Received EGFR-TKI Therapy Research Articles

Associations of early adverse events with clinical outcomes in patients with NSCLC treated with EGFR tyrosine kinase inhibitors.

e20551 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) constitute the primary treatment modality for EGFR-mutant non-small cell lung cancer (NSCLC). While efficacious, EGFR TKIs are associated with adverse events (AEs) like dermatologic toxicities, diarrhea, and stomatitis. This study examined the prognostic implications of these on-target AEs in NSCLC patients receiving EGFR TKI therapy. Methods: A retrospective cohort study was conducted, encompassing advanced NSCLC patients treated with first-line EGFR TKIs within two distinct healthcare delivery systems in Taiwan between June 2011 and December 2019. Patients were stratified by TKI type, and those who had received AE reliever medications within 180 days prior to EGFR TKI initiation were excluded. We examined correlations between AEs and key endpoints: time to next treatment (TTNT) and overall survival (OS). To minimize immortal time bias, a landmark analysis at 60 days post-treatment initiation was utilized. On-target AEs were identified based on the issuance of at least two prescriptions for AE management on different dates within this period. Multivariable Cox proportional hazards models were utilized to evaluate the association between AEs and clinical endpoints, and a random-effects meta-analysis was performed to combine findings from both institutions. Results: Our analysis included 1,605 patients on gefitinib, 848 on erlotinib, and 1,236 on afatinib. Despite potential variations in AE reporting due to prescribing behaviors, the incidence of AE within the first 60 days of treatment was highest for afatinib, particularly with diarrhea (76.7%) and stomatitis (14.9%), followed by erlotinib with notable skin reactions (49.4%). Gefitinib showed the lowest incidence rates across all examined AEs. Of note, afatinib-treated patients who experienced diarrhea within the initial 60 days demonstrated a statistically significant extension in OS (HR 0.75, 95% CI 0.60-0.92). No significant prognostic link was found for other AEs in afatinib users or any AEs among users of gefitinib and erlotinib. Sensitivity analyses, incorporating modified AE definitions, corroborated these outcomes. Conclusions: Identifying AEs via prescription records for symptom relief poses methodological challenges and introduces uncertainty. Nevertheless, the occurrence of diarrhea within the first 60 days of therapy emerged as a significant predictor of enhanced OS in EGFR-mutant NSCLC patients receiving afatinib. This finding suggests a potential prognostic implication. The correlation was not evident in patients treated with first-line gefitinib or erlotinib.

Transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature in early-stage EGFR-mutant non-small-cell lung cancer.

e20571 Background: In a previous pilot study, we classified early-stage EGFR-mutant NSCLC according to two transcriptomic subtypes (i.e., terminal respiratory unit [TRU], which was related with the downregulation of a proliferative-related pathway; and non-TRU, which was related with the activation of a proliferative-related pathway) and the presence of a co-existing TP53 mutation. In turn, the clinical significance of the APOBEC mutation signature has not been elucidated clearly owing to the small sample size of the previous pilot study. Thus, this study aimed to validate the predictive value of transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature, to expand our pilot study via the use of additional samples and a long-term follow-up. Methods: We performed whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or FFPE from 101 patients with pathological stage II–IIIA non-squamous EGFR-mutant NSCLC who underwent complete resection between January 2014 and December 2020 at the Samsung Medical Center. This study evaluated the recurrence-free survival (RFS) and progression-free survival (PFS) afforded by EGFR-TKI therapy after recurrence according to transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature. Results: The median duration of the follow-up period was 54.2 months (range, 11.3–107.7 months). Six patients were excluded because of failure of the initial quality control; thus, 95 patients were included in the final analysis. The median age was 61.9 years (range, 44.7–91.0 years), and 75.8% of the patients were never-smokers. Moreover, 51.6% of the patients had stage III disease. Among the 95 patients, 47 (49.5%) patients were in the non-TRU group and 44 (46.3%) patients carried a TP53 mutation. The median RFS was 25.8 months (95% CI, 17.6–34.0 months). Patients with non-TRU and/or TP53 mutation had an inferior RFS compared with patients with TRU and wild-type TP53, regardless of the pathological stage (hazard ratio, 1.9; 95% CI, 1.4–2.7). The APOBEC mutation signature was not associated with RFS ( P = 0.17). Among the 65 patients who experienced radiological recurrence, 59 patients received EGFR-TKI therapy as the first-line treatment. The median PFS of EGFR-TKI therapy was 20.7 months (95% CI, 13.6–26.6 months). However, among these patients, those with the APOBEC mutation signature had a shorter PFS than those without this mutation signature (8.2 vs. 23.5 months, P < 0.05). Conclusions: This study showed consistently that the transcriptomic subtype and TP53 mutation status were predictive factors of RFS, regardless of the pathological stage, in patients with early-stage EGFR-mutant NSCLC. Additionally, the APOBEC mutation signature may be present at the initial diagnosis of early-stage EGFR-mutant NSCLC and was associated with a poor PFS after EGFR-TKI therapy.

