Epidermal Growth Factor Receptor Mutation-positive Patients Research Articles

Efficacy and Safety of Anlotinib in EGFR-Positive Patients with Advanced Lung Adenocarcinoma Compared with Chemotherapy: A Retrospective Study.

There are no standard third-line or beyond treatments for patients with driver mutation-positive advanced lung adenocarcinoma (LUAD). Anlotinib was approved as a third-line multitarget drug in China in 2018. Limited data are available regarding the efficacy and safety of anlotinib compared with chemotherapy. To investigate the efficacy and safety of anlotinib compared with traditional chemotherapy in patients with epidermal growth factor receptor (EGFR)-positive advanced LUAD. We conducted a retrospective study of 83 EGFR mutation-positive patients with advanced LUAD between 2011 and 2022. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, whereas the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Anlotinib-related adverse events (AEs) were recorded to evaluate the safety of anlotinib. 39 patients with LUAD received anlotinib and 44 patients with LUAD received chemotherapy were enrolled in the study. Patients treated with anlotinib exhibited longer PFS (11.2 vs 4.5 months, P < .01) and OS (18.8 vs 15.8 months, P < .05) than patients treated with chemotherapy. There were no significant differences in ORR (7.9% vs 20.5%, P = .129) or DCR (100% vs 93.2%, P = .120) between the two groups. Anlotinib-related AEs grading 3-4 level were observed in 2 (5.1%) patients, no anlotinib-related death was recorded. Cox regression analyses of PFS and OS showed that brain metastases and age < 30 years at diagnosis had negative effects on clinical outcomes. Anlotinib is effective and safe in patients with EGFR-positive advanced LUAD. Patients without brain metastases had better clinical outcomes.

Clinical characteristics and establishment of a 2-year-OS predictive model of EGFR mutation-positive patients with pleural invasion of lung adenocarcinoma.

To investigate the differences between lung adenocarcinoma with the pleural invasion that has EGFR (epidermal growth factor receptor) 19-del or 21L858R mutations in terms of clinical characteristics and outcomes. EGFR mutation-positive patients with pleural metastasis of lung adenocarcinoma diagnosed in the Department of Respiratory Medicine of Yuhuangding Hospital of Yantai City, Shandong Province, from January 2014 to January 2022 were selected. The clinical data of the patients were collected to retrospectively analyze whether the clinical characteristics and prognosis of patients with 19-del or 21L858R mutation subtype were different and analyze the impact of clinical characteristics on the prognosis of patients. The difference in clinical characteristics between the 2 groups was analyzed by SPSS, P < .05. There was statistical significance. Univariate and multivariate regression analysis was performed with R soft. To establish a 2-year overall survival predictive model for patients with EGFR gene 19-del and 21L858R mutations in patients with pleural invasion of lung adenomas and to provide predictive model maps. Receiver operating characteristic curve, calibration curve, and decision curve analysis were used to evaluate the value of the prediction model in this study. Of the 74 patients included, the 19-del mutation group had a higher incidence of pleural thickening (P = .023) and a lower Ki-67 level (P = .035). There was no difference in 2-year overall survival and progression-free survival between the 2 mutations. There were differences in pleural thickening and Ki-67 index between the 2 groups, but no differences in disease outcome between the 2 groups. The nomogram model established based on gender, treatment regimen, CEA, lymph node metastasis, and pleural changes is accurate and feasible.

Should We Perform Repeated Re-biopsy for the Detection of T790M Mutation?

Epidermal growth factor receptor (EGFR) T790M mutations have been detected in the second or third rebiopsy, even if the T790M mutation was not identified in the first rebiopsy. This meta-analysis investigated the EGFR T790M mutation detection rates and its additional advantages with repeated rebiopsies. We searched through the PubMed and EMBASE databases up to June 2022. Studies reporting rebiopsy to identify the EGFR T790M mutation in case of disease progression among patients with advanced non-small cell lung cancer and multiple rebiopsies were included. The quality of the included studies was checked using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Eight studies meeting the eligibility criteria, reporting 1,031 EGFR mutation-positive patients were selected. The pooled EGFR T790M mutation detection rate of the first and repeated rebiopsies were 0.442 (95% confidence interval [CI], 0.411 to 0.473; I2=84%; p < 0.01) and 0.465 (95% CI, 0.400 to 0.530; I2=69%; p < 0.01), respectively. Overall, the pooled detection rate of EGFR T790M mutation was 0.545 (95% CI, 0.513 to 0.576), which increased by 10.3% with repeated rebiopsies. This meta-analysis identified that repeated rebiopsy increases the detection rate of EGFR T790M mutation by 10.3%, even if EGFR T790M mutation is not detected in the first rebiopsy. Our results indicate that the spatiotemporal T790M heterogeneity can be overcome with repeated rebiopsy.

