Local ablative therapy (LAT) for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20545-e20545 ◽  
Author(s):  
Chul Kim ◽  
Nitin Roper ◽  
Chuong D. Hoang ◽  
Eva Szabo ◽  
Maureen Connolly ◽  
...  
Keyword(s):  
Disease Progression ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
T790m Mutation ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
A Prospective Study ◽  
Egfr Tki ◽  
Egfr Tkis

e20545 Background: EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to LAT in patients with oligoprogressive disease (progression at a limited number of anatomic sites). Methods: This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1st/2ndgeneration EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with < = 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva. Results: Between 04/2016 and 01/2017, 15 patients were enrolled (cohort 1: 9, cohort 2: 3, cohort 3: 3). Median age was 57 (range 36-71). Treatment was well tolerated. The most common adverse events (AEs) were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation. Grade 3/4 AEs were observed in 4 (27%) patients. Among evaluable patients, objective response rates prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively, with 6.8 months median PFS (95% CI: 3.4 months-undefined) in cohort 1 and no progressions in cohort 2. To date, 5 patients (33%; cohort 1: 2; cohort 3: 3) had LAT. Two patients with 3 progressing sites underwent a combination of surgery and radiation. Three patients with 1 progressing site underwent surgery alone. Post-LAT PFS and results of molecular analyses will be presented. Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In selected patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies. Clinical trial information: NCT02759835.

scholarly journals Prognostic Value of BIM Deletion in EGFR-Mutant NSCLC Patients Treated with EGFR-TKIs: A Meta-Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Fangfang Lv ◽  
Liang Sun ◽  
Qiuping Yang ◽  
Zheng Pan ◽  
Yuhua Zhang
Keyword(s):  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Deletion Polymorphism ◽  
Asian Populations ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

Background. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable in EGFR-mutant non-small-cell lung cancer (NSCLC) patients. A germline 2903 bp deletion polymorphism of Bcl-2-like protein 11 (BIM) causes reduced expression of proapoptotic BH3-only BIM protein and blocks TKI-induced apoptosis of tumor cells. Yet the association between the deletion polymorphism and response to EGFR-TKI treatment remains inconsistent among clinical observations. Thus, we performed the present meta-analysis. Methods. Eligible studies were identified by searching PubMed, Embase, and ClinicalTrials.gov databases prior to March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) of progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) and 95% CIs of objective response rate (ORR) and disease control rate (DCR) were calculated by using a random effects model. Sensitivity, metaregression, and publication bias analyses were also performed. Results. A total of 20 datasets (3003 EGFR-mutant NSCLC patients receiving EGFR-TKIs from 18 studies) were included. There were 475 (15.8%) patients having the 2903-bp intron deletion of BIM and 2528 (84.2%) wild-type patients. BIM deletion predicted significantly shorter PFS ( HR = 1.35 , 95% CI: 1.10-1.64, P = 0.003 ) and a tendency toward an unfavorable OS ( HR = 1.22 , 95% CI: 0.99-1.50, P = 0.068 ). Patients with deletion polymorphism had lower ORR ( OR = 0.60 , 95% CI: 0.42-0.85, P = 0.004 ) and DCR ( OR = 0.59 , 95% CI: 0.38-0.90, P = 0.014 ) compared with those without deletion. Conclusion. BIM deletion polymorphism may confer resistance to EGFR-TKIs and can be used as a biomarker to predict treatment response to EGFR-TKIs in EGFR-mutant NSCLC patients from Asian populations.

Monitoring of plasma pro-GRP level during EGFR-TKI treatment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10604-10604
Author(s):  
Yuko Kawano ◽  
Atsushi Horiike ◽  
Azusa Tanimoto ◽  
Toshio Sakatani ◽  
Ryota Saito ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Receptor Gene ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Patient Characteristics ◽  
T790m Mutation ◽  
Lung Cancers ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

