|Location of mutation ||Kinase domain (exon 20) |
|Frequency of EGFR mutations in NSCLC || ~10% in the USA |
~35% in Asia
(Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004)
|Frequency of EGFR T790M mutations in EGFR-mutated NSCLC ||<5% of untreated EGFR mutant tumors (Inukai et al. 2006) |
50% of EGFR mutant tumors with acquired resistance to erlotinib/gefitinib (Kobayashi et al. 2005; Pao et al. 2005)
|Implications for Targeted Therapeutics |
|Response to EGFR TKIs ||Confers decreased sensitivity |
|Response to anti-EGFR antibodies ||Currently no role for EGFR mutation in predicting response in NSCLC |
The T790M mutation results in an amino acid substitution at position 790 in EGFR, from a threonine (T) to a methionine (M). This mutation occurs within exon 20, which encodes part of the kinase domain.
T790M after acquired resistance to erlotinib/gefitinib
The T790M mutation can be detected as a "second-site mutation" in more than 50% of EGFR-mutant lung cancers that have developed acquired resistance to erlotinib or gefitinib (Kobayashi et al. 2005; Pao et al. 2005). Interestingly, case reports of patients who develop the T790M mutation as a mechanism of acquired resistance to EGFR TKI therapy have shown that this resistance mutation can be lost after an EGFR TKI free period. These patients then responded to a re-challenge with EGFR TKI (Sequist et al. 2011). Other reports have also shown that patients can re-respond to TKI treatment after a hiatus from targeted therapy (Watanabe et al. 2010). Whether patients should continue or discontinue an EGFR TKI after developing acquired resistance remains to be definitively determined.
Investigating third-generation EGFR TKIs and dual drug inhibition of EGFR in T790M mutant NSCLC is currently an active area of research. In phase I trials, third-generation EGFR TKIs CO-1686 and AZD9291 have demonstrated efficacy in patients who have progressed on prior TKI therapy, including cohorts of patients with EGFR T790M mutant NSCLC (Soria et al. 2013; Ranson et al. 2013). In a phase I study, a 38% response rate was reported with combination afatinib and cetuximab therapy in patients with EGFR T790M-mutant NSCLC (Janjigian et al. 2012).
T790M in untreated EGFR-mutant lung cancers
T790M is rarely (<5%) found in untreated EGFR mutant tumors using conventional testing techniques (Inukai et al. 2006). These "baseline" T790M mutations generally occur concurrently with another EGFR sensitizing mutation and have been found to be associated with decreased sensitivity to EGFR TKIs (Wu et al. 2011).
In approximately half of patients with baseline T790M mutations in their lung cancer, the T790M may be present as an underlying germline mutation. These germline T790M mutations occur infrequently (~0.5% of never smokers with lung cancer; Girard et al. 2010) and may be associated in some instances with familial cancer syndromes (Bell et al. 2005). A clinical trial is in development to better understand the relationship between baseline and germline T790M mutations and to better characterize the risks associated with carrying a germline T790M mutation (Oxnard et al. 2012).
|Reference ||Study Type / Phase ||Line of Treatment ||Treatment Agent ||Mutation Status/Group ||# Patients in Study ||Response Rate ||PFS (months) ||OS (months) |
| Miller et al. 2012 ||Phase IIb/III (LUX-Lung 1) ||3rd–4th (acquired resistance to EGFR TKIs) ||afatinib + best supportive care ||NSCLC progressing on prior erlotinib or gefinitib ||390 ||7% ||3.3 ||10.8 |
|placebo + best supportive care ||NSCLC progressing on prior erlotinib or gefinitib ||195 ||<1% ||1.1 ||12 |
| Katakami et al. 2013 ||Phase II (LUX-Lung 4) ||3rd–4th (acquired resistance to EGFR TKIs) ||afatinib ||NSCLC progressing on prior erlotinib or gefinitib ||62 ||8% ||4.4 ||19 |
Janjigian et al. 2011; Janjigian et al. 2012
||Phase I ||≥ 2nd (acquired resistance to EGFR TKIs) ||afatinib / cetuximab ||EGFR T790M ||53 ||38% || || |
|Soria et al. 2013 ||Phase I ||≥ 2nd (prior EGFR TKI required) ||CO-1686 ||EGFR T790M ||31 (evaluable N=4) ||75% || || |
|Ranson et al. 2013 ||Phase I (AURA) ||≥ 2nd (prior EGFR TKI required) ||AZD9291 ||NSCLC progressing on prior EGFR TKI and T790M expansion cohort ||27 ||2 confirmed PRs reported in T790M mutation positive patients || || |
NOTE: OS = overall survival; PFS = progression-free survival; PR = partial response.