Prognostic Value of the Systemic Immune-Inflammation Index in EGFR Mutation-Positive Lung Adenocarcinoma Patients Treated with Tyrosine Kinase Inhibitors

Introduction: Inflammation is considered a promoting factor in tumorigenesis and progression. Inflammatory parameters calculated from complete blood counts such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII) are related to poor prognosis in lung cancer patients. However, few studies have reported on lung cancer with targeted therapy. This study aimed to explore a correlation between NLR, PLR, and SII to survival rates in advanced lung adenocarcinoma epidermal growth factor receptor (EGFR) mutation-positive with tyrosine kinase inhibitors (TKIs) as the main choice of treatment. Methods: A retrospective observational study obtained 50 medical record data from patients with EGFR mutation-positive lung adenocarcinoma treated by TKIs at Ulin General Hospital Banjarmasin from January 2017 to December 2019. The optimal cut-off values for NLR, PLR, and SII were obtained using the receiver operating characteristic curve (ROC). Kaplan–Meier analyses were used to assess the prognostic value of inflammation parameters in overall survival (OS) and progression-free survival (PFS). Results: The optimal cut-off value for NLR, PLR, and SII was 6.095, 356.935, and 1767.0, respectively. However, only the SII was significantly associated with survival; SII ≥ 1767.0 correlated with shorter OS (18 months vs. 28 months, p = 0.014) and PFS (7 months vs. 12 months, p = 0.004). Conclusion: Pre-treatment SII can be a prognostic factor for survival in EGFR mutation-positive lung adenocarcinoma patients receiving TKIs.

EP08.01-102 Anlotinib Combined with PD-1 Inhibitors May Benefit Advanced Non-small Cell Lung Cancer Patients After Failure of EGFR-TKI Therapy

Approximately 50% of patients with lung adenocarcinoma (LUAD) in Asian populations harbor epidermal growth factor receptor (EGFR) mutations. Although the current front-line third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapy can benefit these EGFR mutation-positive patients, treatments for non-small cell lung cancer (NSCLC) patients with EGFR-TKI resistance are limited. The study aimed to explore the application of both angiogenic and PD-1 blockade in NSCLC patients who had failed EGFR-TKIs.

Exposure-Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting.

Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. A retrospective observational cohort study was performed, including patients receiving 40-80mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166µg/L was taken to explore the exposure-efficacy relationship. A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3-19.1) months and 9.3 (95% CI: 7.2-11.1) months for patients with Cmin,pred < 166µg/L and Cmin,pred ≥ 166µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60-2.01;p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18-7.08;p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

Clinical outcomes of lung adenocarcinoma patients harboring uncommon epidermal growth factor receptor (EGFR) mutations treated with EGFR-tyrosine kinase inhibitors (TKIs).

This study aimed to explore the efficacy of different epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma (AC) patients harboring uncommon EGFR mutations. Between January 1st, 2013 and October 1st, 2019, 2,680 EGFR mutation-positive patients with confirmed stage IIIB/IV lung AC were enrolled from Zhejiang Cancer Hospital. Uncommon EGFR mutations were detected in 132 patients using next-generation-sequencing. Clinicopathological features between patients with uncommon EGFR mutations and common EGFR mutations were evaluated by the chi-square test. The clinical outcomes of patients with uncommon EGFR mutations were analyzed by the Kaplan-Meier method. Of 132 AC patients with uncommon EGFR mutations, 115 received EGFR-TKIs. Second-generation EGFR-TKIs were associated with longer progression-free survival (PFS) (P=0.116) and overall survival (OS) (P=0.005) than first or third-generation EGFR-TKIs. We also found that patients with compound mutations and double uncommon EGFR mutations had longer PFS (P=0.725) and OS (P=0.741) than those with single uncommon EGFR mutation, although the difference was not significant. In addition, third-generation EGFR-TKIs were more effective than the other two agents in patients with primary T790M mutation regarding PFS (P=0.150) and OS (P=0.033), although the difference in PFS was not significant. Patients with uncommon EGFR mutations treated with second-generation EGFR-TKIs showed better PFS and OS. EGFR-TKIs were more effective in patients with compound mutations or double uncommon mutations.