The Role of Brain Radiotherapy before First-Line Afatinib Therapy, Compared to Gefitinib or Erlotinib, in Patients with EGFR-Mutant Non-Small Cell Lung Cancer.

Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR-tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy. Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively. The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups. Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR</>-mutant NSCLC.

Association of Acquired Resistance EGFR Exon 20 T790M Mutation and Treatment Response in Lung Adenocarcinoma Patients Receiving EGFR-TKI

Background: Lung adenocarcinoma patients receiving EGFR-TKI may develop acquired resistance within 7-16 months of treatment initiation, which is characterized by the presence of exon 20 T790M mutations in treatment response patients and can be assessed objectively by CECT and then evaluated by RECIST 1.1. The purpose of this study is to look into the association between acquired resistance EGFR Exon 20 T790M mutation and treatment response in lung adenocarcinoma patients receiving EGFR-TKI. Method: This research is an analytic study with a retrospective cohort design carried out at the Oncology Polyclinic at Haji Adam Malik Hospital from October 2020 to January 2021 in all patients with adenocarcinoma lung cancer who were treated with EGFR-TKI for more than 6 months. After that, an evaluation was carried out based on RECIST 1.1 and then examined for EGFR mutations from liquid biopsy specimens in the form of circulating tumor plasma DNA (ct-DNA) with the droplet digital Polymerase Chain Reaction (ddPCR) method to detect EGFR exon 20 T790M mutations as a marker of acquired resistance. Results: It was found that the majority of subjects were female (64.5%), aged 20-69 years (58%), and non-smokers (67.7%). The most common EGFR mutation was exon 19 deletion (58.1%). The incidence of acquired resistance was found in 10 subjects (32.3%). The distribution of RECIST 1.1 results on positive acquired resistance includes progressive diseases of 35.2%; stable disease of 11.1%; partial response of 33.4%; and 100% complete response. Negative acquired resistance includes 64.8% progressive disease, 88.9% stable disease, 66.6% partial response, and 0% complete response (P=0.93). Conclusion: There is no significant association between the incidence of acquired resistance mutations EGFR exon 20 T790M and treatment response in patients with lung adenocarcinoma who received EGFR-TKI therapy.

A Retrospective Study of Intrathecal Pemetrexed Combined With Systemic Therapy for Leptomeningeal Metastasis of Lung Cancer.

Objective This retrospective study aimed to investigate the clinical features of lung cancer patients with leptomeningeal metastasis (LM) and explore the clinical efficacy and tolerance of intrathecal pemetrexed (IP) combined with systemic antitumor therapy. Methods Thirty-four lung cancer patients (11 men, 23 women) with LM receiving IP at our hospital were retrospectively reviewed between August 2018 and December 2019. Identified cases showed either positive cerebrospinal fluid cytology or typical findings (leptomeningeal enhancement or ventricle broadening) upon imaging examination. Results Before the diagnosis of LM, 24 (70.6%) patients received EGFR-TKI therapy with or without other agents (antivascular therapy, or chemotherapy), 5 (14.7%) patients received chemotherapy, 1 (2.9%) patient received antivascular therapy, and 3 (8.8%) patients received ALK inhibitors. Fourteen (41.2%) patients did not change the systematic regimen at the beginning of IP, while 20 (58.8%) patients changed to antitumor agents. IP was administered for a median of 3 times (range, 1-12 times). The IP dose was 15, 20, 25, 30, and 40 mg in 8 (23.5%), 21 (58.8%), 2 (5.9%), 2 (5.9%), and 1 (5.9%) patient, respectively. In all IP dose levels, the major adverse events were myelosuppression and elevation of hepatic aminotransferases (EHA). Grade 1/2 myelosuppression occurred in 4 (11.8%) patients. Grade 1/2 EHA also occurred in 4 (11.8%) patients. Grades 3/4 adverse events were not observed. After IP and systematic therapy, the clinical manifestations related to LM in 26 (76.5%) patients improved. In the whole cohort, the median overall survival was 20 months. The median time from the initial IP administration until death or the last follow-up was 3.5 months. Conclusions IP showed controllable toxicity and good efficacy, prolonged the survival time, and improved the quality of life when combined with tailored systemic antitumor therapy in lung cancer patients.

