Introduction
In non-small-cell lung cancer (NSCLC), platinum doublet chemotherapy followed by second-line docetaxel monotherapy [
1] or pemetrexed maintenance therapy following first-line platinum doublet chemotherapy [
2] prolongs survival outcomes for patients with non-squamous NSCLC. Based on the efficacy of these treatments, it has been anticipated that they will improve long-term survival of patients with epidermal growth factor receptor (
EGFR) mutation-positive NSCLC after the administration of EGFR tyrosine kinase inhibitors (TKIs).
The treatment of NSCLC has changed considerably in recent years. Following the discovery of the pivotal oncogenic role of
EGFR in unselected NSCLC [
3,
4], the subsequent development of EGFR TKIs provided new therapeutic options for the treatment of this disease. Greater understanding of tumor biology has since led to the discovery that tumors with sensitizing
EGFR mutations, particularly the somatic mutations in
EGFR exons 19 and 21, respond favorably to EGFR TKIs compared with chemotherapy [
5]. To reflect this, EGFR TKIs are recommended in clinical treatment guidelines for NSCLC.
Currently, gefitinib, erlotinib and afatinib are the only EGFR TKIs approved (US Food and Drug Administration, EU and Japan) for the treatment of
EGFR mutation-positive NSCLC [
6,
7]. These approvals were supported by data from several phase III clinical trials, which consistently reported that EGFR TKIs demonstrate significant progression-free survival (PFS) benefits compared with standard chemotherapy [
8]. Median PFS with first-line gefitinib in
EGFR mutation-positive NSCLC ranged between 9.6 and 10.4 months in the pan-Asian IPASS study of gefitinib versus carboplatin/paclitaxel [
9], the Japanese NEJ002 study of gefitinib versus carboplatin-paclitaxel [
10], and the WJTOG3405 study of gefitinib versus cisplatin/docetaxel [
11]. However, despite similar PFS results with gefitinib in these studies, median OS was not consistent; the IPASS study reported a median OS of 21.6 months with gefitinib [
9], whereas a longer median OS of 27.7 months was published in the NEJ002 study [
10] and a median OS of 34.8 months was reported with gefitinib in the Japanese WJTOG3405 study [
11].
Median OS with erlotinib in
EGFR mutation-positive NSCLC was 22.7 months in the phase III OPTIMAL study of erlotinib versus gemcitabine plus carboplatin [
12], and 22.9 months in the phase III EURTAC study of erlotinib versus chemotherapy [
13]. However, as these two studies were conducted outside of Japan, the median OS with erlotinib in Japanese patients with
EGFR mutation-positive NSCLC is currently unknown. PFS for the single-agent erlotinib arm of the Japanese phase II JO25567 study was 9.7 months [
14], which was similar to the 11.8 months median PFS (primary endpoint) reported for the phase II Japanese JO22903 study [
15]. Here, we report final OS data with erlotinib monotherapy in the JO22903 study and present exploratory analyses of OS with respect to
EGFR mutation subtype. We also evaluated whether OS was impacted by the use of post-progression therapy.
Discussion
EGFR TKIs are the standard of care for the first-line treatment of
EGFR mutation-positive NSCLC [
6,
7]. In Japan, the phase II, single-arm JO22903 study demonstrated efficacy of erlotinib monotherapy in
EGFR mutation-positive NSCLC, with a reported median PFS of 11.8 months [
15]. In this updated analysis of the JO22903 study, the 30-month OS rate was 57 % (95 % CI 47–67) and median OS was 36.3 months (95 % CI 29.4–NR). These findings represent a more favorable OS than observed in previous studies of first-line erlotinib in
EGFR mutation-positive NSCLC outside Japan (median OS range 22.9–26.3 months [
12,
13,
16]), and are in line with results from prospective studies of other EGFR TKIs in Japanese populations (median OS range 27.7–34.8 months [
10,
11]). Recently, a median OS of 46.9 months was reported for Japanese patients who received afatinib in the LUX-Lung 3 study [
17], which was longer than that observed in the entire study population [
18]. Across these studies, the median PFS values observed in Japanese and global populations were very similar, at approximately 1 year [
10‐
13,
16‐
18]. Thus, it seems that the current treatment landscape in Japan may be contributing to a longer OS compared with non-Japanese populations, and that OS in Japanese populations can reasonably be expected to reach beyond 3 years.
Although patients with brain metastases have a poor prognosis, which is reflected by the shorter median OS for this subgroup, the findings of this present analysis suggest that erlotinib could be considered effective for patients with brain metastases, as only four patients had CNS progression. This finding is consistent with the phase II ASPIRATION study in Asian patients, which reported that just 4.3 % of patients treated with post-PD erlotinib had new brain lesions [
19]. This role for EGFR TKIs has also been observed in populations not restricted to Japanese or Asian patients [
20‐
22]. A case series of 15 patients with NSCLC with
EGFR mutations and CNS metastases who received cerebrospinal fluid concentration (CSF) examinations during EGFR TKI treatment provides further evidence to support this conclusion. In this case series, CNS response rate was 57 % with a favorable penetration rate of erlotinib in the CSF [
23]. The penetration rate of erlotinib may be dependent on its affinity for p-glycoprotein, which pumps drugs out of the CNS. These findings suggest that erlotinib has a favorable pharmacokinetic profile as a treatment option for patients with brain metastases.