Cluster analysis of deterioration sites after first-line epidermal growth factor receptor-tyrosine kinase inhibitor in epidermal growth factor receptor mutated non-small cell lung cancer.

IntroductionFor epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC), no studies have treated the site of recurrence after first-line tyrosine kinase inhibitor (TKI) treatment as a “metastasis pattern”. This study aims to assess whether these patients have a specific “metastasis pattern” at the site of recurrence after the treatment.Material and methodsData were collected from all consecutive EGFR mutated NSCLC patients between 2009 and 2021. Metastatic patterns were analyzed using cluster analysis in patients with EGFR mutated NSCLC.ResultsDuring the study period, 83 EGFR mutated NSCLC patients were treated with EGFR-TKI. Patients who had no metastases at the time of diagnosis were divided into two groups according to the presence or absence of recurrence of metastases after TKI administration. Patients with metastases at diagnosis were divided into 4 groups by cluster analysis. A statistically significant difference in metastasis frequency was confirmed among these 6 groups (χ2 test, p = 0.0001). Furthermore, when the frequency of metastasis recurrence after TKI administration in these 6 groups was examined, a statistically significant difference was confirmed (χ2 test, p = 0.0001).ConclusionsEven in EGFR mutation-positive patients, the knowledge of the recurrent patterns might be useful for clinical practice in the foreseeable future, as it enables more efficient detection of metastatic disease through imaging, and more effective treatment at predicted metastatic sites.

Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation–positive non–small-cell lung cancer in a real-world setting (OSI-FACT)

BackgroundOsimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation–positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient. MethodsWe performed a retrospective multicentre cohort study for 538 EGFR mutation–positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS). ResultsThe median observation period was 14.7 months (interquartile range 11.4–20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6−not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35–2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11–2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03–2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04–2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01–2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70–5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1–49% (HR 1.66, 95% CI 1.05–2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17–4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05–2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%). ConclusionDuring initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.

EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer.

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.

Interactions between epidermal growth factor receptor tyrosine kinase inhibitors and proton-pump inhibitors/histamine type-2 receptor antagonists in non-small cell lung cancer: a systematic review and meta-analysis.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasingly used for advanced non-small cell lung cancer (NSCLC) as first-line therapy. The bioavailability and efficacy of oral EGFR-TKIs could be affected by acid suppression (AS) therapy such as PPIs and H2RAs which are reported to be over-prescribed. Hence, there is a need to investigate the effect of AS on the overall survival (OS), progression-free survival (PFS) and adverse effect profile in patients treated with EGFR TKIs.MethodsAn electronic database search of Medline and Embase was performed following PRISMA guidelines on 17 January 2021. Studies analyzing interactions between EGFR TKIs and PPIs/H2RAs in NSCLC patients were included. s, non-English or non-Japanese studies or studies using non-EGFR TKIs were excluded. Hazard ratios (HRs) were pooled using generic inverse variance random effects model. Effect sizes for dichotomous variables were pooled using Mantel-Haenszel random effects model. Significance was considered at P≤0.05. Heterogeneity was assessed with Cochran Q-test and I2 test. Publication bias was assessed with funnel plots. The assessment of quality and risk of bias of randomized and non-randomized studies were undertaken with RoB 2 and the ROBINS-I tool respectively.ResultsOut of 1,173 potentially relevant articles, 14 articles were included in the final analysis. The pooled prevalence of AS in patients taking EGFR TKI was 30.71% in 4,010 individuals. Patients who were treated only with EGFR TKI had significantly better OS (HR =1.46, 95% CI: 1.27–1.72; P<0.00001) and PFS (HR =1.63, 95% CI: 1.35–1.98; P<0.00001). The OS for EGFR mutation positive patients only was as similarly significant as the OS in all patients taking EGFR TKI, while the PFS in mutation positive patients was significantly worsened with AS. PPIs resulted in a significantly worsened OS and PFS but H2RAs did not produce significantly different OS and PFS between AS and non-AS users. There were no significant differences in the incidence of rash (OR =0.81, 95% CI: 0.50–1.32; P=0.40), diarrhoea (OR =1.03, 95% CI: 0.63–1.67; P=0.91) or other adverse effects.ConclusionsCo-administration of AS medications with first-generation EGFR-TKIs in NSCLC worsens survival outcomes. Physicians should only prescribe AS medications when absolutely clinically indicated.

