Abstract
Background
This study aimed to investigate the factors associated with prolonged progression‐free survival (PFS) (>36 months) of advanced non‐small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first‐line afatinib.
Methods
We performed a retrospective analysis of data of patients with advanced EGFR‐mutated NSCLC receiving first‐line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022.
Results
The data of 546 treatment‐naïve EGFR‐mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067–0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log‐rank test, p < 0.001).
Conclusions
We found that EGFR‐mutated NSCLC patients receiving first‐line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.
Keywords: afatinib, epidermal growth factor receptor mutation, non‐small cell lung cancer, progression‐free survival
This retrospective study investigated the factors associated with prolonged PFS (>36 months) in 546 advanced EGFR‐mutated NSCLC patients treated with first‐line afatinib. The PFS >36 months group (84 patients) had a significantly higher percentage of uncommon mutations. The PFS ≤36 months group (462 patients) had significantly higher incidences of bone, liver, and adrenal metastases and a higher rate of multiple distant metastases. Liver metastasis was independently associated with shorter PFS.
INTRODUCTION
Epidermal growth factor receptor (EGFR) mutations are common driver mutations of non‐small cell lung cancer (NSCLC). EGFR‐tyrosine kinase inhibitors (TKIs) have emerged as the first‐line therapy for advanced NSCLC patients harboring EGFR mutations and have shown favorable clinical responses. Gefitinib and erlotinib are first‐generation reversible EGFR‐TKIs with initial response rates of 55%–83% and have previously been reported to significantly improve progression‐free survival (PFS) of around 9–13 months compared to platinum‐based chemotherapy for treatment‐naïve EGFR‐mutant NSCLC. 1 , 2
Afatinib, a second‐generation EGFR‐TKI, is an irreversible, oral ErbB family blocker. It has the ability to inhibit EGFR/ErbB1, human epidermal growth factor receptor‐2 (HER2/ErbB2), and ErbB4 signaling. 3 In the phase III LUX‐lung 3 and LUX‐lung 6 trials, afatinib had better clinical efficacy than chemotherapy in untreated advanced EGFR‐mutated NSCLC patients and led to significantly prolonged median PFS of ~11 months. 4 , 5
Although EGFR‐TKIs prolong disease control and have high response rates, acquired resistance, that is, progressive disease on EGFR‐TKI treatment, inevitably develops after first‐line first‐ or second‐generation EGFR‐TKI treatment. 6 , 7 , 8 , 9 , 10 In addition, the factors associated with prolonged PFS due to afatinib treatment have not been examined in depth. In this study, our objective was to investigate the factors associated with prolonged PFS (>36 months) in advanced NSCLC patients harboring the EGFR mutation treated with first‐line afatinib.
METHODS
Study design and patients
This study was based on a retrospective analysis of the lung cancer databases of Linkou and Kaohsiung Chang Gung Memorial Hospital (CGMH) in Taiwan between June 2014 and April 2022. The inclusion criteria were (1) treatment‐naïve advanced (stage IIIB or IV) NSCLC patients harboring the EGFR mutation who (2) received afatinib as the first‐line treatment. Patients were excluded based on the following criteria: (1) they received systemic therapy (target therapy, chemotherapy, or immunotherapy) prior to afatinib or (2) the duration of afatinib treatment was less than 1 week.
All patients enrolled in this study underwent computed tomography (CT) scanning, fluorodeoxyglucose (FDG)‐positron emission tomography (PET), and brain magnetic resonance imaging (MRI) to determine the tumor stage at the initial diagnosis. All patients undergoing CT scans were assessed approximately every 3 months during the course of afatinib therapy to evaluate the treatment response. Brain MRI and PET scans were arranged as needed by the treating physician during the period of afatinib treatment to assist in determining disease status.
The local Institutional Review Board for Human Research approved this study (CGMH IRB no. 201901341A3) and waived the need for informed consent. The study subjects, inclusion criteria, and exclusion criteria are summarized in Figure 1.
FIGURE 1.
Flow chart of enrolment of advanced NSCLC patients harboring EGFR mutations treated with first‐line afatinib, with inclusion and exclusion criteria. EGFR, epidermal growth factor receptor; NSCLC, non‐small‐cell lung cancer.
