Differential prognostic value of tumor and plasma T790M mutations in EGFR TKI-treated advanced NSCLC.

Background: Substitution of methionine for threonine at codon 790 (T790M) of epidermal growth factor receptor (EGFR) represents the major mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer. We determined the prognostic impact and association of secondary T790M mutations with the outcomes of osimertinib and chemotherapy. Methods: Patients (n = 460) progressing from first-line EGFR-TKI treatment were assessed. Tissue and/or liquid biopsies were used to determine T790M status; post-progression overall survival (OS) was analyzed. Results: Overall, 143 (31.1%) patients were T790M positive, 95 (20.7%) were T790M negative, and 222 (48.2%) had unknown T790M status. T790M status [T790M positive versus T790M negative: hazard ratio (HR) 0.48 (95% confidence interval (CI), 0.32-0.70); p < 0.001, T790M unknown versus T790M negative: HR 1.97 (95% CI, 1.47-2.64); p < 0.001] was significantly associated with post-progression OS. T790M positivity rates were similar for tissue (90/168, 53.6%) and liquid (53/90, 58.9%) biopsies (Fisher's exact test, p = 0.433). Tumor T790M-positive patients had significantly longer post-progression OS than tumor T790M-negative patients (34.1 versus 17.1 months; log-rank test, p = 8 × 10-5). Post-progression OS was similar between plasma T790M-positive and -negative patients (17.4 versus not reached; log-rank test, p = 0.600). In tumor T790M-positive patients, post-progression OS was similar after osimertinib and chemotherapy [34.1 versus 29.1 months; log-rank test, p = 0.900; HR 1.06 (95% CI, 0.44-2.57); p = 0.897]. Conclusion: T790M positivity predicts better post-progression OS than T790M negativity; tumor T790M positivity has a stronger prognostic impact than plasma T790M positivity. Osimertinib and chemotherapy provide similar OS benefits in patients with T790M-positive tumors.

Different prognostic meaning of tumor resistant gene detected from tumor or blood in patients with EGFR-mutant lung cancer The study demonstrates that patients with EGFR-mutant lung cancer who develop resistance due to a secondary T790M mutation, defined by tumor or blood T790M positivity, achieve better survival than patients without secondary T790M mutation; this association was mainly contributed by tumour T790M positivity. Oismertinib and chemotherapy led to similar survival in tumour T790M-positive patients. However, compared to osimertinib, chemotherapy was associated with longer survival in blood T790M-positive patients.

Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.

BACKGROUND: In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: Treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared. RESULTS: This study enrolled 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: p = 0.003; OS: p = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib. CONCLUSIONS: This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with EGFR-mutated advanced NSCLC.

Brain metastasis, EGFR mutation subtype and generation of EGFR-TKI jointly influence the treatment outcome of patient with EGFR-mutant NSCLC.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients' outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99-1.48]; p = 0.053), ECOG PS 0-1 (HR 0.71 [95% CI 0.54-0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66-0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0-1 (HR 0.41 [95% CI 0.31-0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13-1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02-4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12-0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28-1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.

Generation and validation of a predictive model for estimating survival among patients with EGFR-mutant non-small cell lung cancer.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC), treatment outcomes vary significantly. Previous studies have indicated that concurrent mutations may compromise the effectiveness of first-line EGFR-TKIs. However, given the high cost of next-generation sequencing, this information is often inaccessible in routine clinical practice. A prediction model based on pre-treatment clinical characteristics may thus offer a more practical solution. This study established a nomogram based on pretreatment clinical characteristics to stratify patients according to optimal treatment strategies. We retrospectively reviewed 761 patients with EGFR-mutant NSCLC who received first- or second-generation EGFR-TKIs at a tertiary referral center between 2010 and 2019. The pretreatment clinical characteristics and progression-free survival data were collected. Using COX proportional hazard regression analysis, we constructed a nomogram based on seven clinically significant prognostic factors: sex, Eastern Cooperative Oncology Group performance status, histology subtype, mutation subtype, stage, and metastasis to the liver and brain. Our nomogram could stratify patients into three groups with different risks for disease progression and was validated in a patient cohort from other hospitals. This risk stratification can provide additional information for determining the optimal first-line treatment strategy for patients with EGFR-mutant NSCLC.

