Abstract
Background: Second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib as first-line treatment has been demonstrated to improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC) harboring an exon 19 deletion (del19) of EGFR compared to platinum-doublet chemotherapy. However, it is unclear whether first-generation EGFR-TKIs improve OS in patients with del19 in the first-line treatment. Patients and Methods: We performed a post-hoc analysis of patients with del19 or L858R mutation of EGFR who received gefitinib in the NEJ002 study, which compared gefitinib to carboplatin-paclitaxel. Results: A total of 58 patients and 57 patients with del19 EGFR received gefitinib and carboplatin-paclitaxel, respectively. No OS differences were observed between patients receiving gefitinib and carboplatin-paclitaxel irrespective of del19 (29.3 months vs. 29.7 months, p=0.53) or L858R (28.4 months vs. 25.1 months, p=0.45). Conclusion: In contrast to afatinib, it is suggested that first-line gefitinib does not improve OS in patients with del19 of EGFR compared with platinum-doublet chemotherapy.
The clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been demonstrated in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (1, 2). Previous randomized phase III studies have proven that the first-generation reversible EGFR-TKIs, such as gefitinib and erlotinib, significantly improve progression-free survival (PFS) compared to platinum-doublet chemotherapy in patients with NSCLC with EGFR mutations (3-6). By contrast, gefitinib and erlotinib failed to produce an improvement in overall survival (OS) compared to platinum-doublet chemotherapy in these same studies. Recently, the results of the combined analysis of LUX-Lung 3 and LUX-Lung 6 studies were reported by Yang and colleagues (7). Both studies were open-label, multicenter, randomized phase III studies that compared the second-generation irreversible TKI, afatinib, with platinum-based chemotherapy (pemetrexed-cisplatin in LUX-Lung 3, and gemcitabine-cisplatin in LUX-Lung 6) in previously untreated patients with EGFR mutation-positive lung adenocarcinoma (8, 9). The primary end-point of these studies was PFS, which was significantly longer in the afatinib-treated group compared to the chemotherapy-treated group. Importantly, this combined analysis of LUX-Lung 3 and LUX-Lung 6 demonstrated that compared to first-line chemotherapy, first-line afatinib significantly improved OS in patients with an exon 19 deletion (del19) of EGFR but not in patients with the L858R mutation. In previous phase III studies comparing gefitinib and erlotinib with chemotherapy, the OS differences by treatment group for patients with del19 or L858R have not been evaluated. To compare first-generation reversible TKI gefitinib with platinum-doublet chemotherapy in patients with del19 or the L858R mutation of EGFR, we reanalyzed the OS data from the NEJ002 study, which examined first-line gefitinib in patients with NSCLC with activating EGFR mutations (3).
Materials and Methods
The eligibility criteria of the NEJ002 study (UMIN-CTR number, C000000376) included the presence of untreated advanced NSCLC harboring an EGFR mutation (del19 or L858R, G719X or L861Q point mutation) without presence of the resistant T790M EGFR mutation (identified using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method), an age of 75 years or younger, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function (3). Patients were randomly assigned to gefitinib (250 mg/day) or paclitaxel (200 mg/m2)/carboplatin (area under the blood concentration-time curve 6.0) on day 1 every 3 weeks (up to six cycles). The NEJ002 study recommended that the crossover regimen as second-line treatment.
Diagram showing patient registration, treatment assignments and exclusions. ITT: Intention-to-treat analysis.
Kaplan–Meier survival curves were constructed for OS, and differences between groups were identified using the log-rank test. Differences in response rates were identified using Fisher's exact test. Each analysis was two-sided, with a 5% significance level and a 95% confidence interval. All analyses were performed using SAS for Windows software (release 9.1, SAS Institute, Cary, NC, USA).
Patients provided their written informed consent. The NEJ002 study was conducted in accordance with the Helsinki Declaration of the World Medical Association. The protocol was approved by the Institutional Review Board of each participating institution. This post-hoc analysis was also approved by the Research Ethics Committee of the Niigata University.
