Postoperative survival of EGFR-TKI-targeted therapy in non-small cell lung cancer patients with EGFR 19 or 21 mutations: a retrospective study

Non-small cell lung cancer (NSCLC) accounts for 80 to 85% of all common types of lung cancer, and NSCLC exhibits the highest morbidity and mortality rate, which is still increasing [1]. Fortunately, developments in lung cancer research over the past decade have codified major advances in the pathogenesis and management of lung cancer, especially adenocarcinoma. The identification of epidermal growth factor receptor (EGFR) mutations in NSCLC and the association between EGFR mutations and gefitinib sensitivity have changed the way lung cancer is diagnosed and treated [2]. Previous retrospective and prospective trials reported that in patients with EGFR mutations, gefitinib or erlotinib produces response rates of 70 to 80%, especially in advanced NSCLC patients with activating EGFR mutations [3, 4]. Furthermore, patients with EGFR mutations have significantly longer survival than those with wild-type EGFR when treated with EGFR tyrosine kinase inhibitors (TKIs) [4‐7]. Testing for EGFR mutations is now recommended to guide patient selection for therapy involving an EGFR inhibitor and a routine postoperative examination, especially in Chinese NSCLC patients [8, 9]. However, published results have often been inconsistent and occasionally contradictory regarding the efficiency of targeted therapy as an independent treatment for NSCLC patients [10]. Most previous studies focus on the efficacy of TKI compared with chemotherapy drugs in patients with EGFR mutations, and there are also conflicting reports on whether patients with EGFR mutations are sensitive to this type of treatment [10, 11]. How to address the clinical utility and predict the benefit of taking EGFR-TKI is still unanswered.

The aim of this retrospective study is to identify EGFR mutations in NSCLC patients and to compare the long-term postoperative outcomes in different EGFR-TKI-targeted therapy effects between the different EGFR mutation groups.

In this study, we retrospectively collected survival data of NSCLC cases to explore the impact on the postoperative survival of NSCLC patients with an EGFR mutation. The EGFR exon 19 deletion that eliminates a leucine–arginine–glutamate–alanine motif in the tyrosine kinase domain of EGFR and the thymine-to-guanine transversion that results in an arginine for leucine substitution at amino acid 858 (L858R) were the two most common EGFR mutations in NSCLC. These mutations represented 85 to 90% of EGFR mutations [12, 13]. In this population, EGFR mutations were identified in 50.33% (1054) of 2094 surgically resected non-small cell lung cancers, and 321 patients with an EGFR exon 19 deletion and 372 patients with exon 21 L858R were identified. These drug-sensitive mutations are noted in approximately 10% of Caucasian patients and up to 50% of Asian patients with NSCLC. In addition, the finding that 33.09% (95%CI, 31.09 to 35.16%) of patients harbored one of the two most common EGFR mutation genotypes was consistent with previous studies in Chinese [14] but was relatively high compared with other Asian populations (Korean population, 27.8%) [15]. In an unselected population-based cohort, 5.4% of the patients had EGFR mutation (4.3% men/6.7% women). Eighty-seven percent were activating mutations. Eight percent of adenocarcinomas and 1.9% of squamous cell carcinomas were mutated. [16] The frequency of EGFR mutations in black patients across all of these studies range from 2 to 19% [17].

Previous studies have suggested that EGFR tyrosine kinase inhibitors are highly effective against mutated-EGFR non-small cell lung cancer given that TKI may increase the binding affinities to these mutant EGFR proteins [18]. Patients with EGFR exon 19 deletions had significantly longer overall survival compared with patients with EGFR L858R after treatment with erlotinib or gefitinib [19]. Our findings confirm the benefit in OS attained with EGFR-targeted agents in Asian patients.