Definitions
The treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), and classified as complete response, partial response, stable disease, and progressive disease based on measurements of the target and nontarget lesions. PFS was defined as the period between the date of afatinib initiation and the date of radiologically documented disease progression, the last dose of afatinib, or death. Overall survival (OS) was the period between the date of afatinib treatment and the date of death. If the patient was still under afatinib therapy or alive during the study period, PFS and OS were censored at the date of April 30, 2022. Uncommon mutations were defined as EGFR mutations other than the exon 19 deletion, or exon 21 Leu858Arg (L858R) mutations such as G719X, L861Q, and S768I, or compound mutations.
Data collection
Demographic data; Eastern Cooperative Oncology Group performance status (ECOG PS); smoking history; tumor histology; disease stage; EGFR mutation type, sites, and number of metastases; afatinib starting dose (40 mg or 30 mg) and dose de‐escalation (40–30 mg); use of bevacizumab; rebiopsy after disease progression (tissue rebiopsy or liquid biopsy); EGFR‐T790M mutation status; and subsequent therapy (target therapy, chemotherapy, immune checkpoint inhibitors, antivascular endothelial growth factor [anti‐VEGF], or combinations), concomitant use of proton pump inhibitors (PPIs), and supportive care were recorded. EGFR mutation tests, including for primary mutations and secondary mutations (T790M) associated with acquired resistance to first‐line target therapy, were performed using various methods, such as direct sequencing, amplification refractory mutation system–Scorpion (ARMS/S) assays, and next‐generation sequencing.
Statistical analysis
Continuous variables are presented as mean ± standard deviation or median (interquartile range) and categorical variables are reported as numbers (percentages). Student's t test or the Mann–Whitney U test was used to compare continuous variables between groups. Categorical variables were tested using the chi‐square test for equal proportions or Fisher's exact test. Risk factors (independent variables) associated with prolonged PFS (dependent variable) were analyzed using univariate analysis in the first step. This was followed by a multivariate logistic regression model with stepwise selection to identify significant predictors. Independent variables with a univariate p‐value <0.20 were entered into the multivariate logistic regression model. The results are presented as odds ratio (OR) and 95% confidence interval (CI). OS and PFS curves were generated as a function of time using the Kaplan–Meier approach and compared using the log‐rank test. All statistical analyses were performed with SPSS Statistics version 26.0, and a two‐sided p‐value <0.05 was considered statistically significant.
RESULTS
Patients
We included 546 EGFR‐mutated advanced NSCLC patients receiving first‐line afatinib in the analysis and examined the factors associated with prolonged PFS. The PFS of 462 patients (84.6%) was less than 36 months and that of 84 patients (15.4%) was more than 36 months. Median PFS and OS were 14.5 months and 27.2 months, respectively.
Comparisons between PFS >36 months group and PFS ≤36 months group
Age, sex, ECOG PS, smoking history, and histology did not differ significantly between the PFS >36 months group and PFS ≤36 months group (Table 1). The mean age of the patients was 63.8 ± 11.3 months. The PFS >36 months group included a significantly higher percentage of older patients, that is, age ≥65 years (p = 0.008). Adenocarcinoma accounted for 98.5% of the histology. The presence of the exon 19 deletion or exon 21 L858R mutation did not differ significantly between the two groups, but the PFS >36 months group had a significantly higher percentage of patients with uncommon mutations like G719X, L861Q, S768I, or compound mutations (p = 0.002).
TABLE 1.
Background characteristics and clinical variables of patients with PFS of >36 months and those with PFS of ≤36 months.