Real-World Pattern of Treatment and Clinical Outcomes of EGFR-Mutant Non-Small Cell Lung Cancer in a Single Academic Centre in Quebec.

The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62–13.44) months for first-line treatment, and 4.4 (95% CI: 1.47–7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9–30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5–27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting.

P60.05 Radiomic Signature to Predict Outcomes in EGFR-Mutant Non-Small Cell Lung Cancer

Lung cancer with a detectable EGFR mutation represents between 15% and 50% of cases depending on the geographic area. There are currently 5 approved tyrosine kinase inhibitors (TKI), including first, second, and third generations. Although osimertinib is currently the standard of care, cost-effectiveness could be improved by identifying a subset of patients who will present longer progression-free survival (PFS) with other more accessible treatments. We propose a non-invasive approach based on radiomics and machine learning to identify these patients' risk of progression. We included histologically proven cases of NSCLC with confirmed EGFR mutations (exon 18, 19, and 21), from patients who started TKI-therapy between January 2012 and January 2020 and had a 12-months follow-up. The primary endpoint was PFS after 12 months of treatment, obtained from RECIST assessment in CT or from death cause. We performed manual volumetric segmentation of lung lesions in CT scans acquired before EGFR-TKI administration and extracted 70 radiomic features using three filter types, obtaining a total of 182 features per patient. We evaluated eight machine learning algorithms with several hyperparameters configurations using leave-one-out cross-validation (LOOCV). The models were compared with the mean accuracy across folds. A total of 44 patients with EGFR variant–positive NSCLC receiving EGFR-TKI therapy were included, of which 19 cases (44%) showed progression at 12 months (age at treatment start: 71 (14) years; 68% females; 16 on erlotinib, 2 on afatinib, 1 on osimertinib) and 25 (66%) presented PFS of more than 12 months (age at treatment start: 74 (9) years; 76% females; 16 on erlotinib, 4 on afatinib, 4 on osimertinib, 1 on gefitinib). The higher LOOCV accuracy was 0.71, obtained using a decision tree that showed a sensitivity of 88% in detecting PFS patients and a negative predictive value of 75% (22 true PFS, 9 true progressions). The selected decision tree used three radiomic features: median intensity in the unfiltered image, minimum intensity in the laplacian-filtered image (sigma=1) and difference entropy in the laplacian-filtered (sigma=3). Additionally, within the PFS group, a random forest classifier distinguished between patients with stable disease and cases of partial response with a mean accuracy of 0.84 on LOOCV. These preliminary results are a promising first step in adopting radiomic signatures as risk factors for treatment choice in NSCLC patients. A larger dataset is needed to increase the significance of results, and this will be achieved by following the methodology pipeline developed for this work: each new patient admitted to our institution for TKI therapy undergoes segmentation and radiomic extraction of the tumor in the baseline CT scan before starting treatment. Building a reliable dataset is a crucial step that opens the door for developing multiple predictive models. A multicenter study, guiding other health institutions to follow the proposed pipeline, would further increase predictive accuracy and robustness of results. This could enable a cost-effective, noninvasive preliminary identification of patients with advanced-stage variant-positive NSCLC who could benefit significantly from EGFR-TKI treatment.

Lazertinib: First Approval

Lazertinib (LECLAZA®) is an oral, third-generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed by Yuhan and Janssen Biotech for the treatment of non-small cell lung cancer (NSCLC). It is a brain-penetrant, irreversible EGFR-TKI that targets the T790M mutation and activating EGFR mutations Ex19del and L858R, while sparing wild type-EGFR. In January 2021, lazertinib received its first approval for the treatment of patients with EGFR T790M mutation-positive locally advanced or metastatic NSCLC who have previously received EGFR-TKI therapy. This article summarizes the milestones in the development of lazertinib leading to this first approval.

Epidermal Growth Factor Receptor Mutation Status and Response to Tyrosine Kinase Inhibitors in Advanced Chinese Female Lung Squamous Cell Carcinoma: A Retrospective Study.

