanced-stage patients who harbor sensitizing mutations will inevitably develop disease progression. This is most commonly due to the development of a second-site mutation in EGFR known as T790M, which accounts for up to 50% of acquired resistance.[12-14] The T790M mutation is characterized by the amino acid substitution of methionine for threonine at position 790, leading to decreased drug binding through steric hindrance and increased binding affinity with ATP at the expense of TKIs.[12,15] While T790M mutations most commonly develop as a resistance mechanism after TKI treatment, rare cases of de novo T790M mutations have been reported. Interestingly, these mutations have usually been identified alongside a second, activating EGFR mutation.[16,17] The rate at which de novo T790M mutations are encountered depends greatly on the population screened and the method used for mutation detection. With direct sequencing, these mutations have been identified in 0.4% to 3% of all non–small-cell lung cancer (NSCLC) patients and in 1% to 8% of all NSCLC patients with an activating EGFR mutation. More sensitive techniques, including mass spectrometry, mutant-enriched polymerase chain reaction (PCR), and colony hybridization assays, have detected T790M mutations in 31% to 79% of patients with activating EGFR mutations.[19-21] De novo T790M mutations can also occur as germline mutations, an occurrence that may confer genetic susceptibility to lung cancer; recent efforts are underway to further define the familial association with T790M.[22-24]
Most studies evaluating the outcomes for patients with de novo T790M mutations treated with TKI therapy are small, retrospective studies that lack survival data. In the Iressa Pan-Asia Study (IPASS), which compared gefitinib vs platinum chemotherapy as front-line treatment for advanced adenocarcinoma, 11 patients were identified with de novo T790M mutations using an amplification-refractory mutation system (ARMS) mutant-enriched PCR method. Of these 11 patients, 7 had concurrent activating EGFR mutations, and 4 of these received gefitinib. Three demonstrated a partial response, while the fourth had stable disease, suggesting that double-mutation patients were sensitive to first-line TKI therapy. Fujita et al retrospectively evaluated 38 patients with TKI-sensitizing EGFR mutations treated with gefitinib and identified a de novo T790M mutation in 30 patients using a highly sensitive colony hybridization assay. The 7 double-mutation patients with strong T790M positivity had a longer time to treatment failure (TTF) on gefitinib (TTF = 41 months) compared with the TTF in double-mutation patients with modest T790M positivity (n = 23; TTF = 7 months; P = .0019) or no T790M positivity (n = 8; TTF = 7 months; P = .0097), suggesting that the presence of a T790M mutation correlated with better outcomes for patients treated with a TKI.
In contrast to these studies, the majority of retrospective studies suggest that de novo T790M mutations confer resistance to TKI therapy. Retrospectively evaluating 30 patients with TKI-sensitive EGFR mutations who were treated with gefitinib, Inukai et al, using mutant-enriched PCR, detected de novo T790M mutations in 3 of the 7 nonresponders but in none of the 19 responders. Rosell et al reported on 129 patients with activating EGFR mutations who were treated with erlotinib; 45 of these patients had a concomitant de novo T790M mutation, identified by mutant-enriched PCR. The median PFS for the double-mutation patients was 12 months, compared with 18 months for those with only the activating EGFR mutation (P = .05). Using a form of ARMS PCR on DNA isolated from circulating tumor cells to identify EGFR mutations, Maheswaran et al demonstrated a reduction in PFS in double-mutation patients treated with gefitinib or erlotinib, compared with the PFS in 16 patients with only EGFR-activating mutations (7.7 months vs 16.5 months; P < .001). More recently, a subset analysis of 95 patients enrolled in the European Tarceva vs Chemotherapy (EURTAC) trial comparing erlotinib vs platinum chemotherapy in patients with advanced EGFR-mutant NSCLC found that for patients with concurrent de novo T790M mutations detected by laser microdissection and peptide nucleic acid–clamping PCR, the PFS with erlotinib was 9.7 months compared with 15.8 months for patients without a concurrent de novo T790M mutation (P = .0185). Similarly, using mass spectrometry methods, Su et al found a shorter PFS in 23 patients with double mutations treated with TKIs compared with the PFS in 33 patients with only EGFR-activating mutations (6.7 months vs 10.2 months; P < .05). Finally, Yu et al retrospectively reviewed 13 patients with de novo T790M mutations and concurrent activating EGFR mutations who were treated with erlotinib; these patients demonstrated a response rate of only 8%, with a median PFS of 1.5 months. The median overall survival for patients with advanced-stage disease was 16 months. The mutations in this study were identified by direct sequencing, locked nucleic acid–based PCR sequencing, or mass spectrometry methods. Taken together, these studies suggest that de novo T790M mutations identified by more sensitive methods may confer a poorer response to standard TKI therapy and essentially “trump” the ability of any coexisting sensitizing EGFR mutation to act as an oncogenic driver in advanced adenocarcinoma.