| Variables | All (n = 546) | PFS >36 months (n = 84) | PFS ≤36 months (n = 462) | p‐value |
|---|---|---|---|---|
| Age (years) | 63.8 ± 11.3 | 65.9 ± 10.6 | 63.4 ± 11.4 | 0.062 |
| Age ≥65 years | 253 (46.3%) | 50 (59.5%) | 203 (43.9%) | 0.008 |
| Age <65 years | 293 (53.7%) | 34 (40.5%) | 259 (56.1%) | 0.008 |
| Sex (male) | 221 (40.5%) | 30 (35.7%) | 191 (41.3%) | 0.334 |
| ECOG PS | ||||
| 0 | 151 (27.7%) | 29 (34.5%) | 122 (26.4%) | 0.126 |
| 1 | 329 (60.3%) | 53 (63.1%) | 276 (59.7%) | 0.563 |
| Current or former smoker | 114 (20.9%) | 14 (16.7%) | 100 (21.6%) | 0.302 |
| Histology | ||||
| Adenocarcinoma | 538 (98.5%) | 82 (97.6%) | 456 (98.7%) | 0.355 |
| Adenosquamous or squamous cell carcinoma | 8 (1.5%) | 2 (2.4%) | 6 (1.3%) | 0.355 |
| Disease stage | ||||
| Locally advanced (IIIB) | 42 (7.7%) | 12 (14.3%) | 30 (6.5%) | 0.014 |
| Metastatic (IV) | 504 (92.3%) | 72 (85.7%) | 432 (93.5%) | 0.014 |
| EGFR mutation type | ||||
| Exon 19 deletion | 250 (45.8%) | 34 (40.5%) | 216 (46.8%) | 0.288 |
| Exon 21 L858R mutation | 228 (41.8%) | 31 (36.9%) | 197 (42.6%) | 0.327 |
| Uncommon mutations | 68 (12.4%) | 19 (22.6%) | 49 (10.6%) | 0.002 |
| Site of metastasis | ||||
| Bone metastasis | 261 (47.8%) | 24 (28.6%) | 237 (51.3%) | <0.001 |
| Pleural metastasis | 250 (45.8%) | 32 (38.1%) | 218 (47.2%) | 0.124 |
| Brain metastasis | 159 (29.1%) | 18 (21.4%) | 141 (30.5%) | 0.092 |
| Liver metastasis | 62 (11.4%) | 3 (3.6%) | 59 (12.8%) | 0.014 |
| Adrenal metastasis | 49 (9.0%) | 1 (1.2%) | 48 (10.4%) | 0.003 |
| Numbers of metastatic sites | ||||
| 0 | 97 (17.8%) | 24 (28.6%) | 73 (15.8%) | 0.005 |
| 1 | 228 (41.7%) | 44 (52.4%) | 184 (39.8%) | 0.032 |
| 2 | 137 (25.1%) | 15 (17.8%) | 122 (26.4%) | 0.096 |
| ≥3 | 84 (15.4%) | 1 (1.2%) | 83 (18%) | <0.001 |
| Starting dose of afatinib | ||||
| 40 mg | 287 (52.6%) | 41 (48.8%) | 246 (53.2%) | 0.454 |
| 30 mg | 259 (47.4%) | 43 (51.2%) | 216 (46.8%) | 0.454 |
| Dose de‐escalation (40–30 mg) | 166 (30.4%) | 37 (44%) | 129 (27.9%) | 0.003 |
| Bevacizumab use | 32 (5.9%) | 4 (4.8%) | 28 (6.1%) | 0.803 |
| PPI use | 229 (41.9%) | 38 (45.2%) | 191 (41.3%) | 0.506 |
Note: Uncommon mutations were EGFR mutations other than exon 19 deletion or exon 21 Leu858Arg (L858R) mutation such as G719X, L861Q or S768I or compound mutations.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; PFS, progression‐free survival; PPI, proton pump inhibitor.
The PFS ≤36 months group had a significantly higher percentage of patients with metastatic disease status, that is, stage IV (93.5% vs. 85.7%), significantly higher incidences of bone (51.3% vs. 28.6%), liver (12.8% vs. 3.6%), and adrenal metastasis (10.4% vs. 1.2%), and a significantly higher rate of multiple distant metastases (≥3 sites) (18% vs. 1.2%) than the PFS > 36 months group (all p < 0.05). The starting dose of afatinib, that is, 30 mg or 40 mg, was not significantly different between the two groups, but the occurrence of dose de‐escalation (40–30 mg) was significantly greater in the PFS >36 months group (44% vs. 27.9%) than in the PFS ≤36 months group (p = 0.003). Anti‐VEGF agent (bevacizumab) use was not significantly different between the two groups. Coadministration of PPIs use (dexlansoprazole, esomeprazole, lansoprazole, pantoprazole, or rabeprazole) was found in 41.9% of all enrolled NSCLC patients, and the proportion of PPIs use was higher in the PFS > 36 months group than in the PFS ≤36 months group (45.2% vs. 41.3%); however, the difference between the two groups did not reach the level of significance (p = 0.506). The OS of patients in the PFS >36 months group was significantly longer than that of patients in the PFS ≤36 months group (median OS of 46.0 months vs. 22.9 months; log‐rank test, p < 0.001) (Figure 2).