BackgroundThe frequency of epidermal growth factor receptor (EGFR) mutations and the efficacy of tyrosine kinase inhibitor (TKI) in Chinese female patients with lung squamous cell carcinoma (SCC) are unknown. This study was designed to investigate the incidence of EGFR mutations and the role of targeted therapy in advanced Chinese female lung SCC patients.MethodsAdvanced female patients diagnosed with lung SCC at the Shanghai Chest Hospital between January 2013 and December 2018 were retrospectively analyzed.ResultsA total of 4223 advanced lung SCC patients were screened, and there were 154 female lung SCC patients who had underwent EGFR mutation detection. Positive EGFR mutations were found in 29.9% (46/154) of female lung SCC patients, including twenty-three 19del mutation (14.9%), twenty-one 21L858R mutation (13.6%) and other mutations (1.4%, 21861Q and 20ins). For 45 EGFR positive mutation female SCC patients, the median progression-free survival (PFS) of patients who received EGFR-TKI therapy (n=38) was 8.0 months (95% CI, 5.4-10.7 months), which was significantly longer than patients who were treated with chemotherapy (8.0 vs. 3.2 months, p=0.024), and the median overall survival (OS) was also longer (24.9 months vs. 13.9 months, p=0.020). The objective response rate (ORR) was 44.7% (17/38), and the disease control rate (DCR) was 81.6% (31/38). For 105 female SCC patients with EGFR negative mutation, the median OS was 18.6 months (95% CI, 14.2-22.9 months) and it was no different from that of EGFR positive mutation patients (18.6 vs. 22.8 months, p=0.377).ConclusionFor advanced Chinese female lung SCC patients with EGFR positive mutations, targeted therapy could confer longer PFS and OS than chemotherapy, but the survival was similar with patients who were negative EGFR mutations.

Changes of Brain Structure in Patients With Metastatic Non-Small Cell Lung Cancer After Long-Term Target Therapy With EGFR-TKI.

PurposeEpidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the routine treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring positive EGFR mutations. Patients who undergo such treatment have reported cognitive decline during follow-up. This study, therefore, aimed to evaluate brain structural changes in patients receiving EGFR-TKI to increase understanding of this potential symptom.MethodThe medical records of 75 patients with metastatic NSCLC (without brain metastasis or other co-morbidities) who received EGFR-TKI therapy from 2010 to 2017 were reviewed. The modified Scheltens Visual Scale and voxel-based morphometry were used to evaluate changes in white matter lesions (WML) and gray matter volume (GMV), respectively.ResultsThe WML scores were higher at the 12-month [8.65 ± 3.86; 95% confidence interval (CI), 1.60–2.35; p < 0.001] and 24-month follow-ups (10.11 ± 3.85; 95% CI, 2.98–3.87; p < 0.001) compared to baseline (6.68 ± 3.64). At the 24-month follow-up, the visual scores were also significantly higher in younger patients (3.89 ± 2.04) than in older patients (3.00 ± 1.78; p = 0.047) and higher in female patients (3.80 ± 2.04) than in male patients (2.73 ± 1.56; p = 0.023). Additionally, significant GMV loss was observed in sub-regions of the right occipital lobe (76.71 voxels; 95% CI, 40.740–112.69 voxels), left occipital lobe (93.48 voxels; 95% CI, 37.48–149.47 voxels), and left basal ganglia (37.57 voxels; 95% CI, 21.58–53.57 voxels) (all p < 0.005; cluster-level false discovery rate < 0.05).ConclusionsAn increase in WMLs and loss of GMV were observed in patients with metastatic NSCLC undergoing long-term EGFR-TKI treatment. This might reflect an unknown side-effect of EGFR-TKI treatment. Further prospective studies are necessary to confirm our findings.

Development and Validation of a Machine Learning Model to Explore Tyrosine Kinase Inhibitor Response in Patients With Stage IV EGFR Variant–Positive Non–Small Cell Lung Cancer

