Abstract
The third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred therapy for patients with EGFR mutant non-small cell lung cancer (NSCLC); however, the therapy faces resistance challenges. We aimed to clarify the resistance patterns of EGFR-TKIs in patients with EGFR mutant NSCLC. In this retrospective study, we analyzed 104 patients with advanced EGFR mutant NSCLC who experienced treatment failure of third-generation EGFR-TKIs. Resistance models were classified as 1) original site failure (OF), distant site failure (DF), and combined failure (ODF) based on the failure site or 2) oligo-progression (OP) and non-oligoprogression based on the disease progression (PD) pattern. Among the patients, 58.7% (n = 61 of 104) developed OF, while 25 (24.0%) and 18 (17.3%) developed DF and ODF, respectively. A high OP rate (76.9%, n = 80) was observed, with primary progression accounting for 30.8%. OF was related to sex (odds ratio = 3.961, 95% confidence interval: 1.629-9.631, P = 0.002). Over 50% of patients with third-generation EGFR-TKI treatment failure developed OF. Sex, central nervous system metastases, and disease stage influenced the resistance patterns of the EGFR-TKI therapy.
Keywords: Non-small cell lung cancer, EGFR-TKI, resistance patterns
Introduction
The leading cause of tumor death in China remains lung carcinomas, including small-cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of lung carcinomas and has a 5-year survival rate of only 18%; approximately 75% of patients with NSCLC are diagnosed at advanced stages [1-3].
In Asian patients with advanced adenocarcinoma, the percentage of epidermal growth factor receptor (EGFR) mutations is 51.4% and reaches 60.7% in patients without a smoking history [4]. The major EGFR mutation types are exon 19 deletion mutation (19del) and exon 21 L858R point mutation (L858R), which account for nearly 85% of cases [5,6]. For patients with EGFR-sensitive mutant NSCLC, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment. The third-generation EGFR-TKIs have shown superior progression-free survival (PFS) and overall survival (OS) over first-generation EGFR-TKIs and chemotherapy in EGFR mutant NSCLC. According to the FLAURA experiment, the median PFS was 18.9 months with third-generation EGFR-TKI osimertinib vs. 10.2 months with first-generation EGFR-TKI gefitinib or erlotinib, and the median OS was 38.6 months (95% confidence interval (CI): 34.5-41.8) with osimertinib vs. 31.8 months (95% CI: 26.6-36.0) with gefitinib or erlotinib in advanced EGFR mutant NSCLC [7,8]. In the AURA trial, the median PFS was distinctly advantageous with osimertinib compared with chemotherapy (10.1 vs. 4.4 months; P < 0.001) as a subsequent therapy for patients with T790M mutant NSCLC [9].
However, almost all patients receiving the third-generation EGFR-TKIs developed acquired resistance. The median time to resistance onset was 18.9 months for first-line therapy and 10.1 months for subsequent therapy [7,9]. Most patients with resistance to EGFR-TKIs developed disease progression (PD) in original sites and experienced oligo-progression (OP). A study showed that original site failure (OF) accounted for 47% of failed treatments, and the most common sites of progression were the lungs in patients with first- or second-generation EGFR-TKI resistance [10]. Another study showed that young patients and those without baseline brain metastases are more likely to experience progression in the original sites after erlotinib failure [11]. Additionally, half of the patients experienced resistance in the original sites, and 70% developed OP after osimertinib failure [12].
Identifying the resistance patterns of third-generation EGFR-TKIs is crucial. Thus, this study aims to explore resistance patterns, the potential predictive factors of resistance patterns, and survival.
Materials and methods
This retrospective study was approved by the ethics committee of The First Affiliated Hospital of Shandong First Medical University and Dongying People’s Hospital. The study was conducted according to the tenets of the Declaration of Helsinki.
Patients
We retrospectively analyzed 197 patients with radiographically confirmed stage IIIB/IIIC to IV NSCLC who experienced third-generation EGFR-TKI failure between October 2016 and August 2023, including 115 patients with The First Affiliated Hospital of Shandong First Medical University and 82 patients with Dongying People’s Hospital. NSCLC was cytologically or pathologically confirmed, and PD was evaluated according to the response evaluation criteria in solid tumors (version 1.1, RECIST 1.1). All patients had 19del, L858R, or EGFR exon 20 T790M point mutation (T790M mutation) with at least one measurable lesion for radiologic evaluation and complete imaging data. Baseline characteristics were sex, age, smoking history, pathological type, EGFR mutation type, treatment lines, Eastern Cooperative Oncology Group Performance Status score, initial central nervous system (CNS) metastasis, clinical stages, the number of organs with metastasis, and the number of oligo-progression.
