Real-world first-line afatinib for advanced EGFR mutation-positive non-small cell lung cancer in Korea: updated survival data

Introduction

Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring activating mutations in the EGFR gene (1). The frequency of EGFR mutations varies according to ethnicity and is higher in Asians than in Western populations. In Asian patients with advanced NSCLC and adenocarcinoma histology, EGFR mutations are found in around half of all tumors. The most common EGFR mutations detected in NSCLC are exon 19 deletion (Del19) and a point mutation (L858R) in exon 21 (2,3).

Approved TKIs include first- (gefitinib, erlotinib), second- (afatinib, dacomitinib) and third- (osimertinib) generation agents. Although treatment with first-line gefitinib, erlotinib and afatinib is the standard of care for EGFR mutation-positive NSCLC, resistance inevitably develops, commonly due to secondary acquisition of the T790M EGFR mutation. The third-generation EGFR TKI, osimertinib is effective against EGFR T790M-positive NSCLC (1). In Korea, osimertinib is not reimbursable currently for first-line treatment and is used as second-line therapy.

In clinical trials, first-line afatinib has consistently shown efficacy with good tolerability in patients with EGFR mutation-positive NSCLC (4-8). Real-world studies have also demonstrated the effectiveness and tolerability of first-line afatinib in these patients (9-11). A single-center retrospective analysis of Korean patients reported that first-line afatinib had superior progression-free survival (PFS) compared to gefitinib or erlotinib (10). In a multicenter real-world study of Korean patients with EGFR mutation-positive NSCLC, initial analysis showed that first-line afatinib was well tolerated with no new safety signals and effectiveness results were encouraging including in patients with baseline brain metastases and/or uncommon EGFR mutations (11). At the time of the previous analysis (data cut-off 4 April 2019), survival data were not mature. Here, we briefly present updated effectiveness results including PFS and overall survival (OS). We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-383/rc).

Methods

Patient population

Details of the study have been published previously (11). Briefly, this was a retrospective, multicenter (15 sites across South Korea) review of electronic records of adult patients (aged >20 years) with advanced EGFR mutation-positive NSCLC enrolled in the Korean Academy of Tuberculosis and Respiratory Disease (KATRD) EGFR cohort who had initiated first-line afatinib between April 2007 and December 2018 (11). Patient subgroups included the presence or absence of baseline brain metastases, afatinib dose reduction, baseline EGFR mutation type, age group, and treatments received.

Statistical analysis

Outcomes were PFS and OS evaluated using Kaplan-Meier survival curves. PFS was defined as the time from initiation of afatinib to objective tumor progression or all-cause death according to RECIST 1.1 criteria. OS was defined as the time from the first dose of afatinib until death. PFS and OS were censored using a data cut-off date of 31 August 2021. A log-rank test and Cox proportional hazards model were used to compare patient subgroups. Statistical analyses were performed using SAS version 9.4. A P value of <0.05 was considered statistically significant.

Ethical statement

The study was conducted in accordance with the guidelines of the Helsinki Declaration (as revised in 2013). The study was approved by the institutional ethics review boards of: Korea University Guro Hospital (No. 2018GR0013), Asan Medical Center (No. 2018-0012), Yonsei University Gangnam Severance Hospital (No. 3-2020-0003), Konkuk University Medical Center (No. KUH1010909), Catholic University Seoul St. Mary’s Hospital (No. KC20RCDI0129), Wonkwang University Hospital (No. WKUH-201606-HR-058), Inha University Hospital Institutional Review Board (No. 2020-01-016), Chungnam National University Institutional Review Board (No. CNUH 2020-02-022-006), Kyungpook National University Chilgok Hospital Institutional Review Board (No. KNUCH 2020-01-010), Hallym University Sacred Heart Hospital Institutional Review Board (No. HALLYM 2020-07-041), Chonnam National University Hwasun Hospital Institutional Review Board (No. CNUHH-2017-179), Daegu Catholic University Medical Center Institutional Review Board (No. CR-18-097), Institutional Review Board of Severance Hospital (No. 4-2019-1214), Pusan National University Yangsan Hospital Institutional Review Board (No. 05-2020-006), and Kosin University Gospel Hospital Institutional Review Board (No. KUGH 2017-11-030). Individual consent for this retrospective analysis was waived.