10604 Background: Lung cancers harboring mutations in the epidermal growth factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but drug resistance invariably emerges. The major acquired mechanisms of resistance are the EGFR T790M mutation or MET gene amplification. Transformation from NSCLC into small-cell lung cancer (SCLC) has been recently identified in acquired resistance to EGFR-TKI. However, it is difficult to predict the transformation during EGFR-TKI treatment because obtaining serial and sufficient specimens for biopsy is difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels could predict SCLC transformation in resistance to EGFR-TKI. Methods: From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC who received EGFR-TKI treatment were enrolled. Plasma was obtained from these patients before EGFR-TKI treatment and when EGFR-TKI treatment failed. Pro-GRP and CEA levels were measured and compared before and after treatment. Results: Patient characteristics for 49 patients (15 men, 34 women) were as follows: median age, 62 years (41–81 years); histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 patients had received EGFR-TKI treatment (45 with gefitinib and 4 with erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the Pro-GRP levels had increased after treatment, but the CEA level did not increase. Objective responses to cytotoxic chemotherapy were noted in all 3 patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma Pro-GRP during EGFR-TKI treatment may be useful for early detection of SCLC transformation in resistance to EGFR-TKI.

Stereotactic body radiotherapy to the lung primary lesion improves the survival of patients with non-oligometastatic NSCLC harboring EGFR activating mutation with first-line EGFR-TKIs: A real-world study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21131-e21131
Author(s):  
Yongmei Liu ◽  
Hao Wei ◽  
Xiaojuan Zhou ◽  
Hui Yang ◽  
Youling Gong ◽  
...  
Keyword(s):  
Disease Progression ◽  
Real World ◽  
Primary Tumor ◽  
Maximal Response ◽  
First Line ◽  
Primary Tumors ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis

e21131 Background: This study aimed to explore the clinical value of SBRT for lung primary lesions of EGFR-mutant NSCLC patients with non-oligometastatic disease during first-line EGFR-TKI treatment. Methods: Patients with stage IV EGFR-mutant NSCLC and more than five metastases at diagnosis were identified. All patients were treated with first-line EGFR-TKIs and SBRT for their primary lesions. The primary end points were the progression-free survival-1 (PFS1, time of first TKI dose relative to disease progression based on RECIST), and PFS2 (time of first TKI dose relative to disease progression after SBRT). The secondary endpoints were overall survival (OS) and safety. Results: 79 patients were enrolled, including 45 patients who received SBRT for their primary tumor at the maximal response of EGFR-TKI (the preemptive RT group) and 34 patients who received SBRT for their primary tumor after the occurrence of oligo-progression (the delayed RT group). The preemptive RT group had a significantly better median PFS1 than the delayed RT group (22.3 months vs. 12.9 months, P = 0.0031). The median PFS2 in the preemptive RT and delayed RT groups were 22.3 and 28.9 months, respectively (P = 0.17). The median OS did not differ significantly between the preemptive RT group and the delayed RT group (46.6 versus 51.3 months, P = 0.54). No severe toxicities (≥ grade 3) were recorded. Conclusions: This real-world study showed that preemptive RT to lung primary tumors is a feasible option for patients with EGFR-mutant non-oligometastatic NSCLC who had stable disease during first-line EGFR-TKI treatment, with significantly improved PFS and OS.

scholarly journals The combination of fibrinogen concentrations and the platelet-to-lymphocyte ratio predicts survival in patients with advanced lung adenocarcinoma treated with EGFR-TKIs

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110040
Author(s):  
Qiong He ◽  
Yamin Li ◽  
Xihong Zhou ◽  
Wen Zhou ◽  
Chunfang Xia ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Characteristic Curve ◽  
Performance Status ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Platelet To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Egfr Mutant ◽  
Egfr Tkis

Objective This study aimed to identify a predictive marker of response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant advanced lung adenocarcinoma. Methods A cohort of 190 patients with EGFR-mutant advanced lung adenocarcinoma was analyzed. Receiver operating characteristic curve analysis was used to evaluate the optimal cutoffs for fibrinogen levels, the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) for predicting progression-free survival (PFS). Univariate and multivariate survival analyses were performed to identify factors correlated with PFS and overall survival (OS). Results High NLR was associated with worse performance status. In univariate analysis, fibrinogen levels, NLR, and PLR were correlated with OS and PFS. In multivariate analysis, all three variables remained predictive of OS, whereas only fibrinogen levels and PLR were independent prognostic factors for PFS. Furthermore, the combination of fibrinogen levels and PLR (F-PLR score) could stratify patients into three groups with significantly different prognoses, and the score was independently predictive of survival. Conclusion The F-PLR score predicted the prognosis of patients with EGFR-mutant advanced lung adenocarcinoma who received EGFR-TKIs, and this score may serve as a convenient blood-based marker for identifying high-risk patients.