Treatment and follow-up
Oral osimertinib (80 mg) or almonertinib (110 mg) was administered once daily until PD or intolerable toxicity. All patients underwent contrast-enhanced computed tomography (CECT) of the chest, abdomen, bones, and pelvis at baseline. When EGFR-TKIs were administered, CECT was conducted every 6 weeks for 18 months and subsequently every 12 weeks until PD.
Definition
According to Al-Halabi, the resistance patterns were divided into OF, distant site failure (DF), and combined failure (ODF) [10]. PD at original sites (primary/metastatic) was categorized as OF, and progression at new sites was defined as DF. Concurrent OF and DF were considered ODF. Resistance patterns were divided into oligo-progression (OP) and non-oligoprogression (NOP), with OP defined as ≤ 5 metastasis sites and ≤ 3 organs [13].
Responses to third-generation EGFR-TKIs were classified as complete response (CR), partial response (PR), stable disease (SD), or PD. Objective response rate (ORR) was classified as the percentage of patients who obtained CR and PR, and disease control rate (DCR) was the percentage of patients who obtained CR, PR, and SD.
PFS was recorded as the time between the initiation of third-generation EGFR-TKI therapy and clinical progression or death (whichever occurred first). OS indicated the time between the initiation of third-generation EGFR-TKI therapy and death from any cause.
Statistical analysis
PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test in GraphPad Prism 8. The logistic regression model was used to estimate the relationship between resistance patterns and clinical characteristics, including the EGFR mutation type (L858R vs. 19del), age (≥ 65 vs. < 65 years), sex (female vs. male), smoking history (yes vs. no), best response evaluation (PR vs. SD and PD vs. SD), initial oligometastatic status (yes vs. no), initial CNS metastasis (yes vs. no), treatment line (subsequent line vs. first line), and disease stage (IV vs. IIIB/IIIC). For each resistance pattern (OF, DF, or ODF), the rest of the models were treated as competing events. The multivariate logistic regression model was used for further analysis to identify predictive factors of resistance patterns and evaluate the odds ratios (ORs) and 95% CI. The multivariate analysis included all clinical characteristics with P < 0.2 in the univariate analysis. All statistical analyses were conducted using SPSS Statistics version 26.0 (IL, Armonk, NY, USA). All p-values were two-sided, with P < 0.05 being considered statistically significant.
Results
Baseline characteristics
In total, 197 patients treated with third-generation EGFR-TKIs were screened, and 104 who experienced PD and were followed up constituted the study population (Figure 1). The mean age was 60 (range: 34-85) years. There were 68 women (65.4%) and 56 non-smokers (82.7%). Similarly, 46 participants had 19del mutations, and 58 had L858R mutations. In addition, 38 patients (36.5%) received first-line therapy, and 66 (63.5%) received subsequent treatment. The lymph nodes (74.0%) experienced PD the most, followed by the lungs (54.8%), bones (52.9%), and other sites. Most patients (n = 53, 51.0%) had ≤ 3 organ metastases, and 41 (39.4%) had oligo-metastases. Twenty-three patients had previously undergone radical surgery. Detailed baseline characteristics of the patients before the initiation of EGFR-TKI treatment are provided in Table 1.
Figure 1.
Flowchart of patient enrollment.
Table 1.