Results

As reported previously (11), most patients in the KATRD EGFR cohort treated with first-line afatinib (N=422) were male (54.3%), never smokers (52.1%), with stage IVA/B disease (91.9%), adenocarcinoma (95.3%), Eastern Cooperative Oncology Group (ECOG) performance status <2 (72.5%), and received the approved afatinib starting dose (40 mg, once daily; 82.9%). The most received treatment following progression to afatinib was cytotoxic chemotherapy (71.6%) followed by 3^rd generation TKIs (16.7%) (Table S1). Overall, 39.8% had baseline brain metastases, and common baseline EGFR mutations detected were Del19 (59.0%) and L858R (25.1%) (11).

Kaplan-Meier analyses of the cohort (n=421) showed that median PFS was 20.2 months [95% confidence interval (CI): 17.5–24.5] and median OS was 48.6 months (95% CI: 40.8–56.4). OS rates at 36 and 60 months were 60.1% and 42.3%, respectively.

Subgroup analyses showed that the presence vs. absence of baseline brain metastases was associated with significantly reduced median PFS (14.9 vs. 28.0 months; P<0.001) and median OS (32.2 vs. 65.6 months; P<0.001). Figure 1 shows Kaplan-Meier survival curves for OS in patients with/without brain metastases. Comparative OS rates at 36 and 60 months in patients with or without brain metastases were 45.4% vs. 70.0% and 25.8% vs. 52.5%, respectively.

Figure 1 Kaplan-Meier overall survival curves in patients with (BM+) or without (BM−) baseline brain metastases. BM, brain metastasis; CI, confidence interval; OS, overall survival; NR, not reached.

Among patients with brain metastasis, 41.4% were not receiving treatment during initial lung cancer diagnosis (Table S2). Among patients who were not receiving treatment, the objective response rate of 0.712 (0% complete response, 71.2% partial response, 17.3% stable disease, and 11.5% progressive disease). There was no statistically significant difference between patients with brain metastasis who received vs. did not receive brain metastasis treatment in terms of PFS (14.5 vs. 14.4 months; P=0.683) and OS (30.6 vs. 40.9 months; P=0.220) (Figures S1,S2).

The presence of common baseline EGFR mutations (Del19, L858R) was associated with significantly prolonged OS (49.6 vs. 30.1 months; P=0.017). Comparative OS rates at 36 and 60 months in patients with or without common EGFR mutations were 61.3% vs. 43.4% and 44.0% vs. 20.6%, respectively. Individually, a statistically significant increase in PFS was seen in patients with Del19 (20.8 vs. 15.6 months; P=0.009) while statistically significant lower PFS was seen in patients with L858R (15.6 vs. 19.9 months; P=0.017) (Figures S3,S4). However, no statistical differences in OS were seen when comparing the presence vs. absence of Del19 (P=0.432) and L858R (P=0.553) (Figures S5,S6).

The presence of acquired EGFR T790M mutation was associated with significantly reduced median PFS (18.6 vs. 21.9 months; P=0.0005), but there were no significant differences in median OS between T790M+ and T790M− groups (52.5 vs. 48.6 months; P=0.263). There were no significant differences in OS based on the presence or absence of exon 18 mutations (G719A, G719C, G719S) (P=0.315; Figure S7) or exon 20 mutation S768I (P=0.503; Figure S8).

There were no significant differences in PFS or OS for patients stratified by afatinib dose reduction or by age group (<70/≥70 years) (Table 1). Lastly, there was also no significant difference in OS based on treatment received after progression to afatinib (P=0.239; Figure S9).