T790M detection rate after first-line combination therapy with bevacizumab and EGFR-TKIs in advanced NSCLC (TERRA Study).

Real-world data regarding the T790M mutation rate after acquiring resistance to first-line combination therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab in patients with advanced non-small-cell lung cancer (NSCLC) are limited. The present study was aimed at analyzing predictors of acquired T790M mutations in this patient group. A total of 107 patients who received first-line combination therapy with EGFR-TKIs and bevacizumab at 11 tertiary referral centers in Taiwan were enrolled in this multicenter retrospective study. Survival data and genomic test results after acquiring resistance were analyzed. We discovered that patients who received a combination of afatinib, a second generation EGFR-TKI, and bevacizumab showed better progression-free survival (PFS). After disease progression, 59 patients (55.1%) were confirmed to test positive for EGFR T790M. A longer duration of first-line therapy could be a predictor of subsequent T790M mutations. To our knowledge, this is one of the few and early studies to demonstrate the T790M mutation rate after first-line combination therapy with an EGFR-TKI and bevacizumab. Whether the longer PFS afforded by the addition of bevacizumab could lead to subsequent T790M mutations needs further investigation.

Comprehensive assessment of pretreatment sarcopenia impacts on patients with EGFR-mutated NSCLC treated with afatinib.

BACKGROUND: This study aimed to comprehensively evaluate the efficacy and toxicity of afatinib in patients with sarcopenia, an important prognostic factor for treatment efficacy and toxicity in patients with cancer. METHODS: The clinical features of patients with advanced NSCLC treated with frontline afatinib between 2014 and 2018 at a medical center in Taiwan were retrospectively reviewed. Sarcopenia was evaluated based on the total cross-sectional area of skeletal muscles assessed by computed tomography (CT) imaging at the L3 level. Baseline characteristics, response rates, survival rates, and adverse events (AEs) were compared between sarcopenic and nonsarcopenic patients. RESULTS: A total of 176 patients evaluated for sarcopenia by CT and treated with afatinib were enrolled in the current study. Sarcopenia was significantly associated with good performance status, low body mass index (BMI), low body surface area (BSA), and low total mass area (TMA). Sarcopenia did not influence the response rate (69.2% vs. 72.0%, p = 0.299), progression-free survival (median 15.9 vs. 14.9 months, p = 0.791), or overall survival (median 26.5 vs. 27.2 months, p = 0.441). However, BSA ≤ 1.7 and the 40 mg afatinib dose were associated with dose reduction. TMA was the only independent factor for afatinib discontinuation due to AEs. CONCLUSION: Sarcopenia was not associated with treatment efficacy or toxicity among patients with NSCLC harboring common mutations treated with afatinib, indicating sarcopenic patients should not be excluded from afatinib treatment. Other factors, such as BSA and TMA, were associated with dose reduction and afatinib discontinuation, respectively, which may require additional evaluations in future studies.

