Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial

Lung cancer is the leading cause of cancer related mortality worldwide [1]. In European lung adenocarcinoma patients, the incidence of mutations of epidermal growth factor receptor (EGFR) gene is between 5 to 10% [2‐4]. Currently, three EGFR tyrosine kinase inhibitors (EGFR-TKIs) including the first-generation, reversible TKI erlotinib and gefitinib as well as the second-generation irreversible TKI afatinib are approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR activating mutations [5]. For all three agents, the classic mutations of L858R and exon 19 microdeletions can serve as positive predictive biomarkers for response. Of note, a number of additional so called rare EGFR mutations are also sensitizing for EGFR-TKI therapy [4]. Erlotinib was demonstrated to delay symptom progression, improve quality of life and prolong survival as a first-line treatment when compared to standard chemotherapy in patients with exon 19 deletions or exon 21 (L858R) substitution mutations of EGFR [6, 7]. In addition, erlotinib is also approved by the European Medicines Agency for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen (with no mutation analysis requirement) as well as for switch maintenance treatment in patients with locally advanced or metastatic NSCLC with EGFR activating mutations and stable disease after first-line chemotherapy [8].

EGFR mutations are associated with adenocarcinoma histology and more often found in non-smokers. Especially in Asian populations it is also more frequent in females often associates with younger age [9]. These epidemiological characteristics often influence the screening strategy. The presence of KRAS mutations is in general mutually exclusive with EGFR mutations and associates with the lack of response to EGFR-TKIs [10‐12].

Our multicenter, phase IV clinical trial was designed to determine the efficacy and safety of erlotinib in routine clinical practice and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection in Caucasian patients.

In contrast to Asian lung adenocarcinoma patients, there is relatively less information about the first-line EGFR-TKI treatment response rates and progression-free survival in Caucasian cohorts. Our non-randomized, multicenter, phase IV clinical trial including first-line erlotinib treated lung adenocarcinoma patients with activating EGFR mutations was conducted for the very reason. The ORR in our study is in accordance with studies from East-Asia where RRs were found to be 70–75% [13, 14]. Interestingly, the LUX-Lung 2 phase II trial of the second-generation covalent TKI inhibitor afatinib demonstrated similar RR in classic EGFR mutant patients [15]. Of note, the 12.8-months median PFS in our cohort is in the range of previously published data (9.4–11.9 months) from other studies [14, 16].

Previously, three major randomised, phase III first-line studies have shown a tendency for improved response to erlotinib in patients with exon19 microdeletion-positive tumors when compared to L858R-positive cases [6, 7, 17]. This tendency has not been observed in the current study, however, the number of patients is limiting the identification of smaller differences in the progression-free survival. Of note, there was no difference at all in the smoking status of patients in the exon 19 and exon 21 mutation subgroup.

While smoking is clearly the most important factor in the development of lung cancer, the prognostic and predicitve significance of smoking status is context dependent. In several studies, never-smokers have improved OS, however, the increased survival is at least in part due to the overall better performance score and the lack of smoking related comorbidities [18‐21]. In standard chemotherapy regimens, predictive value of smoking status is limited [19, 22, 23] or only slightly increased survival can be demonstrated in never-smokers when compared to smokers [24, 25]. In contrast, never-smokers seem to have survival benefits in cohorts that include EGFR-TKI treated patients [4]. Owing to the fact that mutation of EGFR gene is more frequent in non-smokers [26, 27], our study was biased towards never-smokers. Of note, in the ever smoker group there are 4 patients out of 6 are censored beyond one-year that might suggest a decreasing relative risk over time. Nevertheless, there are only 20 patients in the ever smoker subcohort including 3 current smokers. Thus the size of the subcohort prevent us from studying the time-dependent impact of smoking on the progression–free survival. Nevertheless, we found a significantly improved progression-free survival in never-smokers. One reason might be the smoking induced additional mutational load that can lead to the presence of tumor cell clones with resistance mutations and thus lead to earlier emergence of therapy resistance.

In the present patient cohort ECOG PS was a significant predictor of PFS. It is in line with a number of other studies where better performance status associated with improved anti-EGFR therapy response [4, 28].

Other studies have previously demonstrated that disseminated disease stage have an impact of progession-free survival in EGFR-TKI treated patients [29]. In the current study, there were only 6 non-metastatic patients included, thus the exploratory analysis of stage as a predictor was limited to M1a and M1b subgroups. Of note, patients with metastasis limited to the lung and pleural or pericardial effusion had a signficantly longer PFS when compared to patients with distant organ dissemination.

Overall, our phase IV clinical trial demonstrated that the companion diagnostic method could identify lung adenocarcinoma patients with activating EGFR mutation with a frequency that was found in other Caucasian patient populations. Furthermore, it has been demostrated that the first-line erlotinib treatment of this patient cohort had an efficacy and safety profile similar to previous large randomized phase III clinical trials.