FIGURE 2.
Kaplan–Meier curves of overall survival of patients with PFS >36 months and PFS ≤36 months who received first‐line afatinib. PFS, progression‐free survival.
Post‐progression treatments after first‐line afatinib
A total of 180 (33%) patients received secondary EGFR‐T790M mutation tests (75% underwent tissue rebiopsy and 25% circulating tumor DNA testing) after progression following first‐line afatinib; 74 (41.1%) of these patients showed EGFR‐T790M positivity (Table 2). A significantly higher proportions of patients in the PFS ≤36 months group underwent secondary EGFR‐T790M mutation testing and showed EGFR‐T790M positivity (both p < 0.001) compared to the PFS >36 months group.
TABLE 2.
EGFR‐T790M mutation status and post‐progression treatments after first‐line afatinib of patients with PFS of >36 months and those with PFS of ≤36 months.
| Treatments | All (n = 546) | PFS >36 months (n = 84) | PFS ≤36 months (n = 462) | p‐value |
|---|---|---|---|---|
| EGFR‐T790M mutation test | 180 (32.9%) | 8 (9.5%) | 172 (37.2%) | <0.001 |
| Tissue rebiopsy | 135 (24.7%) | 5 (6%) | 130 (28.1%) | <0.001 |
| ct‐DNA | 45 (8.2%) | 3 (3.6%) | 42 (9.1%) | 0.128 |
| EGFR‐T790M mutation‐positive | 74 (13.6%) | 2 (2.4%) | 72 (15.6%) | <0.001 |
| Post‐progression treatments | ||||
| Osimertinib | 100 (18.3%) | 15 (17.9%) | 85 (18.4%) | 0.906 |
| Erlotinib | 10 (1.8%) | 2 (2.4%) | 8 (1.7%) | 0.656 |
| Gefitinib | 24 (4.4%) | 1 (1.2%) | 23 (5%) | 0.152 |
| Almonertinib | 6 (1.1%) | 0 (0%) | 6 (1.3%) | |
| Chemotherapy | ||||
| Platinum‐based doublet | 117 (21.4%) | 3 (3.6%) | 114 (24.7%) | <0.001 |
| Single agent | 22 (4%) | 1 (1.2%) | 21 (4.5%) | 0.227 |
| Immune checkpoint inhibitors | ||||
| Combined with chemotherapy | 7 (1.3%) | 0 (0%) | 7 (1.5%) | |
| Single agent | 1 (0.2%) | 0 (0%) | 1 (0.2%) | |
| Bevacizumab | 16 (2.9%) | 0 (0%) | 16 (3.5%) | |
| Ramucirumab | 1 (0.2%) | 1 (1.2%) | 0 (0%) | |
| No systemic treatment or supportive care | 238 (43.6%) | 55 (65.5%) | 183 (39.6%) | <0.001 |
Abbreviations: EGFR, epidermal growth factor receptor; PFS, progression‐free survival; ct, circulating tumor.
Approximately one quarter of patients (n = 141, 25.8%) received target therapy after initial afatinib progression; 100 (18.3%) patients took the third‐generation EGFR TKI, osimertinib. The two groups did not differ significantly in the use of any of the target therapies (osimertinib, erlotinib, gefitinib, and almonertinib) after progression. Another quarter of patients (n = 139, 25.5%) received systemic chemotherapy (platinum‐based doublet or single agent) after progression, and the rate of platinum‐based doublet treatment was significantly higher in the PFS ≤36 months group than in the PFS >36 months group (24.7% vs. 3.6%) (p < 0.001). Eight patients (1.5%) in the PFS >36 group and 17 patients (3.1%) in the PFS ≤36 group were treated with immune checkpoint inhibitors and anti‐VEGF agents (bevacizumab or ramucirumab), respectively. Another 238 patients (43.6%) did not receive subsequent systemic treatment or chose supportive care, and the percentage was significantly higher in the PFS > 36 months group (p < 0.001).