An end-to-end efficacy evaluation approach for identifying progression risk after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy in patients with stage IV EGFR variant-positive non-small cell lung cancer (NSCLC) is lacking. To propose a clinically applicable large-scale bidirectional generative adversarial network for predicting the efficacy of EGFR-TKI therapy in patients with NSCLC. This diagnostic/prognostic study enrolled 465 patients from January 1, 2010, to August 1, 2017, with follow-up from February 1, 2010, to June 1, 2020. A deep learning (DL) semantic signature to predict progression-free survival (PFS) was constructed in the training cohort, validated in 2 external validation and 2 control cohorts, and compared with the radiomics signature. An end-to-end bidirectional generative adversarial network framework was designed to predict the progression risk in patients with NSCLC. The primary end point was PFS, considering the time from the initiation of therapy to the date of recurrence, confirmed disease progression, or death. A total of 342 patients with stage IV EGFR variant-positive NSCLC receiving EGFR-TKI therapy met the inclusion criteria. Of these, 145 patients from 2 of the hospitals (n = 117 and 28) formed a training cohort (mean [SD] age, 61 [11] years; 87 [60.0%] female), and the patients from 2 other hospitals comprised 2 external validation cohorts (validation cohort 1: n = 101; mean [SD] age, 57 [12] years; 60 [59.4%] female; and validation cohort 2: n = 96, mean [SD] age, 58 [9] years; 55 [57.3%] female). Fifty-six patients with advanced-stage EGFR variant-positive NSCLC (mean [SD] age, 52 [11] years; 26 [46.4%] female) and 67 patients with advanced-stage EGFR wild-type NSCLC (mean [SD] age, 54 [10] years; 10 [15.0%] female) who received first-line chemotherapy were included. A total of 90 (26%) receiving EGFR-TKI therapy with a high risk of rapid disease progression were identified (median [range] PFS, 7.3 [1.4-32.0] months in the training cohort, 5.0 [0.6-34.6] months in validation cohort 1, and 6.4 [1.8-20.1] months, in validation cohort 2) using the DL semantic signature.The PFS decreased by 36% (hazard ratio, 2.13; 95% CI, 1.30-3.49; P < .001) compared with that in other patients (median [range] PFS, 11.5 [1.5-64.2] months in the training cohort, 10.9 [1.1-50.5] in validation cohort 1, and 8.9 [0.8-40.6] months in validation cohort 2. No significant differences were observed when comparing the PFS of high-risk patients receiving EGFR-TKI therapy with the chemotherapy cohorts (median PFS, 6.9 vs 4.4 months; P = .08). In terms of predicting the tumor progression risk after EGFR-TKI therapy, clinical decisions based on the DL semantic signature led to better survival outcomes than those based on radiomics signature across all risk probabilities by the decision curve analysis. This diagnostic/prognostic study provides a clinically applicable approach for identifying patients with stage IV EGFR variant-positive NSCLC who are not likely to benefit from EGFR-TKI therapy. The end-to-end DL-derived semantic features eliminated all manual interventions required while using previous radiomics methods and have a better prognostic performance.

Value of interim 18F-FDG PET/CT for predicting progression-free survival in stage ⅢB/IV EGFR-mutant non–small-cell lung cancer patients with EGFR-TKI therapy

ObjectivesWe retrospectively investigated the prognostic value of FDG-PET performed for patients with Stage ⅢB/IV EGFR-mutant non–small-cell lung cancer (NSCLC) receiving EGFR tyrosine kinase inhibitor (TKI) therapy. MethodsA total of 78 patients newly diagnosed with Stage ⅢB/IV EGFR-mutant NSCLC who received baseline and interim PET/CT examination and were treated with EGFR-TKI therapy were included. Interim PET was performed after 4–6 weeks of treatment. Cox proportional hazards regression analysis was used to assess the association between quantitative 18F-FDG PET/CT parameters, other clinicopathological factors and progression-free survival (PFS), non-durable clinical benefit (non-DCB). Five interim PET variables were analyzed in this study in the prediction of non-DCB. ResultsThe one-year and two-year progression-free survival rates of the patients were 33.9% (28.6–39.2%) and 20.7% (16.1–25.3%), respectively. Multivariable analysis indicated that interim PET relevant factors ΔSUVmax (p = 0.002, p = 0.014) and ΔSUVmean (p = 0.000, p = 0.030) were independent risk factors for predicting the PFS or non-DCB of patients receiving EGFR-TKI treatment. The optimal cutoff values of the parameters in the tumor survival analyses were 56.74% for ΔSUVmax (p = 0.002) and 36.48% for ΔSUVmean (p = 0.001). ΔSUVmax had the highest diagnostic value in the prediction of non-DCB. The one-year progression-free survival rates (95% confidence intervals) of patients with ΔSUVmax ≥ 56.74% and ΔSUVmax <56.74% were 59.5% (44.2–74.8%) and 5.7% (0.0–13.3%), respectively (p = 0.000). ConclusionAn early PET scan after 4–6 weeks can effectively predict the PFS and non-DCB of patients with Stage ⅢB/IV EGFR-mutant NSCLC receiving EGFR-TKI therapy.

Propensity score analysis of overall survival between first- and second-generation EGFR-TKIs using real-world data.

We constructed a data set of EGFR‐mutant non–small‐cell lung carcinoma (NSCLC) patients, and compared the overall survival of first‐generation (1G), and second‐generation (2G) EGFR‐tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR‐mutated NSCLC patients who received EGFR‐TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR‐TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR‐TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5‐33.5] in the 1G group (gefitinib, 32.0 [28.1‐35.8]; erlotinib, 27.5 [23.9‐31.7]), and 38.6 [32.2‐NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR‐TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR‐TKI was superior to that of the 1G EGFR‐TKIs, suggesting the potential of sequential therapy of 2G EGFR‐TKI followed by osimertinib. (HR 0.419, P = .0519) Real‐world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR‐TKI had a trend of longer OS compared with 1G EGFR‐TKIs.