Baseline characteristics of 104 patients
| Variable | Number | Percent |
|---|---|---|
| Gender | ||
| Male | 36 | 34.6 |
| Female | 68 | 65.4 |
| Age (year) | ||
| ≥ 65 | 41 | 39.4 |
| < 65 | 63 | 60.6 |
| Smoking history | ||
| Former | 18 | 17.3 |
| Never | 86 | 82.7 |
| Disease stage | ||
| IIIB | 12 | 11.5 |
| IV | 92 | 88.5 |
| EGFR mutation | ||
| 19del | 46 | 44.2 |
| 21exon | 58 | 55.8 |
| Treatment Lines | ||
| First line | 38 | 36.5 |
| Second line | 66 | 63.5 |
| Oligo-metastasis before initiation TKI | ||
| Yes | 41 | 39.4 |
| No | 63 | 60.6 |
| Number of organs with metastases per patient | ||
| ≤ 3 | 53 | 51.0 |
| > 3 | 51 | 49.0 |
| Central nervous system metastasis | ||
| Yes | 44 | 42.3 |
| No | 60 | 57.7 |
| Surgery | ||
| Yes | 23 | 22.1 |
| No | 81 | 77.9 |
| Distribution of metastases before TKI initiation | ||
| Lymph nodes | 77 | 74.0 |
| Lung | 57 | 54.8 |
| Bone | 55 | 52.9 |
| Brain | 43 | 41.3 |
| Pleura | 14 | 13.5 |
| Liver | 9 | 8.7 |
| Others | 40 | 38.5 |
EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
Resistance patterns
Primary progression accounted for 30.8% of PD (n = 32 of 104). The lungs (45.2%) were the most common organs with PD, followed by the brain (22.1%), lymph nodes (20.2%), and bone (18.3%). For different treatment lines, OF remained the most common PD pattern. However, for patients with subsequent-line treatment, 65.2% (n = 43 of 66) developed OF, while 47.4% (n = 18 of 38) of patients with first-line treatment had OF. The progression sites are listed in Table 2. After PD, 13 patients were treated with radiotherapy, 49 received chemotherapy, and 32 continued the original EGFR-TKI therapy.
Table 2.
Characteristics of 104 patients after disease progression
| Variable | OF | DF | ODF | Overall | ||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|||||
| n | % | n | % | n | % | n | % | |
| Oligo-progression | 54 | 67.5 | 20 | 25 | 6 | 7.5 | 80 | 76.9 |
| Primary progression | 24 | 23.1 | 3 | 2.9 | 5 | 5.8 | 32 | 30.8 |
| First line | 18 | 47.4 | 13 | 34.2 | 7 | 18.4 | 38 | 36.5 |
| Subsequent line | 43 | 65.2 | 12 | 18.2 | 11 | 16.6 | 66 | 63.5 |
| Organs harboring progression | ||||||||
| Lung | 25 | 41.0 | 11 | 44.0 | 11 | 61.1 | 47 | 45.2 |
| Brain | 14 | 23.0 | 6 | 24.0 | 3 | 16.7 | 23 | 22.1 |
| Others | 13 | 21.3 | 4 | 16.0 | 7 | 38.9 | 24 | 23.1 |
| Bone | 8 | 13.1 | 6 | 24.0 | 5 | 27.8 | 19 | 18.3 |
| Lymph nodes | 8 | 13.1 | 4 | 16.0 | 9 | 50.0 | 21 | 20.2 |
| Adrenal glands | 3 | 4.9 | 3 | 12.0 | 1 | 5.6 | 7 | 6.7 |
| Liver | 2 | 3.3 | 2 | 8.0 | 3 | 16.7 | 7 | 6.7 |
| Number of organs with progression | ||||||||
| 1 | 51 | 49 | 18 | 17.3 | 5 | 4.8 | 74 | 71.2 |
| 2 | 7 | 6.7 | 5 | 4.8 | 6 | 5.8 | 18 | 17.3 |
| 3 | 2 | 1.9 | 1 | 1.0 | 6 | 5.8 | 9 | 8.7 |
| 4 | 0 | 0 | 1 | 1.0 | 2 | 1.9 | 3 | 2.9 |
OF, original site failure; DF, distant site failure; ODF, combined failure.
Furthermore, 58.7% of patients experienced OF (n = 61 of 104), while 25 (24.0%) and 18 (17.3%) developed DF and ODF, respectively. The most common organs with OF were the lungs (n = 25 of 61, 41.0%), brain (n = 14 of 61, 23.0%), and bone (n = 8 of 61, 13.1%). Similarly, the lungs (n = 11 of 25, 44.0%), brain (n = 6 of 25, 24.0%), and bone (n = 6 of 25, 24.0%) were the most common sites of DF. While the lungs (n = 11 of 18, 61.1%), lymph nodes (n = 9 of 18, 50.0%), and bone (n = 5 of 18, 27.8%) were the most common organs with ODF.