Factors associated with prolonged progression‐free survival
After adjusting for significant confounding variables, a multivariate logistic regression model showed that liver metastasis was significantly negatively and independently associated with prolonged PFS (adjusted OR 0.246 [95% CI: 0.067–0.908]; p = 0.035) (Table 3). The PFS and OS of patients with liver metastasis were significantly shorter than those of patients without liver metastasis (median PFS 11.7 months vs. 15.0 months, log‐rank test, p < 0.001; median OS 19.7 months vs. 29.9 months, log‐rank test, p = 0.004) (Figure 3).
TABLE 3.
Multivariate logistic regression analysis of factors associated with PFS of >36 months of patients treated with first‐line afatinib for advanced epidermal growth factor receptor‐mutated non‐small cell lung cancer.
| Variables | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| OR (95% CI) | p‐value | Adjusted OR (95% CI) | p‐value | |
| Age | 1.021 (0.999–1.043) | 0.062 | ||
| Age ≥65 years | 1.876 (1.169–3.011) | 0.009 | ||
| Sex (male) | 0.788 (0.486–1.278) | 0.334 | ||
| ECOG PS 0 | 1.469 (0.896–2.411) | 0.128 | ||
| Current or former smoker | 0.724 (0.391–1.339) | 0.303 | ||
| Disease stage III | 2.400 (1.175–4.903) | 0.016 | ||
| Disease stage IV | 0.417 (0.204–0.851) | 0.016 | ||
| Exon 19 deletion | 0.774 (0.483–1.242) | 0.289 | ||
| Exon 21 L858R mutation | 0.787 (0.487–1.272) | 0.328 | ||
| Uncommon mutations | 2.464 (1.365–4.448) | 0.003 | ||
| Bone metastasis | 0.380 (0.229–0.631) | <0.001 | ||
| Pleural metastasis | 0.689 (0.428–1.109) | 0.125 | ||
| Brain metastasis | 0.621 (0.356–1.084) | 0.094 | ||
| Liver metastasis | 0.253 (0.077–0.827) | 0.023 | 0.246 (0.067–0.908) | 0.035 |
| Adrenal metastasis | 0.104 (0.014–0.763) | 0.026 | ||
| One site metastasis | 1.662 (1.042–2.651) | 0.033 | ||
| Two sites metastasis | 0.606 (0.334–1.099) | 0.099 | ||
| ≥2 sites metastasis | 0.295 (0.166–0.524) | <0.001 | ||
| ≥3 sites metastasis | 0.055 (0.008–0.401) | 0.004 | ||
| Bevacizumab use | 0.775 (0.265–2.269) | 0.642 | ||
Abbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; OR, odds ratio; PFS, progression‐free survival.
FIGURE 3.
Kaplan–Meier analysis of (a) PFS and (b) OS of patients with liver metastasis and patients without liver metastasis. OS, overall survival; PFS, progression‐free survival.
DISCUSSION
The primary insight of this study with a relatively large number of advanced NSCLC patients with EGFR‐activating mutations treated with first‐line afatinib was that distant organ metastasis was negatively associated with prolonged PFS and liver metastasis was independently associated with shorter PFS.
Afatinib was effective and safe in a subset of elderly patients (i.e., older than 65 years) with EGFR mutation‐positive NSCLC and may provide favorable outcomes. 11 , 12 , 13 , 14 Subgroup analyses of LUX‐lung trials indicated that advanced age did not influence the clinical benefit of afatinib, which was superior to chemotherapy (LUX‐lung 3 and LUX‐lung 6) or gefitinib (LUX‐lung 7) in terms of prolonged PFS. The adverse events associated with afatinib in older patients were similar to those in the overall population. 11 Another phase II study (NEJ027) also showed that afatinib was associated with high response rates and prolonged PFS and OS in elderly (age ≥75 years) EGFR‐mutated NSCLC patients (objective response rate of 75.7%, median PFS of 14.2 months, and median OS of 35.2 months). 12 In our study, the PFS >36 months group had a significantly higher proportion of older patients (age ≥65 years) than the PFS ≤36 months group (p = 0.008), which also indicates that afatinib was tolerable and efficacious and could prolong PFS in the elderly.