BRAF fusion in lung cancer.

e21598 Background: BRAF was a part of RAS/MAPK pathway, which regulated the proliferation, differentiation, migration, and apoptosis of cells. BRAF V600E was a potential treatment target for non-small cell lung cancer and other tumors. While BRAF fusion was rare in lung cancer. Here we focus on BRAF fusion in lung cancer. Methods: We retrospectively reviewed next-generation sequencing (NGS) results of lung cancers, with or without treatment history. The samples were subjected to NGS using 59 or 1021-gene panel, which enables simultaneously assess snv, indel, rearrangements and cnv variations. Patients with BRAF fusion were collected and used to analysis. Results: We found eighteen lung cancers have BRAF fusion from about twelve thousand patients, 13 are females. The median age at diagnosis was 47-year old (range 28 to 70). Tested samples included 13 tissues, 5 plasma, and 2 pleural effusion. BRAF fusion could occur in different stage, 12 stage Ⅳ and 1 stage Ⅰ, other were unknown. There were 14 lung adenocarcinoma, 1 squamous cell carcinoma and 1 adenosquamous carcinoma, other two patients were unknown. The partner genes of BRAF fusion were distinctly among the patient, TRIM24 was relatively common. The median tumor mutation burden (TMB) was 4.8muts/Mb (range 0 to 15.4), with low TMB-H frequency (10.5%, defined 9 as cutoff value). Seven patients had no system treatment history, and 1 had concurrent EGFR L858R mutation. Nine patients received EGFR-TKI therapy, 1 received ALK-TKI therapy, and 1 received chemotherapy. Among the EGFR-TKI treated patients, 7 received first and third generation TKI sequential therapy, the median TTD (time to discontinue) of TKIs was 26 months (range 17 to 46). The EGFR mutation still exist when EGFR-TKIs resistance, included EGFR primary mutation, T790M, and C797S, concurrent with BRAF fusion. Except for BRAF fusion, there also had other complex resistance mechanism occurred, like HER2 mutation, KRAS mutation, etc. Conclusions: BRAF fusion had low frequency in lung cancer and occurred at different stage during disease development. BRAF inhibitors maybe a potential strategy for BRAF fusion lung cancers. As TKIs resistance mechanism, BRAF fusion is a huge clinical challenge, indicate the importance of further research.

Discovery of survival predictor and early monitoring biomarkers for EGFR tyrosine kinase inhibitor therapy in lung adenocarcinoma by integrative omics analysis

Epidermal growth factor receptor (EGFR) mutation is a predictor of the initial treatment efficacy of tyrosine kinase inhibitors (TKIs) in advanced lung adenocarcinoma (ADC). Unfortunately, neither EGFR mutations nor molecular markers can accurately monitor cancer progression or predict patient survival. EGFR‐TKI susceptibility‐associated biomarkers to benefit lung ADC patients are in high demand. Plural effusion (PE) has been recognized as a promising source for biomarker discovery. By integrating PE proteomic and tissue genomic analyses, we herein identified fifteen proteins as potential biomarkers of EGFR‐TKI resistance. Among these candidates, cadherin‐3 (CDH3) attracted our attention, as we observed that the CDH3 protein expression level was indeed positively correlated with malignancy as well as EGFR‐TKI resistance in our verified cancerous tissues, PEs and cell lines. Importantly, altered soluble CDH3 (sCDH3) levels in the serum could be used to monitor the efficacy of EGFR‐TKIs at one month after treatment. Furthermore, the baseline serum sCDH3 level was associated with progression‐free survival in ADC patients with mutant but not wild‐type EGFR. Finally, we observed that the baseline serum sCDH3 level was positively associated with tumor stage and overall survival in advanced non‐small cell lung cancer patients. Our results collectively establish a biomarker dataset for EGFR‐TKI resistance and sCDH3 is identified as a survival predictor and real‐time indicator of treatment efficacy in ADC patients received EGFR‐TKI therapy.Support or Funding InformationMinistry of Science and Technology, Taiwan, R.O.C. (108‐2320‐B‐182‐007‐MY3) and Chang Gung Medical Research Fund (CORPD1J0091, CMRPD1H0081‐3, CMRPD1H0641‐2, CMRPD1H0082 and BMRP894).