Discussion

A previous publication on the effectiveness of first-line afatinib in the KATRD EGFR cohort of patients with advanced EGFR mutation-positive NSCLC (data cut-off 4 April 2019) reported median time-to-treatment discontinuation (TTD) of 17.8 months and an overall response rate of 62.6%. Afatinib was well-tolerated and treatment-related adverse events (mainly diarrhea and rash) were managed effectively with dose reductions (11). Here, we provide an update on the previous analysis and provide additional insight into the effectiveness of first-line afatinib on subgroups of patients based on brain metastasis and baseline EGRF mutations.

In this brief updated analysis, median PFS was 20.2 months and median OS was 48.6 months. Median OS was superior to that reported in other real-world clinical studies of EGFR mutation-positive NSCLC patients. Two global studies of patients treated with sequential afatinib and osimertinib reported median OS of 37.6 months (12) and 36.5 months (13) and median OS was longer in Asian patient subgroups in both studies (44.8 and 42.3 months, respectively). Chart review of Japanese patients treated with afatinib reported a median OS of 38.6 months (14). In two retrospective Taiwanese studies, median OS was 39.1 months in patients treated with afatinib (15) and 37.0 months in patients who received first-line gefitinib, afatinib or erlotinib (16). The median PFS observed in this study was almost twice longer than that reported in pooled analyses of patients with uncommon EGFR mutations (11 months) (17) and in EGFR-TKI-naïve patients (13 months) (18). However, recent prospective trials and real-world studies conducted in Japan and Korea reported similar PFS of 16–20 months (7,19,20). Thus, first-line Afatinib followed by a second-line osimertinib may present a new treatment strategy for a specific subset of patients who are prone to developing T790M as a resistance mechanism. This is supported by a recently published data from the retrospective “Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive non-small cell lung cancer in South Korea (TOAST)” study showed that first-line afatinib treatment with various second-line treatments, including osimertinib, is an effective therapeutic strategy for EGFR mutation-positive NSCLC patients (21). The median PFS observed in this study was also comparable to the PFS of the combination therapy of erlotinib with ramucirumab, an anti-VEGF-R2 antibody, among patients with EGFR-mutated advanced NSCLC (22). However, the trial reported higher incidence rates of grade ≥3 adverse events than reported for afatinib in our previous publication (11). Further, a large real-world comparison study of TKIs in Europe reported statistically significant PFS and 1-year OS of afatinib compared with erlotinib and gefitinib (23). These results support the real-world effectiveness and safety of afatinib.

Baseline brain metastases, which were present in nearly 40% of patients, were associated with significantly reduced PFS and OS. However, there was no statistically significant difference in PFS and OS between patients who received additional treatment for their brain metastasis compared with those who did not. Common baseline EGFR mutations (Del19, L858R) were also associated with significantly prolonged median OS. When analyzed separately, Del19 mutation was associated with increased PFS but L858R mutation was associated with lower PFS. Association of the presence of the Del19 mutation at baseline (but not the L858R mutation) with prolonged OS was previously reported in patients treated with sequential afatinib and osimertinib with increases in median OS by 4 months (12) and 1.5 months (13). Thus, it is likely that first-line Afatinib to be beneficial in patients with baseline Del19 mutation.

A retrospective South Korean study which categorized uncommon EGFR mutations (n=64) according to their incidence showed that first-line afatinib was effective in patients with NSCLC harboring “major uncommon” (G719X and L861Q), and compound EGFR mutations. Median OS was 30.6 and 29.1 months, respectively. However, survival in patients with “minor uncommon” mutations (exon 20 insertion, S768I, and de novo T790M) was reduced: median OS was 8.5 months (24). We did not observe statistically significant differences in OS based on the presence of uncommon mutations in Exon 18 (G719A, G719C, G719S) or exon 20 (S768I).

No significant differences in survival were found between patients stratified by the presence/ absence of T790M EGFR mutation treated with afatinib and subsequent therapy with osimertinib/chemotherapy. Sequential afatinib and osimertinib is known to be superior to sequential afatinib and chemotherapy for NSCLC harboring a T790M mutation (25).