Afatinib is a second-generation, irreversible TKI that has demonstrated preclinical activity against T790M mutations. The LUX-Lung 1 and LUX-Lung 4 studies evaluated afatinib in a cohort of patients clinically enriched but not tested for the T790M mutation who had progressed on at least 12 weeks of erlotinib or gefitinib. Unfortunately, the response rates were only 7% and 8%, respectively, with PFS of 3.3 and 4.4 months, respectively, suggesting that afatinib may not be active in patients with acquired T790M mutations.[29,30] However, a recent pooled analysis from the LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 trials demonstrated a response rate of 14.3% and a disease control rate of 64% for 14 patients with de novo T790M mutations, with or without activating EGFR mutations, who were treated with first-line afatinib; these results suggest potential activity of this drug in patients who harbor de novo mutations.
T790M mutations develop as a mechanism of resistance after initial TKI therapy for sensitizing EGFR mutations. Management of rare de novo mutations remains controversial. In double-mutation patients with both de novo T790M and sensitizing EGFR mutations, first-line treatment with a reversible TKI may not be optimal, particularly when the population of T790M-mutant cells may be detected by more sensitive molecular techniques. In these cases, cytotoxic chemotherapy may offer the best chance for response, although afatinib may have activity. As molecular mutation testing is integrated more fully into clinical practice, and as detection methods become more sensitive, oncologists are likely to encounter more patients with double mutations. We await further studies addressing the role of other treatment options, including second- and third-generation TKI therapies, which may help improve outcomes.
Financial Disclosure:Dr. Levy and Dr. Li serve as paid consultants and speakers for both Genentech and Boehringer Ingelheim. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin Oncol. 2011;29(suppl):abstr CRA7506.
2. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958-67.
3. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9:154-62.
4. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-57.
5. Mitsudomi T, Morita S, Yatabe Y, 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;11:121-8.
6. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-8.
7. Zhou C, Wu YL, Chen G, 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;12:735-42.
8. Rosell R, Carcereny E, Gervais R, 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;13:239-46.
9. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent Iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122-8.
10. Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-34.
11. Wu YL, Zhou C, Hu CP, 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;15:213-22.
12. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786-92.
13. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.
14. Heuckmann JM, Rauh D, Thomas RK. Epidermal growth factor receptor (EGFR) signaling and covalent EGFR inhibition in lung cancer. J Clin Oncol. 2012;30:3417-20.
15. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 2008;105:2070-5.
16. Thomas A, Xi L, Carter CA, et al. Concurrent molecular alterations in tumors with germ line epidermal growth factor receptor T790M mutations. Clin Lung Cancer. 2013;14:452-6.
17. Yamane H, Ochi N, Yasugi M, et al. Docetaxel for non-small-cell lung cancer harboring the activated EGFR mutation with T790M at initial presentation. OncoTargets Ther. 2013;6:155-60.
18. Yu HA, Arcita ME, Hellman MD, et al. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol. 2014;25:423-8.
19. Fujita Y, Suda K, Kimura H, et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J Thorac Oncol. 2012;7:1640-4.
20. Rosell R, Molina MA, Costa C, et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib- treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res. 2011;17:1160-8.
21. Su KY, Chen HY, Li KC, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 2012;30:433-40.
22. Bell DW, Gore I, Okimto RA, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Gen. 2005;37:1315-6.
23. Oxnard GR, Miller VA, Robson ME, et al. Screening for germline EGFR T790M mutations through lung cancer genotyping. J Thorac Oncol. 2012;7:1049-52.
24. INHERIT EGFR-Studying germline EGFR mutations. ClinicalTrials.gov identifier: NCT01754025. Available from: http://clinicaltrials.gov/ct2/show/NCT01754025. Accessed February 24, 2014.
25. Fukuoka M, Wu YL, Thongprasert S, et al. 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. 2011;29:2866-74.
26. Inukai M, Toyooka S, Ito S, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res. 2006;66:7854-8.
27. Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359:366-77.
28. Costa C, Molina MA, Drozdowsky A, et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res. 2014;20:2001-10.
29. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528-38.
30. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31:3335-41.
31. Yang JC-H, Sequist LV, Geater SL, et al. Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: findings from three trials of afatinib in EGFR mutation-positive lung cancer. Presented at the15th World Congress of Lung Cancer; October 27–31, 2013; Sydney, Australia.