Circulating cell-free plasma tumour DNA shows a higher incidence of EGFR mutations in patients with extrathoracic disease progression

BackgroundNon-invasive monitoring of epidermal growth factor receptor (EGFR) mutations conferring sensitivity and resistance to tyrosine kinase inhibitors (TKIs) is vital for efficient therapy of lung adenocarcinoma (LADC). Although plasma circulating cell-free tumour DNA (ctDNA) is detectable at an early stage, the size of the tumour does not strongly correlate with concentration of whole cell-free DNA (cfDNA), including normal leucocyte DNA. We sought to examine the clinical features of patients with LADC whose cfDNA examination held clues for analysis of cancer genomics.MethodsForty-four plasma samples from 37 patients with LADC receiving EGFR-TKI therapy, including 20 who developed resistance, were prospectively subjected to droplet digital PCR-cfDNA analysis to detect EGFR mutations and analysed according to clinical features.ResultscfDNA samples from 28 (64%) of the 44 samples were positive for TKI-sensitive mutations. Samples from 19 (95%) of the 20 EGFR-TKI-resistant patients were positive for TKI-sensitive mutations. In 24 patients without TKI resistance, 7 (54%) of 13 patients with regional lymph node metastases, 4 (67%) of 6 patients with advanced T stage (T3 or T4) and 8 (57%) of 14 patients with extrathoracic disease progression were also positive for TKI-sensitive mutations. cfDNA analysis from patients with acquired TKI-resistance disease or extrathoracic disease progression correlated with a high detection rate of TKIsensitive mutations (acquired resistance: risk ratio=2.53, 95% CI 1.50 to 4.29; extrathoracic disease progression: risk ratio=5.71, 95% CI 0.84 to 36.74).ConclusionscfDNA in patients with EGFR-TKI-resistance or extrathoracic disease progression may be useful for analysis of cancer genomics.Trial registration numberUMIN 000017581.

Adverse Prognostic CT Findings for Patients With Advanced Lung Adenocarcinoma Receiving First-Line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapy.

The purpose of this study is to investigate adverse prognostic CT findings in patients with advanced-stage lung adenocarcinoma who are receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy as first-line therapy. We included 199 patients (71 men and 128 women; mean ± SD age, 64.3 ± 11.2 years) with stage IIIB or IV lung adenocarcinoma who received first-line EGFR-TKI therapy between January 2009 and December 2015. Clinical findings and imaging parameters on CT images obtained before TKI therapy were analyzed, including tumor size, TNM category according to the seventh edition of the American Joint Committee on Cancer lung cancer TNM staging system, tumor type, the presence of cavity or necrosis, pleural effusion, and metastasis to pleura, lung, and distant organs. Response evaluation was performed according to the Response Evaluation Criteria in Solid Tumor version 1.1 guidelines. Correlation of clinical and radiologic findings with durations of progression-free survival (PFS) and overall survival (OS) was evaluated using a Cox proportional hazard model. Pleural effusion (hazard ratio [HR], 2.095; 95% CI, 1.394-3.147; p < 0.001) and an N2 or N3 tumor category (HR, 2.145; 95% CI, 1.280-3.594; p = 0.004) were significantly associated with a short PFS duration in multivariate analysis. Older age (HR, 1.040; 95% CI, 1.014-1.067; p = 0.002), an N2 or N3 tumor category (HR, 2.427; 95% CI, 1.068-5.518; p = 0.034), pleural effusion (HR, 1.903; 95% CI, 1.105-3.276; p = 0.020), and distant metastasis (HR, 2.795; 95% CI, 1.356-5.765; p = 0.005) were associated with a short OS duration in multivariate analysis. Pre-TKI therapy CT findings of pleural effusion and high N-category tumors are associated with short durations of PFS and OS in patients with lung adenocarcinoma who are receiving EGFR-TKI therapy.

Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma.

ObjectiveWe previously reported that the staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS) and postoperative recurrence survival (PRS) has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database.Patients and methodsWe retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014.ResultsEGFR mutants (M) were detected in 16/56 patients (29%). The patients with EGFR M had a better OS than those with EGFR wild-type (WT) status (5-year survival: 50.3% vs 43.1, P=0.133). There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656), and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033). The 3-year PRS rate for patients with M/pathologic stage (p-stage) I–II (87.5%) was better than that for patients with M/p-stage III (60.0%), WT/p-stage I–II (52.7%), and WT/p-stage III (43.8%). There was a significant difference between patients with M/p-stage I and WT/p-stage I–II or WT/p-stage III (P=0.021 and 0.030, respectively). During the study period, of the 16 patients with mutants, 12 patients (75%) received EGFR-tyrosine kinase inhibitor (TKI) therapy and among the 40 patients with WT, no patient received EGFR-TKI therapy. Multivariate survival analysis showed that patients with EGFR-TKI therapy had a statistically significant association with favorable PRS (hazard ratio 0.271; 95% confidence interval 0.074–1.000; P=0.050).ConclusionEGFR status and p-stage were found to be essential prognostic factors for estimating PRS using this database. The recurrent patients with EGFR M and EGFR-TKI therapy had a statistically significant association with favorable PRS.