Most patients had OP (n = 80 of 104, 76.9%), while 24 (23.1%) developed NOP. Among patients with OP, 31.3% developed primary progression, and most experienced OF (n = 54 of 80, 67.5%). In a subgroup of patients with OP, the most common organ was the lungs (n = 30 of 80, 37.5%), followed by the brain (n = 17, 21.3%), bones (n = 12, 15.0%), and lymph nodes (n = 8, 10.0%).
Predictors of OF
In the univariate analysis, sex, initial CNS metastases, and treatment line were selected for further analysis. The multivariate analysis revealed sex (OR = 3.961, 95% CI: 1.629-9.631, P = 0.002) and initial CNS metastases (P = 0.044) as independent predictors of OF (Table 3). Female patients and those with initial CNS metastases tended to develop OF.
Table 3.
Logistic regression model for predictors of original site failure
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| ORs | 95% CI | P value | ORs | 95% CI | P value | |
| EGFR mutation type (L858R vs. 19del) | 1.375 | (0.626, 3.017) | 0.428 | |||
| Age (≥ 65 vs. < 65) | 1.387 | (0.619, 3.107) | 0.427 | |||
| Sex (female vs. male) | 4.246 | (1.802, 10.005) | 0.001 | 3.961 | (1.629, 9.631) | 0.002 |
| Smoking history (yes vs. no) | 0.654 | (0.236, 1.813) | 0.414 | |||
| Best response evaluation (PR vs. SD) | 0.967 | (0.399, 2.340) | 0.940 | |||
| Best response evaluation (PD vs. SD) | 1.050 | (0.341, 3.236) | 0.932 | |||
| Initial Oligometastatic status (yes vs. no) | 1.172 | (0.526, 2.613) | 0.698 | |||
| Initial CNS metastasis (yes vs. no) | 2.851 | (1.237, 6.567) | 0.014 | 2.480 | (1.024, 6.008) | 0.044 |
| Treatment line (subsequent line vs. first line) | 2.077 | (0.921, 4.686) | 0.078 | 1.855 | (0.766, 4.490) | 0.171 |
| Disease stage (IV vs. III) | 1.015 | (0.300, 3.439) | 0.981 | |||
CNS, central nervous system; 95% CI, confidence interval; EGFR, epidermal growth factor receptor; ORs, odds ratios; PR, partial response; PD, progressive disease; SD, stable disease.
Predictors of DF
In the univariate analysis, age, sex, smoking history, initial CNS metastases, and treatment line were selected for further analysis. The multivariate analysis indicated initial CNS metastases (OR = 0.191, 95% CI: 0.058-0.635, P = 0.007) as an independent predictor of DF (Table 4). Therefore, patients with initial CNS metastases were more likely to develop DF.
Table 4.
Logistic regression model for predictors of distant site failure
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| ORs | 95% CI | P value | ORs | 95% CI | P value | |
| EGFR mutation type (L858R vs. 19del) | 0.662 | (0.268, 1.634) | 0.371 | |||
| Age (≥ 65 vs. < 65) | 0.515 | (0.193, 1.372) | 0.184 | 0.427 | (0.147, 1.238) | 0.117 |
| Sex (female vs. male) | 0.379 | (0.151, 0.954) | 0.039 | 0.548 | (0.157, 1.917) | 0.347 |
| Smoking history (yes vs. no) | 2.404 | (0.816, 7.084) | 0.112 | 1.422 | (0.315, 6.416) | 0.647 |
| Best response evaluation (PR vs. SD) | 1.355 | (0.477, 3.850) | 0.568 | |||
| Best response evaluation (PD vs. SD) | 1.286 | (0.347, 4.764) | 0.707 | |||
| Initial Oligometastatic status (yes vs. no) | 1.592 | (0.642, 3.947) | 0.316 | |||
| Initial CNS metastasis (yes vs. no) | 0.186 | (0.058, 0.590) | 0.004 | 0.191 | (0.058, 0.635) | 0.007 |
| Treatment line (subsequent line vs. first line) | 0.427 | (0.171, 1.069) | 0.069 | 0.480 | (0.176, 1.311) | 0.152 |
| Disease stage (IV vs. III) | 1.667 | (0.340, 8.172) | 0.529 | |||
CNS, central nervous system; 95% CI, confidence interval; EGFR, epidermal growth factor receptor; ORs, odds ratios; PR, partial response; PD, progressive disease; SD, stable disease.
Predictors of ODF
In the univariate analysis, sex and initial oligometastatic status were selected for further analysis. In the multivariate analysis, no factors were identified as predictors of ODF (Table 5). Similarly, no predictors were found for ODF.