The survival after discontinuation of EGFR-TKIs due to intolerable adverse events in patients with EGFR-mutated non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for advanced non-small cell lung cancer (NSCLC) patients harboring the EGFR mutation. Patients experiencing intolerable adverse events (AEs) would discontinue EGFR-TKIs. This study aimed to evaluate the impact of intolerable AEs and subsequent treatment on the survival of patients who discontinued EGFR-TKIs. PATIENTS: The data of advanced NSCLC patients treated with EGFR-TKIs as frontline treatment at Chang Gung Memorial Hospitals from June 2014 to March 2018 were retrospectively reviewed. RESULTS: A total of 2190 patients were enrolled and treated with frontline EGFR-TKIs. In August 2021, 114 (5.2%) patients experienced intolerable AEs requiring discontinuation of EGFR-TKIs. The time median of EGFR-TKIs discontinuation was 2.56 months. Age >65 years, females, body weight, and body surface area were associated with the occurrence of intolerable AEs for patients treated with afatinib. Patients experiencing skin/paronychia/mucositis and abnormal liver function test had favorable survivals results. Patients who received subsequent EGFR-TKIs treatment, experienced better progression-free survival (PFS), total PFS (from frontline line EGFR-TKIs), and overall survival (OS) compared to patients receiving chemotherapy or no treatment. Patients undergoing subsequent EGFR-TKIs had better total PFS (median, 14.9 vs. 11.3 months, p = 0.013) and OS (median, 31.3 vs. 20.1 months, p = 0.001) than patients who did not discontinue because of AEs. Favorable OS was validated by propensity score matching. CONCLUSION: Patients experiencing intolerable AEs during EGFR-TKI treatment should consider switching to an alternative EGFR-TKI, which increase the survival results as compared to those patients who did not experience intolerable AEs.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR-TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations. METHODS: A total of 230 treatment-naive patients with NSCLC harboring uncommon EGFR mutations treated with first-line EGFR-TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS. RESULTS: Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR-TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS. CONCLUSION: Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations.

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation.

Introduction: Uncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear. Methods: This retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database. Results: Between 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively). Conclusions: Our study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

Impact of T790M Mutation Status on Later-Line Osimertinib Treatment in Non-Small Cell Lung Cancer Patients.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) designed to overcome acquired T790M resistance mutations in non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib in patients without acquired T790M mutations has not been well studied. This study aimed to evaluate the efficacy of osimertinib in patients treated with first- and second-generation EGFR-TKIs followed by later-line osimertinib treatment. Patients: The clinical data and survival outcomes of 172 patients with advanced NSCLC treated with osimertinib following frontline EGFR-TKIs at Chang Gung Memorial Hospital from 2014 to 2018 were retrospectively reviewed. T790M mutations were detected using tissue sequencing and/or liquid biopsy. Results: A total of 172 EGFR-mutated NSCLC patients treated with frontline EGFR-TKI therapy followed by later-line osimertinib were enrolled in the current study and divided into three groups based on the T790M status (positive, negative, or unknown T790M). Patients with NSCLC harboring acquired T790M mutation treated with osimertinib had the best objective response rate (ORR) (52.6%, 25.0%, and 32.0%, p = 0.044), disease control rate (DCR) (79.3%, 41.7%, and 68.0%, p = 0.011), and progression-free survival (PFS, median PFS, 12.6, 3.1, 10.4 months, p = 0.001) among the three groups (positive, negative, and unknown T790M, respectively). However, a marked difference was found between positive and negative T790M mutations but not between positive and unknown T790M mutations. Univariate analysis was performed to identify potential prognostic factors for PFS in 172 patients treated with osimertinib. Lung metastasis (p < 0.001), brain metastasis (p < 0.009), number of metastatic sites (p < 0.001), PFS with frontline EGFR-TKIs (p = 0.03), and T790M status (p = 0.006) were identified as prognostic factors for PFS with osimertinib. Multivariate analysis showed that lung metastasis (p < 0.001) and PFS with frontline EGFR-TKIs and T790M status were independent prognostic factors. Conclusion: This study confirmed the greater efficacy of later-line osimertinib for NSCLC with acquired T790M mutation than for NSCLC without acquired T790M mutation. Detection of the T790M mutation after frontline treatment (first- and second-generation EGFR-TKI) is crucial for prolonging the survival of NSCLC patients harboring EGFR mutation. Osimertinib may be considered an option for NSCLC with unknown T790M mutations, as a certain subpopulation may benefit from osimertinib.

Sequential treatment in advanced non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. METHODS: Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. RESULTS: Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0-67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5-34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. CONCLUSION: This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34−0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37−0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41−0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19−0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Epidermal growth factor receptor tyrosine kinase inhibitors for de novo T790M mutation: A retrospective study of 44 patients.