The Survival of Advanced Non-small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Thailand: A Single Institution Review

Background: Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase inhibitor (TKI) can improve progression free survival in patients with treatment naive EGFR mutant metastatic non-small cell lung cancer (NSCLC) compared with platinum-based chemotherapy, but no statistically significant difference is observed in overall survival. The survival time of EGFR mutant NSCLC patients treated with at least two systemic chemotherapy regimens and one EGFR TKI was 34.8 months in a previous study. Objective: The present study was to determine the median survival time of advanced NSCLC patients who received EGFR-TKIs in Chulabhorn Hospital. Materials and Methods: We retrospectively reviewed the medical records of advanced NSCLC cases treated with EGFR TKIs in Chulabhorn Hospital during 2009 to 2011. Results: Among 243 advanced NSCLC cases, 72 patients received EGFR TKIs. EGFR mutation status was positive in 14 (19.17%) patients. The median overall survival time was 30.04 months (95% CI: 18.71 to 49.48 months) in all patients, compared with 49.49 months (95% CI: 15.93 to NR) in EGFR mutation-positive patients (n=14). No statistically significant difference of overall survival was noted between EGFR mutation status groups (p=0.51). Conclusion: The median survival time for Thai patients treated with EGFR TKIs was comparable to historical data and irrespective of EGFR mutation status. Keywords: Metastatic non-small cell lung cancer, EGFR TKIs, Survival

Detection of epidermal growth factor receptor (EGFR) mutations from preoperative circulating tumor DNA (ctDNA) as a prognostic predictor for stage I-III non-small cell lung cancer (NSCLC) patients with baseline tissue EGFR mutations.

BackgroundPlasma circulating tumor DNA (ctDNA) may be a surrogate, minimally invasive approach to tissue-based epidermal growth factor receptor (EGFR) mutation detection in non-small cell lung cancer (NSCLC) patients. However, the predictive ability of preoperative ctDNA EGFR mutation test on long-term postoperative survival and tumor metastasis development has not been extensively investigated.MethodsStage I–III NSCLC patients with tissue EGFR mutations were enrolled in this study (n=174). The ctDNA EGFR mutations were identified in paired preoperative plasma samples. EGFR mutation testing was performed using Scorpion amplified refractory mutation system (ARMS) technology. The correlation between ctDNA EGFR mutation status and clinicopathologic parameters was analyzed. By combining at least 5 years of follow-up data, we assessed the relationship between ctDNA EGFR mutation status and disease-free survival (DFS) and overall survival (OS).ResultsPlasma-based ctDNA EGFR mutations were detected in 27 patients. The mutation types were exactly matched with those in paired tissue samples. Blood test sensitivity was closely associated with N stages, tumor-node-metastasis (TNM) stages and tumor differentiation (P<0.001). The overall 5-year survival rate was 18.5% versus 76.9% for ctDNA EGFR mutation-positive and ctDNA EGFR mutation-negative patients, respectively. For patients with ctDNA EGFR mutation positive, the median OS and DFS were 29.00±2.55 and 19.00±2.50 months, respectively, which were both significantly better than those in the ctDNA EGFR mutation-negative subgroup (P<0.001). ctDNA EGFR mutation was an independent risk factor of OS and DFS [hazard ratio (HR) 3.289, 95% confidence interval (CI), 1.816–5.956, P<0.001; HR, 4.860, 95% CI, 2.660–8.880, P<0.001]. For stage III patients with exon 19 deletion or L858R mutations in both tissue and plasma samples, tyrosine kinase inhibitor (TKI) therapy showed significantly better OS (P=0.025) and possible DFS benefit (P=0.060) than did chemotherapy.ConclusionsEGFR mutation testing using the Scorpion-ARMS method in preoperative plasma could be a strong predictor for postoperative survival and metastasis of NSCLC patients. Thus, the subset of this population may be benefit from targeted strategies and management.

Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer

The response rate for osimertinib is high among patients with untreated epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, there exist no biomarkers to predict the efficacy of the same. This study investigated whether BIM-γ mRNA expression in circulating tumor cells (CTCs) predicts poor outcomes for osimertinib treatment in patients with EGFR mutation-positive NSCLC. Patients with advanced EGFR-tyrosine kinase inhibitor-untreated NSCLC or post-operative recurrence with EGFR-sensitive mutations (exon 19 deletion or L858R mutation) were included. Informed consent was obtained from all participants. The candidate biomarker BIM-γ was measured in CTCs after blood collection (10mL of whole blood) at baseline. CTCs were collected with the ClearCell FX system, and quantitative real-time PCR was performed. Relative expression of BIM-γ mRNA from CTCs, as normalized to the reference gene (GAPDH mRNA), was calculated using the KCL22cell line for calibration. We enrolled 30 EGFR mutation-positive NSCLC patients treated with osimertinib during the period from April 2018 through December 2019. All the patients had an EGFR mutation at the primary site: exon 19 deletion in 15 cases and L858R in 15 cases. Median CTC count at baseline was 12 (range 3-127)/7.5mL, and median BIM-γ mRNA expression was 0.073 (range 0-1.37). Furthermore, the response rate to osimertinib was worse in patients with high than in those with low BIM-γ mRNA expression (n=15 each) (26.6% vs. 73.3%, respectively; p=0.011). Progression-free survival did not significantly differ between groups (p=0.13). BIM-γ mRNA overexpression in CTCs from EGFR mutation-positive NSCLC patients is a potential a biomarker for poor response to osimertinib. UMIN:00032055.

Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer

BackgroundActivated epidermal growth factor receptor (EGFR) mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma EGFR mutation abundance, especially of the ultra-low abundance of EGFR mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear.MethodsWe qualitatively detected baseline EGFR status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of EGFR mutations through next-generation sequencing (NGS). Every 8–12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of EGFR sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant TP53 mutations, and clinical response to TKIs.ResultsThis prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for EGFR mutation–positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma EGFR mutation abundance was 0.1%, the ORRs of TKI-treated patients were significantly different (60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01–0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of EGFR sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant TP53 mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12–5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples.ConclusionsLiquid biopsy screening based on highly sensitive NGS is reliable for detecting drug resistance and actionable somatic mutations. The plasma abundance of the EGFR driver mutation affected clinical response to EGFR-TKIs in advanced NSCLC patients; prolongation of PFS was also observed in patients with an ultra-low abundance of EGFR sensitizing mutations.

Identifying advanced stage NSCLC patients who benefit from afatinib therapy using 18F-afatinib PET/CT imaging

ObjectivesNon-small cell lung cancer (NSCLC) tumors harboring common (exon19del, L858R) and uncommon (e.g. G719X, L861Q) activating epidermal growth factor receptor (EGFR) mutations are best treated with EGFR tyrosine kinase inhibitors (TKI) such as the first-generation EGFR TKI erlotinib, second-generation afatinib or third-generation osimertinib. However, identifying these patients through biopsy is not always possible. Therefore, our aim was to evaluate whether 18F-afatinib PET/CT could identify patients with common and uncommon EGFR mutations. Furthermore, we evaluated the relation between tumor 18F-afatinib uptake and response to afatinib therapy. Materials and methods18F-afatinib PET/CT was performed in 12 patients: 6 EGFR wild type (WT), 3 EGFR common and 3 EGFR uncommon mutations. Tumor uptake of 18F-afatinib was quantified using TBR_WB60−90 (tumor-to-whole blood activity ratio 60−90 min post-injection) for each tumor. Response was quantified per lesion using percentage of change (PC): [(response measurement (RM)–baseline measurement (BM))/BM]×100. Statistical analyses were performed using t-tests, correlation plots and sensitivity/specificity analysis. ResultsTwenty-one tumors were identified. Injected dose was 348 ± 31 MBq. Group differences were significant between WT versus EGFR (common and uncommon) activating mutations (p = 0.03). There was no significant difference between EGFR common versus uncommon mutations (p = 0.94). A TBR_WB60−90 cut-off value of 6 showed the best relationship with response with a sensitivity of 70 %, a specificity of 100 % and a positive predictive value of 100 %. Conclusion18F-afatinib uptake was higher in tumors with EGFR mutations (common and uncommon) compared to WT. Furthermore, a TBR_WB60−90 cut-off of 6 was found to best predict response to therapy. 18F-afatinib PET/CT could provide a means to identify EGFR mutation positive patients who benefit from afatinib therapy.