Prognostic value of plasma EGFR ctDNA in NSCLC patients treated with EGFR-TKIs.

ObjectiveEpidermal growth factor receptor (EGFR) specific mutations have been known to improve survival of patients with non-small-cell lung carcinoma (NSCLC). However, whether there are any changes of EGFR mutations after targeted therapy and its clinical significance is unclear. This study was to identify the status of EGFR mutations after targeted therapy and predict the prognostic significance for NSCLC patients.MethodsA total of forty-five (45) NSCLC patients who received EGFR-TKI therapy were enrolled. We identified the changes of EGFR mutations in plasma ctDNA by Amplification Refractory Mutation System (ARMS) PCR technology.ResultsIn the 45 cases of NSCLC with EGFR mutations, the EGFR mutation status changed in 26 cases, in which, 12 cases (26.7%) from positive to negative, and 14 cases (31.1%) from T790M mutation negative to positive after TKI targeted therapy. The T790M occurance group had a shorter Progression -Free-Survival (PFS) than the groups of EGFR mutation undetected and EGFR mutation turned out to have no change after EGFR-TKI therapy (p < 0.05).ConclusionsAccording to this study, it’s necessary to closely monitor EGFR mutations during follow-up to predict the prognosis of NSCLC patients who are to receive the TKI targeted therapy.

Abstract 5247: Predominance of EGFR mutations responsible for resistance to tyrosine kinase inhibitors among tumor DNAs assessed by picoliter droplet digital PCR analysis of cell-free plasma DNAs

Abstract Introduction &amp; Objectives: The new generation EGFR-tyrosine kinase inhibitors (TKIs), which suppress the kinase activity of EGFR proteins with secondary T790M substitution, are being developed to overcome resistance to therapy using conventional EGFR-TKI. Non-invasive monitoring of EGFR gene mutations conferring sensitive (i.e., L858R and various types of exon 19 deletion mutations) and T790M mutations to TKIs are inevitable for efficient therapy of lung adenocarcinoma (LADC) using conventional and/or new generation EGFR-TKIs. We aimed to evaluate the utility of picoliter droplet digital PCR (pdPCR)-based cell-free plasma DNA (cfDNA) examination to assess the tumor progression status of LADC patients against EGFR-TKI treatments. Experimental Design: cfDNAs from eight LADC patients acquiring resistance to EGFR-TKIs including gefitinib or erlotinib were subjected to pdPCR assay that enables us to assess fractions of EGFR DNAs with T790M, L858R and representative exon 19 deletion mutations among all EGFR DNAs. Each cfDNA sample was subjected to two pdPCR assays, one for T790M mutation and the other for either of TKI-sensitive exon 19 deletion or L858R mutation (determined before EGFR-TKI therapy). Mutation positivity was decided according to a threshold set based on cfDNAs from mutation-negative LADC patients, and fractions of T790M mutated EGFR DNAs among EGFR DNAs with TKI-sensitive mutations were estimated. The pdPCR assay for exon 19 deletion was designed to detect loss of the wild-type signal and therefore could detect exon 19 deletions of representative exon 19 in-flame deletion mutations while the L858R and T790M assays were designed to specifically detect DNA with corresponding single nucleotide variations. Results: All eight patients examined after acquiring resistance to EGFR-TKIs showed positivity for TKI-sensitive mutations, and five of them (62.5%) also for T790M mutations. The mutation status of cfDNAs from four patients was consistent with those of their re-biopsied tissues from the lesion acquiring resistance. T790M mutation was deduced to have occurred in a variety of fractions (7-97%) of tumor DNAs. Conclusions: pdPCR-based examination of cfDNAs will present a robust non-invasive assessment of tumor progression status against EGFR-TKI treatments by informing us of the predominance of T790M mutated DNAs among tumor DNAs. A prospective study to validate the utility of the pdPCR assay is on-going on patients with NSCLC receiving EGFR-TKI therapy. Citation Format: Yoshitaka Seki, Yutaka Fujiwara, Takashi Kohno, Erina Takai, Kuniko Sunami, Hidehito Horinouchi, Shintaro Kanda, Hiroshi Nokihara, Noboru Yamamoto, Shun-ichi Watanabe, Kazuyoshi Kuwano, Yuichiro Ohe. Predominance of EGFR mutations responsible for resistance to tyrosine kinase inhibitors among tumor DNAs assessed by picoliter droplet digital PCR analysis of cell-free plasma DNAs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5247. doi:10.1158/1538-7445.AM2015-5247