Utility of a novel quantitative EGFR-mutated protein analysis using AQUA system for EGFR-TKI treatment in non-small cell lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18064-e18064
Author(s):  
Koichi Goto ◽  
Genichiro Ishii ◽  
Kaori Fujimoto-Ouchi ◽  
Masatoshi Shirane ◽  
Tatsuro Saito ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
New Technology ◽  
Objective Response ◽  
Response Duration ◽  
Protein Levels ◽  
Clinical Benefits ◽  
Tki Treatment ◽  
Low Sensitivity ◽  
Egfr Tkis

e18064 Background: Lung cancer carrying EGFR mutation (muEGFR) expresses good response to EGFR tyrosine kinase inhibitors (TKIs). However, not all patients (pts) with mutation showed similar clinical benefits from EGFR-TKIs. Heterogeneity of tumor cells is considered to be one plausible reason. MuEGFR was usually genotyped in qualitative manner in present clinical practice. In addition, new technology of AQUA system enables us to measure protein levels objectively with considering expression heterogeneity in tissues. Here we investigated the correlation between AQUA score obtained from each specimen and the response and the response duration by EGFR-TKIs. Methods: Slice sections from genotyped 105 pts with muEGFR and 33 pts with wild-type EGFR were stained by E746-A750 deletion (6B6)- and L858R (43B2)-specific antibodies. Homo- or heterogeneous staining and muEGFR protein levels of these specimens were evaluated with AQUA system. Results: Concordance rate between genotypes and AQUA-based phenotypes (deletion and L858R), with cut-off values based on ROC curve, were 60% and 82%. Low sensitivity of 6B6 was due to lucking of reactivity for other deletion variants. Alternatively, specificities of both antibodies were 96% and 92%, indicating highly selectivity to muEGFR protein. The AQUA score of 27 pts treated with EGFR-TKIs were varied (8.7 – 907.4) but the falls plot analysis indicated that pts with high AQUA score showed better objective response. Specimens of partial response (PR) had significantly higher AQUA score than those of progression disease (136.5 vs 9.8, p=0.014). When divided pts into two groups based on median AQUA score, the pts with high AQUA score showed a tendency of longer treatment duration (21 mo vs 14 mo, p=0.162). These results indicate that AQUA-based analysis can classify pts carrying genotyped muEGFR into susceptible and less susceptible ones to EGFR-TKIs. Conclusions: We observed that pts with high AQUA score were more sensitive to EGFR-TKIs. It is important for predicting sensitivity to EGFR-TKIs to investigate not only genotyping but also muEGFR protein levels by using AQUA system.

EGFR-TKI benefit for NSCLC patients with EML4-ALK rearrangement.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18035-e18035
Author(s):  
Zhijie Wang ◽  
Jie Wang ◽  
Yi Long Wu ◽  
Hua Bai ◽  
Xu-Chao Zhang ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Alk Rearrangement ◽  
Mutant Type ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki

e18035 Background: EML4-ALK rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). To identify the biological profiles of these patients, we examined the clinico-pathologic characteristics and treatment outcomes of NSCLC patients based on EML4-ALK and EGFR mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization (FISH) confirmed by immunohistochemistry (IHC), and EGFR mutations were determined using denaturing high-performance liquid chromatography (DHPLC). Results: Of the 151 patients screened, 113 had complete follow-up data as an analysis set. The incidence of EML4-ALK was 9.7% (11/113) using FISH, in which 10 cases had sufficient specimens for IHC confirmation and all were positive. Overall, EML4-ALK and EGFR mutations were largely mutually exclusive (p = 0.033), although two patients harbored concurrent mutations. EML4-ALK rearrangement was associated with resistance to EGFR-TKIs compared with the EGFR mutant type and WT/Nonrearrangement type (p = 0.001 for objective response rate; p = 0.004 for disease control rate; p = 0.021 for progression-free survival [PFS]). In terms of patients who received platinum-based doublet chemotherapy, no significant differences were observed in PFS between the EML4-ALK type, EGFR mutant type, and WT/Nonrearrangement type. Moreover, two patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared with single EML4-ALK-rearranged patients. Conclusions: This study presents several biological features of EML4-ALK NSCLC. It is largely mutually exclusive to EGFR mutations, resistant to EGFR-TKI. Coexistence of ALK rearrangement and EGFR mutation in patients with advanced NSCLC might represent a separate genotype with unique biological characteristics.