Why do people with exon 19 del have better survival than people with L858R? Firstly, one of the reasons was that EGFR subtype exon 19 del had higher affinities to TKIs than L858R. A study by Carey et al. [20] showed that relative binding affinity of TKI to the EGFR kinase domain was 23 times higher in the EGFR 19 deletion mutation subtype compared with EGFR L858R subtype. Another study of in vitro kinetic assay by Mulloy et al. [21] also indicated a higher affinity of TKI for exon 19 deletion than L858R mutation. Secondly, another reason of better survival with EGFR exon 19 than exon 21 L858R mutations is due to differential inhibition of downstream signals. In the study by Okabe et al. [22], TKI inhibited the phosphorylation of EGFR, Akt and Erk, to a greater degree in exon 19 deletion cells than in L858R cells. Zhu et al. [23] indicated that cell proliferation was inhibited more significantly in EGFR 19 del cells than in EGFR L858R cells in the presence of TKI. Lastly, EGFR-TKI resistant T790M mutation is more frequently encountered in pretreatment samples from patients with the L858R mutation than those with the exon 19 mutation [24]. This result suggests another possible mechanism to explain the better efficacy of EGFR-TKI in deletion 19 patients.

In this retrospective study, we also review the correlation between EGFR mutations and clinical factors that are predictive of response to TKI treatment. Patients with EGFR exon 19 deletions had significant improvements in DCR compared with patients with EGFR L858R after TKI treatment (93.70 vs. 84.31%, P = 0.018), but they had similar response rates (28.35 vs. 22.87%, P = 0.281). DCR may more accurately reflect drug efficacy and be a good candidate for one of the surrogate markers for novel types of anticancer agents in first-line and second-line or later settings [25]. Our findings strengthen this rationale. Previous randomized trials reported that the response rates to EGFR-TKIs exceed 60 to 70% in US patients [26]. However, in postoperative patients in this study, we only observed an ORR of 25%.

Gefitinib and erlotinib are first-line EGFR-TKIs that are effective at treating NSCLC. In our study, the response rates to gefitinib were 27.91 and 23.47% in the EGFR exon 19 deletion group and EGFR L858R group, respectively. The response rates to erlotinib were 47.62 and 18.18%, respectively. Significant differences in response rates determined by different mutations were observed with erlotinib. Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, is a new treatment option for pretreated patients with advanced non-small cell lung cancer [26, 27]. A randomized, double-blind, phase 3 non-inferiority trial with 400 patients demonstrated that icotinib was non-inferior to gefitinib in terms of PFS but had less drug-related adverse events compared with gefitinib [27]. Our result was consisted with this study, which showed that no prolonged PFS in patients treated with icotinib were found. It showed a higher DCR and a longer OS after EGFR-TKI treatment than gefitinib and erlotinib in both exon 19 deletion and EGFR L858R group. In most studies [27, 28], icotinib have less adverse effect than other TKIs. Maybe this could improve the integrated state of patients and has better results. Moreover, the higher dose of icotinib was also well tolerated [28].

Several limitations should be taken into account when considering the results of this study. First, it was a retrospective study, not a randomized trial, and lacked a placebo control. Furthermore, all patients were postoperative patients with lung cancer who received a EGFR mutation test, and our study population may not represent the general population. Additionally, a sample size of 363 patients was sufficient to provide representative and reliable results, but it may not be sufficient for subgroup analysis. These observations warrant further confirmation in prospective studies. Further investigation is also needed to clarify the molecular mechanisms behind the varying efficacies of EGFR-TKI treatment in patients with these mutations. The efficacy of a new generation of EGFR-TKIs targeting these mutations also should be elucidated.

EGFR mutations in exons 19 or 21 are correlated with clinical factors that are predictive of the response to TKI and postoperative survival in NSCLC. Patients with EGFR exon 19 deletion mutations had a longer median overall survival time compared with patients with exon 21 L858R point mutations, but the median progression-free survival time did not differ significantly. Significant variability in the DCR was noted for the different EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR exon 19 deletion mutations, but not in patients with L858R point mutations. Icotinib is a new treatment option for NSCLC, which may offer survival benefits.