Clinical utility of plasma EGFR mutation detection with quantitative PCR in advanced lung cancer: A meta-analysis

ObjectivesTo assess the clinical utility of quantitative PCR (qPCR) assays, a routinely used test for detection of epidermal growth factor receptor (EGFR) mutation in circulating tumour DNA (ctDNA) in treatment-naive advanced lung cancer patients. Materials and MethodsWe performed a meta-analysis of randomized controlled trials (RCTs) with individual patient data. Eligible RCTs compared EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy in first line setting for advanced lung cancer, and included tumour EGFR+ (tEGFR+) with paired ctDNA results using real-time (quantitative) PCR. We assessed the proportion of tEGFR + detected by ctDNA, and compared the effectiveness of EGFR-TKI versus chemotherapy in ctDNA + and ctDNA- subgroups. ResultsSix randomized clinical trials included 1058 tEGFR + patients with paired baseline EGFR ctDNA testing. Of these, 460 (43 %) tested ctDNA- (ctDNA+ 57 %). Progression-free survival was longer for EGFR-TKI versus chemotherapy for both ctDNA+ (HR 0.28; 95 % CI 0.22−0.36, p < 0.00001) and ctDNA- subgroups (HR 0.37; 95 % CI 0.28−0.49, p < 0.00001; p-interaction = 0.14). Objective response rate (odds ratio 6.21; 95 % CI 4.25–9.07, p < 0.00001 vs 6.44; 95 % CI 4.21–9.87, p < 0.00001) and overall survival (HR 0.82; 95 % CI 0.70–1.04 vs HR 0.77; 95CI% 0.59–1.00) similarly favoured EGFR-TKI in both ctDNA + and ctDNA- subgroups respectively. ConclusionOur findings indicate that approximately two in five tissue EGFR mutation-positive patients will not be detected using a qPCR assay, but would still potentially benefit from highly effective EGFR-TKI treatment. A negative EGFR ctDNA result via qPCR testing is therefore insufficient to exclude benefit from EGFR-TKI. Attempts should be made to repeat EGFR testing with a tissue biopsy in this patient group. As newer ctDNA assays with better sensitivity become available, the clinical impact for any false negatives will remain an important consideration.

Icotinib versus Cisplatin Plus Docetaxel as Adjuvant Chemotherapy in Patients with Stage II (N1+) Non-Small Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study.

PurposeThe superior efficacy of first-line treatment with icotinib over that of standard chemotherapy has been well demonstrated in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, whether icotinib is superior to cisplatin plus docetaxel as adjuvant chemotherapy in patients with stage II (N1+) NSCLC selected by EGFR mutation is controversial.MethodsA total of 43 patients with completely resected stage II (T1-2N1M0) NSCLC and proven sensitive EGFR mutation (19Del or L858R) between January 2010 and December 2019 were included in our study. The disease-free survival (DFS) and overall survival (OS) were analyzed in 22 patients treated with icotinib and 21 patients treated with cisplatin plus docetaxel. Factors affecting DFS and OS were assessed by the Kaplan-Meier (KM) estimator and univariate Cox regression analysis.ResultsOur cohort included 22 icotinib patients and 21 cisplatin plus docetaxel patients with a median follow-up of 35.5 months and 38 months, respectively. Survival time was significantly longer in the icotinib group than in the chemotherapy group, with a median DFS of 47 months (95% CI, not reached) versus 18 months (95% CI, 12.4–23.6; HR 0.16; 95% CI, 0.07–0.35; log-rank p<0.0001). In the icotinib group, the most common adverse effects (AEs) were skin rash (40.9%) and elevated alanine aminotransferase (22.7%), whereas in the cisplatin plus docetaxel group, the most common AEs were nausea or vomiting (90.5%), anorexia (71.4%), and fatigue (71.4%). No deaths were treatment-related.ConclusionIn this study, we demonstrated that in EGFR mutation-positive patients with completely resected stage II (T1-2N1M0) NSCLC, icotinib might provide DFS benefits, and reduced drug toxicity compared to cisplatin plus docetaxel. Thus, icotinib may be a reasonable option for adjuvant chemotherapy in patients with pathological stage II (N1+) NSCLC with EGFR mutation.