Table 5.
Logistic regression model for predictors of combined failure
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| ORs | 95% CI | P value | ORs | 95% CI | P value | |
| EGFR mutation type (L858R vs. 19del) | 0.990 | (0.356, 2.751) | 0.984 | |||
| Age (≥ 65 vs. < 65) | 1.285 | (0.460, 3.586) | 0.632 | |||
| Sex (female vs. male) | 0.347 | (0.123, 0.978) | 0.045 | 0.389 | (0.135, 1.117) | 0.079 |
| Smoking history (yes vs. no) | 0.547 | (0.114, 2.621) | 0.450 | |||
| Best response evaluation (PR vs. SD) | 0.735 | (0.239, 2.260) | 0.591 | |||
| Best response evaluation (PD vs. SD) | 0.681 | (0.155, 2.997) | 0.611 | |||
| Initial Oligometastatic status (yes vs. no) | 0.378 | (0.115, 1.244) | 0.110 | 0.439 | (0.130, 1.477) | 0.183 |
| Initial CNS metastasis (yes vs. no) | 1.111 | (0.399, 3.093) | 0.840 | |||
| Treatment line (subsequent line vs. first line) | 0.886 | (0.312, 2.518) | 0.820 | |||
| Disease stage (IV vs. III) | 0.584 | (0.141, 2.415) | 0.458 | |||
CNS, central nervous system; 95% CI, confidence interval; EGFR, epidermal growth factor rece,ptor; ORs, odds ratio; PR, partial response; PD, progressive disease; SD, stable disease.
Predictors of OP
In the univariate analysis, sex, initial oligometastatic status, and disease stage were used for further analysis. The multivariate analysis revealed disease stage (OR = 3.912, 95% CI: 1.062-14.408, P = 0.040) as an independent predictor of OP (Table 6). Patients with Stage IV disease tended to show OP.
Table 6.
Logistic regression model for predictors of oligo-progression
| Variable | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| ORs | 95% CI | P value | ORs | 95% CI | P value | |
| EGFR mutation type (L858R vs. 19del) | 1.683 | (0.672, 4.216) | 0.266 | |||
| Age (≥ 65 vs. < 65) | 1.795 | (0.670, 4.809) | 0.245 | |||
| Sex (female vs. male) | 2.333 | (0.919, 5.927) | 0.075 | 2.277 | (0.852, 6.086) | 0.101 |
| Smoking history (yes vs. no) | 0.737 | (0.233, 2.329) | 0.604 | |||
| Best response evaluation (PR vs. SD) | 1.091 | (0.387, 3.078) | 0.869 | |||
| Best response evaluation (PD vs. SD) | 0.923 | (0.255, 3.338) | 0.903 | |||
| Initial Oligometastatic status (yes vs. no) | 2.333 | (0.838, 6.497) | 0.105 | 1.740 | (0.595, 5.086) | 0.311 |
| Initial CNS metastasis (yes vs. no) | 0.830 | (0.331, 2.078) | 0.690 | |||
| Treatment line (subsequent line vs. first line) | 1.055 | (0.411, 2.711) | 0.911 | |||
| Disease stage (IV vs. IIIB/IIIC) | 4.111 | (1.186, 14.253) | 0.026 | 3.912 | (1.062, 14.408) | 0.040 |
CNS, central nervous system; 95% CI, confidence interval; EGFR, epidermal growth factor receptor; ORs, odds ratio; PR, partial response; PD, progressive disease; SD, stable disease.
Response
CR, PR, SD, and PD were discovered in 0, 50, 34, and 20 patients, respectively. The ORR was 48.1% (n = 50 of 104), and the DCR was 80.8% (n = 84 of 104). Fifty patients achieved PR, including OF in 58.0% (n = 29), DF in 26.0% (n = 13), and ODF in 16.0% (n = 8). Thirty-nine patients (78.0%) who achieved PR experienced OP, while 11 had NOP. Thirty-four patients achieved SD, including OF in 58.8% (n = 20), DF in 20.6% (n = 7), and ODF in 20.6% (n = 7). Of the patients who achieved SD, 26 (76.5%) showed OP, and 8 (23.5%) showed NOP. Twenty patients achieved PD, including OF in 60.0% (n = 12), DF in 25.0% (n = 5), and ODF in 15.0% (n = 3). Of these, 15 (75.0%) showed OP, and 5 (25.0%) had NOP. The ORR of OF, DF, and ODF were 47.5% (n = 29 of 61), 52.0% (n = 13 of 25), and 44.4% (n = 8 of 18), respectively. The DCR of OF, DF, and ODF were 80.3% (n = 49 of 61), 80% (n = 20 of 25), and 83.3% (n = 15 of 18), respectively. The ORR of OP vs. NOP was 49% vs. 46% (P = 0.802), and the DCR was 81% vs. 79% (P = 0.776). The resistance patterns of OF, DF, and ODF were not significantly different among patients with and without PR (P = 0.880), similar to the resistance patterns of OP and NOP (P = 0.802).