Afatinib was effective in elderly patients ≥70 years of age and supports results from the Japanese phase 2 trial of EGFR mutation-positive patients aged ≥75 years with advanced NSCLC who achieved a median OS of 35.2 months (26), subgroup analyses of older patients (≥65 and ≥75 years) in the LUX-Lung 3, 6 and 7 clinical trials (27), and results from the GIDEON prospective non-interventional study demonstrating higher median PFS in patients ≥70 years (28). Effectiveness of afatinib was also shown in patients who had the dose reduced to 20 or 30 mg. Systematic review of six studies which compared 30 mg with 40 mg doses of afatinib concluded that effectiveness, as evaluated by PFS, appeared to be similar in patients who had no brain metastasis (29). The GIDEON study also reported comparable effectiveness of starting dose of <40 and 40 mg (30). These results suggest first-line afatinib to be an effective treatment option in elderly patients with an option for dose adjustment.

As noted in the previous publication which reported primary analyses from the KATRD cohort (11), study limitations mainly relate to the retrospective study design. Nevertheless, our study represents real-world clinical practice and provides useful insights regarding the use of first-line afatinib for the treatment of advanced EGFR mutation-positive NSCLC in Korea. Assessment of PFS in this study was conducted by the investigators rather than by blinded independent central reviewers, which may contribute to the slightly longer PFS observed in this study.

Conclusions

In conclusion, afatinib was effective in Korean patients with EGFR mutation-positive NSCLC with a median OS of over 4 years. The presence of baseline brain metastases and/or uncommon EGFR mutations were associated with reduced survival. In the absence of baseline brain metastases, median OS was more than 5 years.

Acknowledgments

Under the direction of the authors, medical writing and editorial assistance was provided by Robert A. Furlong PhD and David P. Figgitt PhD, ISMPP CMPP^TM, Content Ed Net, with funding from Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-383/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-383/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-383/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-383/coif). Y.S.C. declares being a stockholder in BicBio; Y.C.K. has received grants from AstraZeneca and honoraria from AstraZeneca, Merck Sharp & Dohme, Roche, Novartis, Janssen, Amgen, Ono Pharma, Bristol Myers Squibb, and Takeda; I.J.O. has received grants from AstraZeneca and Roche, personal fees from Gencurix, Janssen, Merck Sharp & Dohme, Ono Pharma, Panagene, Pfizer, Roche, and Yuhan, and honoraria from Amgen, AstraZeneca, Eli Lilly, Janssen, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, and Yuhan; S.Y.L. has received honoraria from Boehringer Ingelheim; T.W.J. has received honoraria from Boehringer Ingelheim. The other authors have no conflicts of interest to disclose.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the guidelines of the Helsinki Declaration (as revised in 2013). The study was approved by the institutional ethics review boards of Korea University Guro Hospital (No. 2018GR0013), Asan Medical Center (No. 2018-0012), Yonsei University Gangnam Severance Hospital (No. 3-2020-0003), Konkuk University Medical Center (No. KUH1010909), Catholic University Seoul St. Mary’s Hospital (No. KC20RCDI0129), Wonkwang University Hospital (No. WKUH-201606-HR-058), and Inha University Hospital Institutional Review Board (No. 2020-01-016), Chungnam National University Institutional Review Board (No. CNUH 2020-02-022-006), Kyungpook National University Chilgok Hospital Institutional Review Board (No. KNUCH 2020-01-010), Hallym University Sacred Heart Hospital Institutional Review Board (No. HALLYM 2020-07-041), Chonnam National University Hwasun Hospital Institutional Review Board (No. CNUHH-2017-179), Daegu Catholic University Medical Center Institutional Review Board (No. CR-18-097), Institutional Review Board of Severance Hospital (No. 4-2019-1214), Pusan National University Yangsan Hospital Institutional Review Board (No. 05-2020-006), and Kosin University Gospel Hospital Institutional Review Board (No. KUGH 2017-11-030). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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