Understanding real-world outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20589-e20589
Author(s):  
Ancilla Fernandes ◽  
Karen E Skinner ◽  
Mark Stephen Walker ◽  
Melissa Pavilack ◽  
Ari M. Vanderwalde
Keyword(s):  
Treatment Period ◽  
Real World ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
2Nd Generation ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Tki Treatment ◽  
Egfr Tkis

e20589 Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) are recommended for patients (pts) with EGFR mutation ( EGFRm) positive non-small cell lung cancer (NSCLC). Limited data are available for real-world outcomes in pts who experience progression on 1st-/2nd-generation EGFR TKIs, which was the focus of this study. Methods: A retrospective chart review of pts with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed 1/1/2008—1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Pts were classified into cohorts based on TKI initiation (1L or 2L) and EGFRm status. Progression-free survival (PFS) and overall survival (OS) were evaluated for the TKI treatment period and the post-progression period. Results: The study included 364 pts: 77.7% white, 17.3% African American; mean (SD) age 66.3 (11.3) years. PFS and OS were longer for 1L and EGFRm+ pt cohorts during the TKI treatment period. After progression, 25.3% (80/316) pts continued TKI, while around half received chemotherapy (56.3%; 178/316). The effects of other variables evaluated as predictors of PFS and OS were largely nonsignificant. Conclusions: Outcomes were worse after progression irrespective of EGFRm status and whether TKI was initiated 1L or 2L. This finding highlights the need for therapeutic options that improve outcomes in pts after progression on a 1st-/2nd-generation EGFR TKI. [Table: see text]

Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9056-9056 ◽  
Author(s):  
Hiroe Kayatani ◽  
Keisuke Aoe ◽  
Kadoaki Ohashi ◽  
Hiroshige Yoshioka ◽  
Akihiro Bessho ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Her2 Protein ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr Tkis

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

scholarly journals Efficacy of EGFR-TKI Plus Chemotherapy or Monotherapy as First-Line Treatment for Advanced EGFR-Mutant Lung Adenocarcinoma Patients With Co-Mutations

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengyu Yang ◽  
Ya Chen ◽  
Yanan Wang ◽  
Shuyuan Wang ◽  
Minjuan Hu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
First Generation ◽  
Progression Free Survival ◽  
Poor Response ◽  
Time To Progression ◽  
Free Survival ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Generation Sequencing ◽  
Egfr Tkis

BackgroundCo-mutations was associated with poor response to EGFR-TKIs. First-generation EGFR-TKIs combined with chemotherapy was reported to be more effective than TKIs alone in advanced lung adenocarcinoma patients.ObjectiveThis retrospective study aimed to explore whether EGFR-mutant patients with co-mutations can benefit from EGFR-TKIs plus chemotherapy.Patients and MethodsWe retrospectively collected data of 137 EGFR-mutant patients with advanced lung adenocarcinoma who underwent next-generation sequencing in our hospital in 2018. Among them, 96 were treated with EGFR–TKIs alone and 41 received EGFR–TKIs plus chemotherapy. We analyzed the progression-free survival (PFS) of patients with co-mutations using different treatments.ResultsConcurrent TP53 mutations, especially exon 4 and 6, were associated with a markedly shorter time to progression on EGFR-TKI monotherapy (11.4 months vs. 16.6 months, P=0.003), while EGFR–TKIs plus chemotherapy would benefit those patients more (with TP53: 11.4 months vs. 19.1 months, P=0.001, HR=0.407; without TP53: 16.6 months vs. 18.9 months, P=0.379, HR=0.706). The incidence of T790M after resistance was equal in patients treated with different treatments (53% vs. 53%, P=0.985).ConclusionsIn our study, concurrent TP53 mutations were found to be risk factors for EGFR-TKI monotherapy, but TKI combined with chemotherapy could eliminate this heterogeneity.

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