BACKGROUND: This study aimed to evaluate possible treatment strategies for patients with de novo T790M mutation-positive (T790M+) non-small-cell lung cancer (NSCLC). METHODS: Patients diagnosed with de novo T790M+ NSCLC and treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) between 2011 and 2018 at a regional hospital in Taiwan were retrospectively reviewed. Their clinicopathological characteristics and subsequent treatment information were collected, and potential prognostic factors were identified using univariate and multivariate analyses. RESULTS: All tumors with T790M mutations coexisted with sensitizing mutations. Through the last follow-up in May 2021, afatinib and osimertinib demonstrated better progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than gefitinib and erlotinib. Additionally, patients with low T790M ratios had better PFS than those with high T790M ratios, implying that the proportion of T790M+ tumors determined the response to EGFR-TKIs. Multivariate analysis confirmed that both EGFR-TKI treatment (osimertinib hazard ratio [HR] 0.06, 95% confidence interval [CI] 0.01-0.30; afatinib HR 0.09, 95% CI 0.02-0.39) and a low T790M ratio (HR 0.29, 95% CI 0.12-0.69) were independently favorable prognostic factors for patients with de novo T790M+ NSCLC. Median PFS was 6.1 (95% CI 4.4-7.8) months. In addition, patients treated with first-generation (1G)/second-generation (2G) EGFR-TKIs followed by osimertinib (n = 8) demonstrated the best OS compared with patients treated with frontline osimertinib (n = 5) or 1G/2G EGFR-TKIs without osimertinib (n = 28, p < 0.01). CONCLUSION: Sequential TKIs may represent an alternative option for de novo T790M mutation, particularly frontline afatinib and tumors with low T790M ratios.

The different overall survival between single-agent EGFR-TKI treatment and with bevacizumab in non-small cell lung cancer patients with brain metastasis.

Comparison of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy or with bevacizumab in real-world non-small cell lung cancer (NSCLC) patients was lacking. 310 patients of advanced NSCLC with common EGFR mutation receiving first-generation EGFR-TKI monotherapy or with bevacizumab were included and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analysed. Patients receiving EGFR-TKI and bevacizumab were significantly younger, had better performance status and with high incidence of brain metastasis (55.8%). In the propensity-score matched cohort, PFS (13.5 vs. 13.7 months; log-rank p = 0.700) was similar between the two groups. The OS (61.3 vs. 34.2 months; log-rank p = 0.010) and risk reduction of death (HR 0.42 [95% CI 0.20-0.85]; p = 0.017) were significantly improved in EGFR-TKI plus bevacizumab group. Analysis of treatment by brain metastasis status demonstrated EGFR-TKI plus bevacizumab in patients with brain metastasis was associated with significant OS benefit compared to other groups (log-rank p = 0.030) and these patients had lower early-CNS and early-systemic progressions. The secondary T790M did not significantly differ between EGFR-TKI plus bevacizumab and EGFR-TKI monotherapy groups (66.7% vs. 75.0%, p = 0.460). Forty-one (31.1%) and 31 (23.5%) patients received subsequent osimertinib and chemotherapy, respectively. The post-progression OS of osimertinib and chemotherapy were 22.1 and 44.9 months in EGFR-TKI plus bevacizumab group and were 10.0 and 14.1 months in EGFR-TKI monotherpay group, respectively. First-generation EGFR-TKI with bevacizumab improved treatment efficacy in real-world patients of NSCLC with EGFR mutation. Patients with brain metastasis received additional OS benefit from this treatment.

Real-world Afatinib Outcomes in Advanced Non-small Cell Lung Cancer Harboring EGFR Mutations.