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Simple SummaryThe present study showed the comprehensive analysis of disease characteristics and treatment patterns in uncommon EGFR mutation-positive NSCLC at a major cancer center. This study showed the efficacy of 1G or 2G EGFR-TKIs as the 1L treatment, and subsequent therapy including 3G EGFR-TKIs in the real-world setting.Approximately 10% of the epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are uncommon EGFR mutations. Although the efficacy of second (2G) or third generation (3G) EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon EGFR mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon EGFR mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon EGFR mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon EGFR mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major EGFR mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8–13.5), 11.7 months (95% CI: 6.6–16.7), 7.7 months (95% CI: 4.9–17.4), and 5.0 months (95% CI: 3.7–6.1) for major uncommon EGFR mutation (G719X, L861Q), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9–34.2), 28.8 (95% CI: 24.4–33.4), 13.5 months (95% CI: 7.4–27.8), and 9.4 months (95% CI: 3.4–10.5) for major uncommon EGFR mutation (G719X), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6–16.9), and 37.5 months (95% CI: 35.4–39.6) for common EGFR mutation-positive NSCLC. After failing 1L EGFR-TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G EGFR-TKI after failing the first-line EGFR-TKI, the ORR and PFS for 3G EGFR-TKI were 80% and 8.9 months (95% CI: 8.0–9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8–39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

Expanding the Definition of Oligometastatic in Lung Adenocarcinoma

The term oligometastatic is defined as having up to 3 metastatic lesions at the time of diagnosis. More recent studies have incorporated up to 5 metastatic sites, though patients with >3 metastatic areas were highly under-represented in these trials. Current ongoing trials are looking to expand the definition of oligometastatic to 10 sites or less, however presently there is limited data in the modern setting to suggest patients with more than 5 metastatic sites have similar oncologic outcomes to those with 5 or less sites of disease. The purpose of this study is to evaluate oncologic outcomes based on the number of metastatic sites at the time of diagnosis in patients with lung adenocarcinoma. A retrospective analysis of metastatic lung adenocarcinoma patients with known Epidermal Growth Factor Receptor (EGFR) status who underwent treatment from 2009 to 2018 at our institution was performed. All patients included underwent upfront staging with body positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) brain imaging; number of metastatic sites was counted individually. Overall survival (OS) was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing OS. Additional variables included in the analysis were age, gender, race, smoking history, presence of brain metastases, pleural disease, and number of oligometastatic sites. Among the 429 adenocarcinoma patients included, the breakdown of total number of upfront metastases were as follows: 1-3 (40.8%), 4-5 (13.3%), 6-10 (17.2%), 11-20 (11.0%), >20 (17.7%). Median OS was as follows: 1-3 (34 mo; 95% confidence interval [CI], 22-46 mo), 4-5 (22 mo; 95% CI, 16.9-27.1), 6-10 (23 mo; 95% CI, 13.7-32.3), 11-20 (33 mo; 95% CI, 23.6-42.4), >20 (22 mo; 95% CI, 12.9-31.1) (log-rank p=0.055). Under multivariate analysis including all patients, presence of >20 metastatic sites (hazard ratio [HR] 1.84; 95% CI, 1.24-2.72; p=0.002) was associated with worse OS, with no differences in OS seen in patients with 4-5 (HR 1.26; p=0.301), 6-10 (HR 1.43; p=0.067), and 11-20 sites (HR 1.15; p=0.562) (reference 1-3 sites). On subset multivariate analysis of EGFR mutation-positive patients, having >20 metastatic sites (HR 2.55; 95% CI, 1.50-4.33; p=0.001) was again associated with worse OS, with no differences seen in patients with 4-5 (HR 1.02; p=0.955), 6-10 (HR 1.51; p=0.179), and 11-20 sites (1.02; p=0.964) (reference 1-3 sites). The definition of oligometastatic disease will continue to evolve with future studies in the era of better systemic therapies and more refined radiation techniques. In our patient population, specifically those with EGFR mutation-positive disease, there appears to be relatively similar survival differences in patients with up to 20 metastatic sites, suggesting the potential benefit for more aggressive local therapies in these individuals. For patients with >20 metastatic sites, outcomes continue to be poor.