Uncommon mutations, that is, mutations other than exon 19 deletion and exon 21 L858R mutation, account for around 10% of EGFR mutations in patients with NSCLC. 15 , 16 , 17 , 18 A post hoc analysis of LUX‐lung 2, LUX‐lung 3, and LUX‐lung 6 trials demonstrated that afatinib was beneficial for patients with uncommon EGFR mutations (75 patients, 12%), especially Gly719Xaa (G719X) in exon 18, Leu861Gln (L861Q) in exon 21, and Ser768Ile (S768I) in exon 20. 15 Our recent report also showed that first‐line afatinib was effective against treatment‐naïve advanced NSCLC harboring uncommon mutations (G719X, L861Q, or S768I) with favorable outcomes (objective response rate of 63.3% and a disease control rate of 86.7%) and that the G719X mutation was independently associated with favorable PFS. 16 In the present study, the PFS >36 months group had a significantly higher percentage of patients with uncommon mutations (19 patients, 22.6%), although a multivariate analysis did not find that this difference was significant.
In a previous study, ~30%–40% of NSCLC patients had metastatic disease at the time of initial diagnosis, and distant metastasis at diagnosis was an unfavorable prognostic factor that could influence clinical outcomes. 10 The liver is a more uncommon site of metastasis than bone, pleura, and the brain and is associated with poor survival of patients with advanced NSCLC. 19 , 20 , 21 In a previous cohort study, a multivariate analysis showed that the liver was the only site of metastasis that was significantly associated with worse survival in EGFR‐mutated NSCLC patients mostly treated with erlotinib or gefitinib (hazard ratio 1.83, p < 0.04). 19 Our study showed that the incidences of bone, liver, and adrenal metastases were all significantly different between the PFS >36 months group and PFS ≤36 months group and that liver metastasis was independently and negatively associated with prolonged PFS (adjusted OR 0.246, p = 0.035). In addition, the median OS of patients with liver metastasis was significantly shorter than that of patients without liver metastasis (19.7 months vs. 29.9 months, p = 0.004). Therefore, molecular tests and personalized therapy should be discussed earlier with these groups of patients.
Vascular endothelial growth factor‐mediated angiogenesis shares downstream signal transduction pathways with EGFR and is responsible for oncogenesis and acquired EGFR‐TKI resistance. 22 Bevacizumab is a humanized monoclonal antibody directed against VEGF‐A. Previous prospective clinical trials showed that erlotinib combined with bevacizumab significantly prolonged PFS compared to erlotinib alone but had no significant effects on OS. 23 , 24 , 25 Our recent real‐world cohort studies showed that patients receiving only afatinib treatment had a median PFS (16.1 months vs. 15.0 months; p = 0.500) and median OS (32.1 months vs. 42.0 months; p = 0.700) similar to those of patients receiving afatinib plus bevacizumab. 26 Afatinib combined with bevacizumab was equally as effective as erlotinib combined with bevacizumab in terms of the objective response rate, disease control rate, median PFS, and median OS. 27 In the present study, median PFS and median OS did not differ significantly between patients receiving the afatinib and bevacizumab combination and those receiving afatinib only (13.8 vs. 14.5 months [p = 0.782] and 37.5 vs. 26.3 months [p = 0.052], respectively). The proportion of patients receiving the bevacizumab and afatinib combination was not significantly different between the PFS >36 months group and the PFS ≤36 months group.
Acquired resistance, defined as systemic disease progression based on RECIST criteria, will eventually occur after a median of 9.2–14.7 months of EGFR‐TKI treatment. The EGFR T790M mutation is the most common (around 50%–60%) mechanism of acquired resistance following first‐ and second‐generation EGFR‐TKI treatment. 6 , 7 , 8 , 9 , 10 Osimertinib is a third‐generation oral, irreversible EGFR‐TKI that selectively targets both EGFR‐activating mutations and exon 20 T790M resistance mutations. 28 , 29 , 30 The AURA3 trial showed positive results, and osimertinib is approved worldwide for patients with metastatic T790M‐positive NSCLC who show disease progression after first‐ or second‐generation EGFR‐TKI treatment. 31 Our study found that only one‐third of patients (n = 180, 32.9%) underwent an EGFR‐T790M mutation test in real‐world practice, either as tissue rebiopsy or a circulating tumor DNA test, and less than half (n = 74, 41.1%) of these patients were positive for the T790M mutation. A total of 100 patients (18.3%) received osimertinib as post‐progression treatment after first‐line afatinib. In addition, a significantly higher percentage of patients in the PFS ≤36 months group received palliative platinum‐based chemotherapy, whereas a significantly higher proportion of the patients in the PFS >36 months group chose supportive care without systemic therapy after progression following initial afatinib treatment.