BACKGROUND/AIM: Afatinib is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib can overcome the treatment resistance-associated EGFR T790M mutation, and the sequence of afatinib followed by osimertinib is an effective therapeutic strategy for NSCLC patients. This study comprehensively evaluated the outcomes of sequential therapy following frontline afatinib and identified predictive factors for T790M mutation acquisition. PATIENTS AND METHODS: Data from patients with advanced NSCLC treated with frontline afatinib at a Taiwanese hospital group from June 2014 to March 2018 were retrospectively reviewed. The EGFR T790M mutation was detected by tissue sequencing or liquid biopsy. The patients' clinicopathological features were collected, and univariate and multivariate analyses were performed to identify potential predictive and prognostic factors. RESULTS: A total of 635 patients treated with afatinib were enrolled in this study. Until August 2021, 553 patients experienced progression, and 225 patients underwent T790M mutation testing. The T790M positive rate was 54.2%. Both exon 19 deletion and progression-free survival were associated with T790M positivity. Osimertinib was found to be effective in T790M-positive but not T790M-negative NSCLC. The median overall survival (OS) was 61.8 months for patients with T790M mutation undergoing later-line osimertinib compared with 30.1 months for patients without T790M mutation undergoing chemotherapy only. Osimertinib independently prolonged OS after afatinib progression. CONCLUSION: This study confirmed the efficacy of sequential afatinib and osimertinib treatment. T790M mutation detection and osimertinib availability are important for prolonging survival in patients with NSCLC harboring EGFR mutations.

Comparison of Different Tyrosine Kinase Inhibitors for Treatment of Poor Performance Status Patients with EGFR-Mutated Lung Adenocarcinoma.

The aim of this retrospective study was to investigate the tolerability and survival outcomes of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment in patients with a performance status ≥ 2. The data for 517 patients treated with EGFR-TKIs between January 2011 and January 2018 at a regional hospital in northern Taiwan were analyzed. Clinical and pathological features were collected, and univariate as well as multivariable analyses were undertaken to identify potential prognostic factors. The overall objective response rate, median progression-free survival (PFS), and median overall survival (OS) were 56.3%, 11.4 months, and 15.3 months, respectively. The mutation status (exon 19 deletion), locally advanced disease, dose adjustment, and the lack of liver and pleural metastasis were independent and favorable prognostic factors for PFS. Age < 60 years, mutation status (exon 19 deletion), dose adjustment, and lack of lung, liver, and no pleural metastasis were independent and favorable prognostic factors for OS. GFR-TKIs demonstrated acceptable efficacy and safety in the current cohort. Dose adjustment was identified as an independent prognostic factor for both PFS and OS, regardless of which EGFR-TKIs were used. The current research provided novel evidence of the clinical prescription of frontline EGFR-TKIs for EGFR-mutated lung adenocarcinoma patients with a PS score ≥2.

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of 2190 patients with EGFRm+ NSCLC cancer who were treated with EGFR-TKIs (including gefitinib, erlotinib, and afatinib) at the branches of a hospital group between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) data were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors to create a nomogram for risk stratification. Univariate analysis identified 14 prognostic factors, and multivariate analysis confirmed the pretreatment independent factors, including Eastern Cooperative Oncology Group performance status, morphology, mutation, stage, EGFR-TKIs (gefitinib, erlotinib, or afatinib), and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. Based on these factors, a novel nomogram was created and used to stratify the patients into five different risk groups for PFS and OS using recursive partitioning analysis. This risk stratification can provide additional information to clinicians and patients when determining the optimal therapeutic options for EGFRm+ NSCLC.

Afatinib Treatment Alone or with Bevacizumab in a Real-World Cohort of Non-Small Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Mutation.