Survival analysis
As of the last follow-up on July 31, 2024, with a median follow-up time of 39.3 (range: 11.7-95.9) months. All patients developed PD. The median PFS was 11.8 (range: 0.5-55.1) months, and the median OS was 47.6 (range: 0.97-77.20) months (Figure 2). We compared the PFS and OS of EGFR-TKIs as first- and second-line treatments and found no statistically significant difference in the median PFS (13.0 vs. 11.6 months, P = 0.746); however, there was a significant difference in the median OS (NA vs. 41.2 months, P = 0.030) (Figure 3). There was no statistically significant difference in the median PFS among the three groups (11.9 vs. 11.6 vs. 14.1 months, P = 0.755). However, a significant difference was observed in the median OS (33.6 vs. NA vs. 53.6 months, P = 0.007) (Figure 4). In addition, we compared the median PFS and OS between patients with OP and those with NOP. No significant difference was observed in the median PFS (11.6 vs. 14.0 months, P = 0.059) or OS (43.5 months vs. NA, P = 0.173) (Figure 5).
Figure 2.
Survival curves of all patients. A. Progression-free survival. B. Overall survival.
Figure 3.
Survival curves of first-line and subsequent line patients. A. Progression-free survival. B. Overall survival.
Figure 4.
Survival curves of OF, DF and ODF patients. A. Progression-free survival. B. Overall survival.
Figure 5.
Survival curves of oligo-progression and non-oligoprogression patients. A. Progression-free survival. B. Overall survival.
Discussion
Our study revealed that approximately 58.7% (n = 61) of patients with third-generation EGFR-TKI resistance experienced failure in the original sites, and 76.9% (n = 80) developed OP. Primary site failure accounted for 30.8%, and the lungs were the most affected organs concerning PD. These patients may obtain survival benefits from local treatment. The female was more likely to develop failure in the original sites. Additionally, the third-generation EGFR-TKIs as first-line treatment had significantly longer OS than as subsequent-line treatment, and patients with ODF had a better survival benefit.
Over 50% of patients experienced OF (n = 61, 58.7%), followed by DF (24.0%) and ODF (17.3%). Our results are similar to those of previous studies on first- and second-generation EGFR-TKIs [10,11]. Tang et al. showed that OF, DF, and ODF accounted for 41.25%, 42.5%, and 16.25%, respectively, in patients with advanced NSCLC who experienced icotinib failure [14]. Patel et al. showed that OF accounted for 60.2% of resistance in patients with EGFR mutant NSCLC who experienced erlotinib failure, and lungs (60%) were the most common metastatic organs [11]. In our study, 76.9% of patients developed OP. Similarly, we observed that OF accounted for 30.8% of failure, and the distribution of PD lesions was as follows: lungs (45.2%), brain (22.1), lymph nodes (20.2%), and bone (18.3%). A Swiss cohort study reported that 77% of patients developed OP, and 23% developed NOP; the metastatic sites included the lungs (62%), brain (30%), lymph nodes (30%), and bone (27%) [15]. Guo et al. reported that 50% (n = 25 of 50) of patients developed OF, 22% (n = 11 of 50) developed DF, and 28% (n = 14 of 50) experienced ODF among those with osimertinib treatment failure [12]. Additionally, 70% of patients experienced OP [12].