Patients with an exon 19 deletion appeared to have longer OS in our analysis than those with exon 21 L858R
EGFR mutation-positive NSCLC. This is similar to the results of a meta-analysis of seven trials (
n = 1649), which concluded that patients with an exon 19 deletion had better efficacy outcomes than patients with exon 21 L858R
EGFR mutation-positive NSCLC, regardless of which EGFR TKI they received [
24]. These data suggest that patients with exon 19 deletion and exon 21
L858R EGFR mutation are clinically distinct populations that should be evaluated further.
In the present study, there was no apparent difference in OS according to subsequent treatments. Median OS was similar for patients who received EGFR TKIs as post-PD therapy (
n = 36), which were mainly continuous erlotinib administration following RECIST PD (
n = 21) (Table
3), and for those who did not. In contrast to our findings, in a retrospective study of patients with activating
EGFR mutations (
n = 123) who were treated with EGFR TKIs, OS showed a trend in favor of continuing versus discontinuing EGFR TKI treatment following RECIST PD (33.0 versus 21.2 months, respectively;
p = 0.054) [
25]. Furthermore, a retrospective clinical modeling study that evaluated the usefulness of EGFR TKI failure pattern for selecting subsequent management, suggested that the efficacy of EGFR TKI continuation differed between patients with gradual progression, local progression, and dramatic progression [
26]. Thus, one hypothesis for the inconsistency between studies is the difference in the EGFR TKI failure pattern. Meanwhile, in the present study, various EGFR TKIs were used as post-PD therapy (i.e., erlotinib beyond progression, erlotinib re-challenge after another treatment, and other therapies), which should be noted as one of the limitations. As effective post-PD therapy options are important for patients with disease recurrence, any benefit of EGFR TKI re-administration or continuation after PD requires further study.
At this updated analysis, no new safety signals for erlotinib were observed; single-agent erlotinib was well tolerated and had an acceptable and manageable safety profile in
EGFR mutation-positive NSCLC. The safety profile of erlotinib was also in line with previous studies of first-line erlotinib [
13], with the most common AEs being rash and diarrhea.
In conclusion, single-agent erlotinib resulted in a median OS of 36.3 months in the first-line treatment of EGFR mutation-positive NSCLC. Subgroup analyses of OS suggested that the presence of brain metastases was a negative prognostic factor, as these patients had shorter median OS compared with other subgroups. No further differences in OS between specific EGFR subgroups were observed. Although many patients went on to receive additional EGFR TKI therapy following progression, there was no significant difference in median OS for patients who received EGFR TKI as post-PD therapy compared with those who did not. The findings of this single-arm study should be validated in randomized controlled trials.
Compliance with ethical standards
Conflict of interest
Noboru Yamamoto received honoraria from AstraZeneca, Eli Lilly, Pfizer and Chugai Pharmaceutical. He also received research funding from Daiichi-Sankyo, Kyowa-Kirin, Chugai Pharmaceutical, Eli Lilly, Takeda, Quintiles, Bristol-Myers Squibb, Astellas, Taiho, Pfizer, Novartis and Eisai. Koichi Goto received research funding from Chugai Pharmaceutical. Makoto Nishio received honoraria from Chugai Pharmaceutical, Boehringer Ingelheim and AstraZeneca. He also received research funding from Chugai Pharmaceutical and AstraZeneca. Kenichi Chikamori received honoraria from Chugai Pharmaceutical. He also received research funding from Chugai Pharmaceutical and Bristol-Myers Squibb. Toyoaki Hida received honoraria from Chugai Pharmaceutical, Taiho, AstraZeneca and Boehringer Ingelheim. He also received research funding from Chugai Pharmaceutical, Taiho, AstraZeneca, Boehringer Ingelheim, Clovis Oncology and Astellas. Makoto Maemondo received honoraria from Chugai Pharmaceutical, AstraZeneca and Boehringer Ingelheim. He also received research funding from Chugai Pharmaceutical, AstraZeneca and Boehringer Ingelheim. Nobuyuki Katakami received honoraria and research funding from Chugai Pharmaceutical. Toshiyuki Kozuki received honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Pfizer, Kyowa Kirin, Sanofi, Taiho and Roche. He also received research funding from Chugai Pharmaceutical, Bristol-Myers Squibb and Pfizer. Hiroshige Yoshioka received honoraria from Boehringer Ingelheim, Eli Lilly and Chugai Pharmaceutical. He also received research funding from Chugai Pharmaceutical, Novartis, Takeda, Pfizer, Merck-Serono, Eli Lilly and Kyowa Kirin. Takashi Seto received honoraria and lecture fees from Chugai Pharmaceutical. Kosei Tajima is an employee of Chugai Pharmaceutical. Tomohide Tamura received honoraria from Chugai Pharmaceutical, Taiho, Ono, Eli Lilly, Eisai, Yakult Honsha, Boehringer Ingelheim and Bristol-Myers Squibb.