BACKGROUND: Treatment outcome between afatinib alone or with bevacizumab in non-small cell lung cancer (NSCLC) patient with epidermal growth factor receptor (EGFR) mutation remains insufficiently reported. METHODS: A total of 405 advanced NSCLC patients with sensitizing-EGFR mutation receiving first-line single-agent afatinib or with bevacizumab were grouped and propensity score-matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analyzed. RESULTS: In the original cohort, 367 (90.6%) patients received afatinib treatment alone and 38 (9.4%) patients received afatinib plus bevacizumab. Patients who received bevacizumab combination were significantly younger (54.6 ± 10.9 vs. 63.9 ± 11.5; p < 0.001) compared to the afatinib alone group. After propensity score matching, the afatinib alone and afatinib plus bevacizumab groups contained 118 and 34 patients, respectively. A non-significantly higher objective response was noted in the afatinib plus bevacizumab group (82.4% vs. 67.8%; p = 0.133). In the propensity score-matched cohort, a bevacizumab add-on offered no increased PFS (16.1 vs. 15.0 months; p = 0.500), risk reduction of progression (HR 0.85 [95% CI, 0.52-1.40]; p = 0.528), OS benefit (32.1 vs. 42.0 months; p = 0.700), nor risk reduction of death (HR 0.85 [95% CI, 0.42-1.74] p = 0.660) compared to the single-agent afatinib. The secondary T790M rate in afatinib plus bevacizumab and afatinib alone groups was similar (56.3% vs. 49.4%, p = 0.794). Multivariate analysis demonstrated that EGFR L858R (OR 0.51 [95% CI, 0.26-0.97]; p = 0.044), EGFR uncommon mutation (OR 0.14 [95% CI, 0.02-0.64]; p = 0.021), and PFS longer than 12 months (OR 2.71 [95% CI, 1.39-5.41]; p = 0.004) were independent predictors of secondary T790M positivity. CONCLUSION: Bevacizumab treatment showed moderate efficacy in real-world, afatinib-treated NSCLC patients with EGFR-sensitizing mutation.

Afatinib treatment in a large real-world cohort of nonsmall cell lung cancer patients with common and uncommon epidermal growth factor receptor mutation.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib-treated cohort in which 516 EGFR-mutated NSCLC patients receiving afatinib as front-line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF /dT790MLAF ), non-T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type-I and the rest as type-II uncommon mutation. Four hundred and sixty-one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression-free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10-8 ). Type-I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60-7.64]; P < .001) and OS (HR 2.56 [95% CI, 1.37-4.75]; P = .003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause-specific HR, 3.16; 95% CI 1.24-8.08; P = .016), and type-I uncommon mutation patients exhibited a significantly higher systemic progression (cause-specific HR, 4.95; 95% CI 2.30-10.60; P = 4.3 × 10-5 ). Tendencies of higher CNS and lower systemic progression were observed in type-II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 [95% CI, 1.18-4.89]; P = .016) and uncommon EGFR mutation (OR 0.08 [95% CI, 0.01-0.48]; P = .021) were independent predictors of secondary T790M. Afatinib-treated NSCLC patients presented an EGFR genotype-specific pattern of disease progression and outcome.

First- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large, real-world cohort of patients with non-small cell lung cancer.

BACKGROUND: There are limited comparisons of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in large, real-world cohorts of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. METHODS: Patients with advanced NSCLC (N = 612) with common EGFR mutations receiving first-line gefitinib/erlotinib and afatinib were grouped and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutations were analyzed. RESULTS: The gefitinib/erlotinib and afatinib groups each contained 206 patients after matching. Compared with gefitinib/erlotinib, patients receiving afatinib achieved longer median PFS (16.3 versus 14.2 months; log-rank test p = 0.020) and had a lower risk of progression [hazard ratio (HR) 0.73 (95% confidence interval (CI), 0.57-0.94); p = 0.017]. Median OS (37.3 versus 34.2 months; log-rank test p = 0.500) and reduction in risk of death [HR 0.89 (95% CI, 0.65-1.23); p = 0.476] did not differ significantly between groups. T790M positivity was significantly higher in the gefitinib/erlotinib than afatinib group (70.9% versus 44.6%, p < 0.001). Multivariate analysis demonstrated that afatinib was independently associated with lower T790M positivity [odds ratio (OR) 0.27 (95% CI, 0.14-0.53); p < 0.001], whereas ⩾12 months PFS after EGFR-TKI treatment [OR 3.00 (95% CI, 1.56-5.98); p = 0.001] and brain metastasis [OR 2.12 (95% CI, 1.08-4.26); p = 0.030] were associated with higher T790M positivity. Sequential third-generation EGFR-TKI treatment was administered to 63 patients, in whom median OS after the second-third-generation and first-third-generation EGFR-TKI sequences were 38.8 and 29.1 months, respectively. CONCLUSION: Compared with gefitinib/erlotinib, afatinib had a higher treatment efficacy and a lower secondary T790M positivity in a large, real-world cohort of Asian patients with EGFR-mutated NSCLC.