T790M in NSCLC: ESMO Biomarker Factsheet

T790M mutation in non-small-cell lung cancer

Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to first- and second-generation tyrosine kinase inhibitors (TKIs) [1], but the efficacy of these agents is often of limited duration because of the emergence of drug resistance [2]. There are several mechanisms of TKI resistance, but EGFR mutation T790M is the most common [2].

T790M mutation

T790M is a recurrent missense mutation within the tyrosine kinase domain of the EGFR gene. The mutation substitutes threonine (T) with methionine (M) at position 790 of exon 20 of EGFR [3]. The mechanism of TKI drug resistance relates to how T790M affects the ATP binding pocket of the EGFR kinase domain. Although initially thought to be related to the steric blocking of the binding of TKIs, it has been suggested that T790M restores the receptor’s ATP affinity to wild type levels, which reduces the potency of the ATP-competitive TKIs in preventing EGFR-mediated signalling [3].

The T790M mutation is most commonly found in cases of non-small-cell lung cancer (NSCLC) carrying a TKI-sensitive EGFR mutation (most frequently an in-frame deletion in exon 19 or an L858R point mutation in exon 21) that have developed resistance after TKI treatment. The first- and second-generation EGFR tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib are highly active against cancers with one of the activating EGFR mutations, with objective response rates of 50 to 70% [4,5]. However, acquired resistance develops after a median of 9 to 13 months and is most commonly due to the EGFR T790M mutation, present in approximately 50 to 60% of resistant cases [5]. In addition, a hereditary lung cancer syndrome with germline EGFR gene T790M mutations has been identified in approximately 1% of NSCLC cases, which also predicts for resistance to standard EGFR TKIs [6].

T790M mutation as a prognostic biomarker in non-small-cell lung cancer

Although previous studies have suggested that acquired T790M mutation after EGFR TKI therapy was associated with longer post-progression survival than in patients without it, associated with less metastatic sites, and a better performance status suggesting the acquired T790M mutation may be indicative of a more indolent disease [7], the primary role of T790M as a biomarker is as a predictive marker of response to TKIs.

T790M mutation as a predictive biomarker in non-small-cell lung cancer

The T790M mutation is an important predictive biomarker in NSCLC and its identification has considerable clinical relevance. The presence of T790M at baseline EGFR-mutation testing using routine clinical molecular testing is rare (<1% of cases) and predicts the lack of response to EGFR TKI therapy (first and second generation TKIs) [8]. Using highly sensitive molecular assays, there is increasing evidence that a low level of the T790M mutation exists before treatment in many patients with EGFR-mutant NSCLC and its presence has been shown to be a negative predictive factor for survival in treatment-naive patients subsequently treated with EGFR-TKI [9,10,11].

With the recent availability of the third-generation EGFR TKI, osimertinib, the presence of T790M identifies patients who are most likely to benefit from treatment with osimertinib [12]. Osimertinib selectively and covalently binds to and inhibits the activity of the mutant forms of EGFR, including the T790M mutant form, preventing EGFR-mediated signalling. Recently, updated phase I and phase II efficacy data have confirmed high objective response rates (ORR) and promising progression-free survival (PFS) rates in patients previously treated with gefitinib or erlotinib and with T790M [13,14]. In a phase III trial of patients with advanced NSCLC and disease progression after first-line EGFR-TKI therapy and documented presence of an EGFR mutation and T790M, osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed: objective response rate 71% (95% CI, 65 to 76) vs. 31% (95% CI, 24 to 40), odds ratio 5.39 (95% CI, 3.47 to 8.48, p<0.001); median duration of PFS 10.1 months vs. 4.4 months, hazard ratio 0.30 (95% CI, 0.23 to 0.41, p<0.001) [15].

Osimertinib is indicated for the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC [12]. The summary of product characteristics for osimertinib specifies that the mutation status is determined through a validated diagnostic test based on a tumour tissue sample or plasma. However, if a plasma-based circulating-tumour DNA (ctDNA) test is used and the result is negative, there is a recommendation to follow-up with a tissue test wherever possible due to the potential for false negative results using a plasma-based test [12]. Other third-generation TKI in development for patients with T790M-positive NSCLC include nazartinib, ASP8273, and PF-06747775 [5].

T790M mutation testing recommendations in non-small-cell lung cancer

Eligibility for treatment with TKIs is dependent on mutation status, requiring routine testing of appropriate cases for EGFR mutations [16]. There are many mutation-testing strategies available, which highlights the need to be aware of any limitation in mutation coverage offered by the technology used, as well as the sensitivity for detecting mutations against a background of wild-type genome [16]. This caution is particularly important for the analysis of ctDNA that requires the use of high sensitive techniques in laboratories with adequate experience in plasma testing [17]. A potential limitation of an EGFR plasma test based on ctDNA is the reported lower rate of mutation detection in patients with intrathoracic disease versus extrathoracic disease, but further studies are required to more fully investigate this potential difference [18,19]. Recommendations for high-quality EGFR mutation testing have been formulated and published by the European EGFR Workshop Group [20], and are further described in an accompanying ESMO Biomarker Factsheet by Professor Keith Kerr.

References

1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129-39.
2. Morgillo F, Della Corte CM, Fasano M, et al. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open 2016; 1:e000060. doi:10.1136/ esmoopen-2016-000060
3. 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.
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12. Tagrisso Summary of Product Characteristics, 2016
13. Ramalingam S, Yang JC-H, Lee CK, et al. Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. J Thorac Oncol 2016; 11 (Suppl 4S): S152 (Abstract LBA1_PR)
14. Yang J, Ramalingam S, Janne PA, Cantarini M, Mitsudomi T. Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol 2016; 11 (Suppl 4S): S152 (Abstract LBA2_PR)
15. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. NEJM; Published online 6 December, 2016. DOI: 10.1056/NEJMoa1612674
16. Kerr KM, Bubendorf L, Edelman MJ, et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 2014; 25:1681–90
17. Reck M, Hagiwara K, Han B, et al. ctDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: The ASSESS Study. J Thorac Oncol 2016; 11(10):1682-9
18. Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686). Clin Cancer Res 2016; 22:2386–95
19. Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 2015; 90(3):509–515
20. Pirker R, Herth FJF, Kerr KM, et al. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. J Thorac Oncol 2010; 5: 1706–713