The female was more likely to develop OF. Tang et al. observed that individuals with 19del were more likely to develop OF after icotinib failure [14]. Takeyasu et al. indicated that patients with 19del mutation are likely to develop primary progression, while those with L858R mutation tend to develop CNS metastasis after osimertinib failure [16]. Patel et al. found that patients without baseline brain metastasis and the younger population are more likely to develop OF after erlotinib failure [11]. Additionally, Al-Halabi et al. revealed that the size of the primary tumor was closely related to OF in the resistance pattern of afatinib, erlotinib, or gefitinib [10]. The factors influencing the resistance patterns include EGFR-TKI therapy, the physical condition of the patients, sample size, and the EGFR mutation type. These predictors require further investigation involving larger sample sizes.
Furthermore, we compared survival between different subgroups after third-generation EGFR-TKI failure. The median PFS did not differ markedly between first- and subsequent-line treatments (13.0 vs. 11.6 months, P = 0.746). However, the median OS was improved with first-line therapy compared with that of subsequent-line therapy. Additionally, we observed no statistical difference in the median PFS between the three patterns; however, ODF had the highest OS. The death percentages associated with OF, DF, and ODF were 54%, 20%, and 28%, respectively. The lower mortality rate in patients with ODF may have contributed to this difference. Tang et al. found no statistical differences in the median PFS or OS among OF, DF and ODF [14]. Wei et al. indicated that patients with OF had the shortest median PFS (6 vs. 11 vs. 10 months, P = 0.0084) [17]. Our study revealed no statistically significant differences in the median PFS or OS between patients with OP and NOP.
Studies have shown that original site progression is the primary resistance pattern after EGFR-TKI failure. Additionally, some research reported that new distant metastases may be caused by residual tumor lesions of original resistant clones [10,11]. The local ablative therapy at the original tumor sites before PD may result in good survival, decreased tumor cell clones of original sites, and decreased distant metastasis. Under extensive CNS involvement, patients should receive whole-brain radiotherapy combined with systemic therapy with high blood-brain barrier penetration as an adjunct [18]. A phase II study showed that for patients with advanced NSCLC, combined first-generation EGFR-TKIs and stereotactic body radiotherapy (SBRT) improve survival ratio and delay acquired resistance development compared with the effects of first-generation EGFR-TKIs alone [19]. Similarly, the study suggested that radiotherapy to original sites alone may be preferable to metastatic lesions [19]. An observational cohort study indicated that patients treated with the first-generation EGFR-TKI + SBRT targeting original sites had a longer PFS than did those treated with the first-generation EGFR-TKI alone (15.50 vs. 9.33 months, P < 0.0020), and the treatment primarily caused a new site failure, particularly 19del, rather than an original site failure [20]. Keane et al. suggested that targeting SBRT to residual lesions reduces the occurrence of disease metastasis in patients treated with the first-generation EGFR-TKIs as the first-line therapy [21].
Patients with OP who undergo local therapy, such as microwave ablation and SBRT, achieve favorable results [22-24]. Some studies reported that patients with OP who received local therapy had at least 6 months of extra disease stabilization [23,25,26]. In individuals experiencing OP with NSCLC treated with the third-generation EGFR-TKIs as the first-line therapy, EGFR-TKI + SBRT caused a significantly longer PFS than did EGFR-TKI alone (Hazard Ratio: 0.46, 80% CI: 0.20-0.61; P = 0.002) [27]. A study indicated that patients with oligo-progressive advanced NSCLC treated with third-generation EGFR-TKIs combined with SBRT experienced delayed disease development and prolonged PFS [28]. A Swiss cohort study showed that patients with OP who received local ablative treatment had more favorable outcomes than did those without local treatment [29]. Furthermore, the combination of EGFR-TKI and SBRT notably hinders PD in patients with oligo-metastatic NSCLC experiencing EGFR-TKI resistance, significantly extending their PFS [30].
As a retrospective analysis, our study has certain limitations, including a relatively small sample size, potential selection bias in obtaining data from patients with PD, and inconformity in the timing of TKI initiation. Compared with those of previous studies, our cohort had no CR and few PR cases, possibly because some patients received chemotherapy or local treatment before TKI therapy, which may have reduced their response to TKI [28,31-33].
Conclusion
In patients with advanced NSCLC who received third-generation EGFR-TKIs, the major resistance was OF. Factors such as sex, CNS metastases, and the disease stage were associated with the resistance patterns. However, the predictors of resistance patterns require substantial investigation using larger sample sizes.
Acknowledgements
All authors reviewed the manuscript and approved it for publication.
Written informed consent was obtained from all patients in this study.
Disclosure of conflict of interest
None.
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