Results
In total, 230 patients were enrolled in the NEJ002 study. In the carboplatin-paclitaxel group, 112 patients (98%) received gefitinib after disease progression (10). By contrast, in the gefitinib group, 74 patients (65%) were treated with platinum-doublet regimen as second-line or later chemotherapy. We identified 225 patients with del19 or L858R who received gefitinib at any point. Patients who had G719X, L861Q or both del19 and L858R were excluded (Figure 1). The data of a total of 212 patients were retrospectively analyzed in this post-hoc analysis.
In patients with EGFR del19, the OS did not differ significantly between the gefitinib-treated group and the carboplatin-paclitaxel-treated group (29.3 months vs. 29.7 months, p=0.52; Figure 2). Similarly, the median OS was not significantly different between two treatment groups in patients with L858R (28.4 months vs. 25.1 months, respectively, p=0.45).
Kaplan–Meier curve for overall survival by treatment arm for patients with exon 19 deletion (A) and those with L858R mutation (B) of epidermal growth factor receptor gene.
Discussion
The combined analysis of LUX-Lung 3 and LUX-Lung 6 demonstrated that afatinib significantly prolonged OS compared to platinum-doublet chemotherapy in untreated patients with del19 of EGFR (7). In contrast to the results from the combined analysis of LUX-Lung 3 and LUX-Lung 6 studies, we observed no differences in OS between patients receiving gefitinib and patients receiving carboplatin-paclitaxel irrespective of del19 or L858R mutation of EGFR.
In contrast to NEJ002, in which most patients treated by first-line chemotherapy received gefitinib thereafter, only about two-thirds of the patients harboring EGFR del19 treated by the first-line chemotherapy received EGFR-TKI (75% and 53% of patients in LUX-LUNG 3 and LUX-LUNG 6, respectively) (7). Because an EGFR-TKI is the most important drug for patients with common EGFR mutations, the decrease in OS in patients with del19 who received first-line chemotherapy could be from the lower percentage of patients treated with EGFR-TKIs post-chemotherapy. Yang and his colleagues demonstrated that 91% of patients with del19 in countries with universal reimbursement policies for EGFR-TKIs received EGFR-TKIs post-chemotherapy in LUX-Lung 3 and LUX-Lung 6. In such countries, OS in patients with EGFR del19 receiving first-line afatinib was found to be increased compared with patients their counterparts receiving first-line chemotherapy. Because very few patients received afatinib in the chemotherapy-treated group, these findings suggested that afatinib has greater antitumor efficacy in patients with del19 compared with first-generation TKIs.
On the other hand, the combined analysis of LUX-Lung 3 and LUX-Lung 6 also demonstrated that OS did not significantly differ among patients receiving first-line afatinib compared to patients receiving first-line chemotherapy in the group with L858R mutation. Previous studies indicated that afatinib has greater antitumor efficacy compared to gefitinib in patients with uncommon mutations (11). Collectively, second-generation irreversible TKI afatinib, compared with first-generation reversible TKIs, appears to possess superior antitumor activity for patients with del19 and uncommon mutations but not those with the L858R mutation.
This post-hoc analysis clarifies that first-line gefitinib does not improve OS in patients with NSCLC with EGFR del19 compared to first-line platinum doublet chemotherapy, although first-line gefitinib contributed to maintaining quality of life (12). When using afatinib, the del19 and the L858R mutation of EGFR may need to be analyzed separately. Moreover, these findings should stimulate investigations to clarify the mechanisms underlying the different clinical responses to afatinib between patients with del19 and those with L858R mutation.
Acknowledgements
The collection of data used in this analysis was supported by the Tokyo Cooperative Oncology Group.
Footnotes
Conflicts of Interest
Dr. Watanabe and Dr. Kobayashi have declared no conflicts of interest; Dr. Inoue reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, grants and personal fees from Chugai, outside the submitted work. Dr. Nukiwa reports personal fees from Boehringer Ingelheim outside the submitted work.
- Received September 21, 2015.
- Revision received October 17, 2015.
- Accepted October 23, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
