Is EGF receptor–tyrosine kinase inhibitor therapy in non-small-cell lung cancer patients with EGFR mutations the best option?

In non-small-cell lung cancer (NSCLC), the discovery that EGF receptor (EGFR) signaling plays a key role in regulating cell proliferation, differentiation and tumorigenesis has emphasized the importance of targeted therapy. Small molecule tyrosine kinase inhibitors of EGFR (EGFR–TKIs), such as gefitinib and erlotinib, compete with ATP for binding to the tyrosine kinase pocket of the receptor, thereby inhibiting receptor kinase activity and EGFR signaling.

Early clinical trials showed that specific NSCLC patient populations experienced a rapid, remarkable and durable response to EGFR–TKI treatment [1]. Clinical characteristics associated with high EGFR–TKI response rates include female gender, Asian ethnicity, never-smoker status and adenocarcinoma [2]. In 2004, several groups demonstrated that remarkable response rates to EGFR–TKIs were seen in NSCLC patients who harbored somatic mutations in EGFR[3–5]. Subsequently, several Phase II trials of EGFR–TKIs in NSCLC patients with EGFR mutations demonstrated a favorable overall response rate. We performed an integration analysis of data from seven clinical trials of gefitinib in NSCLC patients in Japan and showed that overall response rate and progression-free survival (PFS) time in response to gefitinib were 76.4 and 9.7 months, respectively [6]. The substantial clinical benefits of gefitinib led to a Phase III trial to compare the efficacy of first-line gefitinib versus cisplatin plus docetaxel for the treatment of advanced NSCLC patients with EGFR mutations (WJTOG 3405) [7]. The gefitinib group had significantly longer PFS than the cisplatin plus docetaxel group, with a median PFS of 9.2 versus 6.3 months (hazard ratio [HR]: 0.489; p < 0.0001). At approximately the same time as the WJTOG 3405 study, the NEJ002 study confirmed that PFS, the primary end point, was significantly longer in the gefitinib group than in the carboplatin plus paclitaxel group (10.8 vs 5.4 months; HR: 0.30; p < 0.001) [8]. Furthermore, two Phase III trials revealed the PFS benefit of erlotinib compared with standard chemotherapy. In the OPTIMAL study, which was conducted in China, the erlotinib arm had significantly longer PFS than the carboplatin plus gemcitabine arm, with a median PFS of 13.1 versus 4.6 months (HR: 0.16; p < 0.001) [9]. Another Phase III trial (EURTAC) also demonstrated the PFS benefit of erlotinib compared with standard chemotherapy (9.7 vs 5.2 months; HR: 0.37; p < 0.001) [10].

On the basis of the results of these pivotal studies, EGFR–TKIs are now widely recognized as the most effective agents in the treatment of advanced NSCLC harboring EGFR mutation. However, the WJTOG 3405, NEJ002, EURTAC and OPTIMAL studies were not able to demonstrate a definitive overall survival (OS) improvement, and this was most likely due to the large number of patients in the chemotherapy group who received EGFR–TKI in the second-line setting. Updated data of the WJTOG 3405 study demonstrated a median OS of 35.5 and 38.8 months in the gefitinib arm and chemotherapy arm (p = 0.44), respectively; however, 91% of patients in the chemotherapy arm received EGFR–TKI in the second-line setting [11]. Recently, we systematically analyzed postprogression survival (PPS) [12], which is calculated as the median OS minus median PFS, to investigate the effect of therapies instituted after disease progression in patients with advanced NSCLC. In our analysis, the average PPS was 6.5 months in 34 recent Phase III trials (2003 and later trials). On the other hand, extremely long PPS in the chemotherapy arm was achieved in the WJTOG 3405 study (32.5 months). The reason for the prolongation of PPS in the WJTOG 3405 study is that more than 90% of patients in the chemotherapy arm received EGFR–TKI as salvage therapy. Actually, 9.0% of patients with EGFR mutations assigned to first-line standard platinum-doublet chemotherapy who did not receive EGFR–TKI after the first-line setting showed shorter OS (13.5 months), whereas 39.0% of patients in the gefitinib arm who did not receive platinum-doublet chemotherapy had longer OS (45.4 months). Although the biases of this data were considerable, it is reasonable to speculate that the longer survival of patients with EGFR-mutated NSCLC who receive gefitinib is due to the high overall response rate and prolonged PFS associated with EGFR–TKI treatment.

Taken together, the WJTOG 3405, NEJ002, EURTAC and OPTIMAL studies have shown that EGFR–TKIs are key agents in the treatment of EGFR-mutated NSCLC. However, the clinical efficacy of EGFR–TKIs is limited by the development of acquired resistance. Despite the high response rate and prolonged PFS associated with EGFR–TKI treatment, EGFR-mutated NSCLC patients will eventually experience disease progression due to the inevitable development of resistance. The EGFR T790M mutation in exon 20 and the activation of bypass pathways, such as MET amplification [13], have been identified as mechanisms of resistance to EGFR–TKIs. To overcome the acquired resistance associated with T790M mutation, several second-generation EGFR–TKIs, which have strong binding affinity for EGFR (irreversible EGFR–TKIs), have been recently developed. Furthermore, a third-generation EGFR–TKI is now under investigation in early phase clinical trials. This novel agent can selectively target mutant forms of EGFR, including T790M and the common initial activating mutations (L858R and del19), while sparing wild-type EGFR[14]. The combination of EGFR–TKIs with molecularly targeted agents, such as MET inhibitors, has also shown promise for treating acquired resistance by activating bypass pathways.

The use of EGFR–TKIs in the multimodal treatment of locally advanced EGFR-mutated NSCLC has also shown promise. We previously examined the feasibility of gefitinib in combination with concurrent radiotherapy in the treatment of EGFR mutation-positive patients with locally advanced NSCLC [15]. Two patients with EGFR mutations (deletions in exon 19) did not experience local progression and exhibited an OS of >5 years. Given that EGFR mutations are present in a substantial proportion of NSCLC patients [16], even those with locally advanced disease, further trials of combined modality regimens including EGFR–TKIs in molecularly selected populations are warranted. Toward this end, a Phase II clinical trial of radiotherapy in combination with gefitinib for EGFR mutation-positive NSCLC is currently ongoing (WJOG 6911L).

Overall, EGFR–TKI treatment is the best option for advanced NSCLC patients with EGFR mutations. To improve the clinical efficacy of EGFR–TKIs, significant progress is being made in understanding the biology of acquired resistance to EGFR–TKIs in EGFR-mutated NSCLC. Combined modality therapy using EGFR–TKIs holds promise for the treatment of EGFR-mutated NSCLC and is currently under investigation in molecularly selected patients.