The solubility of certain EGFR‐TKIs is pH‐dependent, and PPIs may decrease the absorption of EGFR‐TKIs through altering gastric pH contributing to insufficient drug concentrations in the bloodstream. Several studies have explored the impact of PPIs usage on the efficacy and safety of EGFR‐TKIs in NSCLC patients, and reported a reduction in the effectiveness of EGFR‐TKIs with shorter PFS and OS. 32 , 33 Our study found that 41.9% NSCLC patients had concomitant use of afatinib and PPIs. The proportion of patients receiving the coadministration of afatinib and PPIs was not significantly different between the PFS > 36 months group and the PFS ≤36 months group (45.2% vs. 41.3%; p = 0.506). Therefore, our cohort study showed that the concomitant use of PPIs did not influence the prolonged PFS (>36 months) significantly in NSCLC patients treated with first‐line afatinib.
This study was hindered by a number of limitations. First, demographic and clinical features, treatment protocols or real‐world clinical practices, and health insurance coverage of different ethnic groups can all influence treatment strategies and outcomes of cancer patients. Therefore, as this retrospective study was conducted only in Taiwan, that is, East Asia, its generalizability is limited. Second, we defined the length of prolonged PFS as 36 months; whether a different definition could influence the results may need further investigation. In addition, progressive disease status and progressive sites (target or nontarget lesions) were not assessed and compared between groups. Third, the rebiopsy rate (tissue rebiopsy or liquid biopsy) in this study was low (180 patients [32.9%]) which may be attributed to various factors, including the clinical conditions of patients and health insurance coverage. These factors can influence the subsequent post‐progression treatments and final outcomes. Finally, we retrospectively analyzed lung cancer databases from June 2014 to April 2022, and PFS and OS were defined and censored at the date of 30 April 2022. However, some patients included in this study were still receiving afatinib treatment or were alive during the study period; therefore, the results for PFS and OS should be interpreted cautiously.
In conclusion, we found that front‐line afatinib on its own is encouraged for advanced NSCLC patients with EGFR‐activating mutations who have favorable clinical factors associated with prolonged PFS. Patients with unfavorable clinical factors negatively associated with prolonged PFS, including distant organ metastasis, especially liver metastasis, warrant further molecular tests and other treatment strategies in addition to afatinib.
AUTHOR CONTRIBUTIONS
Li‐Chung Chiu, Ping‐Chih Hsu, and Cheng‐Ta Yang assumed responsibility for the accuracy of the data analysis and drafting of the manuscript. Li‐Chung Chiu, Ping‐Chih Hsu, Chin‐Chou Wang, and How‐Wen Ko designed the study and acquired the data. Li‐Chung Chiu, Ping‐Chih Hsu, and Scott Chih‐Hsi Kuo were responsible for statistical analysis of the data. Li‐Chung Chiu, Ping‐Chih Hsu, Jia‐Shiuan Ju, Pi‐Hung Tung, Allen Chung‐Cheng Huang, and Cheng‐Ta Yang interpreted the results. All authors contributed to the completion of the manuscript and have approved the final version.
FUNDING INFORMATION
This study was supported by grants from Chang Gung Memorial Hospital (CMRPG3L0821, CMRPG3L0822, and CORPG3M0331) and the Taiwan Ministry of Science and Technology (MOST 111‐2314‐B‐182A‐148).
CONFLICT OF INTEREST STATEMENT
On behalf of all the authors, the corresponding author states that there are no conflicts of interest.
ACKNOWLEDGMENTS
The authors would like to express their appreciation to the patients and staff at Chang Gung Memorial Hospital. We thank Mr Yu‐Jr Lin of the Research Services Center for Health Information, Chang Gung University for validating and confirming all the statistics in this study.
Chiu L‐C, Hsu P‐C, Wang C‐C, Ko H‐W, Kuo SC‐H, Ju J‐S, et al. Factors associated with prolonged progression‐free survival of patients treated with first‐line afatinib for advanced epidermal growth factor receptor‐mutated non‐small cell lung cancer. Thorac Cancer. 2024;15(7):529–537. 10.1111/1759-7714.15212
DATA AVAILABILITY STATEMENT
The datasets used or analyzed in the study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used or analyzed in the study are available from the corresponding author on reasonable request.