P76.77 Combination of EGFR-TKIs with Chemotherapy versus EGFR-TKIs alone in EGFR-Mutant Advanced NSCLC with Concomitant Genetic Alterations

9030 Background: Currently,EGFR-TKIs are widely accepted as the standard treatment for EGFR- mutant advanced non-small-cell lung cancer (NSCLC); however, acquired resistance is inevitable. Combination therapy is considered as a strategy to overcome the resistance to EGFR-TKIs. Anlotinib, a novel multi-targeting, small-molecule TKI, has shown active to suppress tumor angiogenesis and growth. However, there is still a lack of evidence supporting the use of EGFR-TKIs in combination with anlotinib for the treatment of NSCLC until now. A multi-center, single-arm, phase II clinical trial was therefore designed to examine the efficacy and safety of EGFR-TKIs combined with anlotinib for treatment-naïve, advanced NSCLC patients, and unravel the possible mechanisms. Methods: This study was conducted in 14 research centers in Fujian, China. The main eligibility criteria were stage IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion,, and L858R), ECOG score 0-2,and age 20 to 75 years and no previous systemic treatment. Patients with asymptomatic brain metastases were admitted.Eligible patients were given gefitinib (250 mg QD) or icotinib (125 mg TID) in combination with anlotinib (10 mg per day, on days 1‒14; 21 days per cycle) until disease progression. The primary endpoint is progression-free survival (PFS) and safety, and the secondary endpoint is overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Peripheral blood was sampled pre-treatment, once every two months during treatment and after disease progression, and T790M mutation was detected in plasma ctDNA using a droplet digital PCR (ddPCR) assay. Results: Of 60 patients enrolled (August 2, 2018 to May 28, 2020). As of February 1, 2021, 37 patients (61.7%) experienced PFS events and 10 (16.7%) died. The ORR was 78.3%, and the DCR was100%.Median PFS was 13.0 months (95%CI,10.7-15.3).The 5 most common treatment-related adverse events included rash (63.3%), fatigue (55.0%), hypertension (48.3%), diarrhea (33.3%) and hand-foot syndrome (30.0%), and grade 3 adverse events included hypertension (5.0%), rash (1.67%), hypertriglyceridemia (1.67%), vomiting (1.67%) and elevated ALT (1.67%); no grade 4 adverse events or drug-related deaths were observed. Peripheral blood samples were collected from 36 patients pre-treatment, and 30.6% were identified with low-frequency de novo T790M mutations, with the mutation-allele frequency (MAF) ranging from 0.01% to 0.28%. Conclusions: The combination of the first-generation EGFR-TKIs and anlotinib shows impressive ORR and DCR, and acceptable toxicity in treatment-naïve advanced NSCLC patients with activating EGFR mutations, and we observed a high proportion of patients harboring de novo EGFR T790M mutations in this study. Clinical trial information: NCT03720873.

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Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

Frontiers in Oncology ◽

10.3389/fonc.2020.610923 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yijia Guo ◽

Jun Song ◽

Yanru Wang ◽

Letian Huang ◽

Li Sun ◽

...

Keyword(s):

Lung Cancer ◽

Treatment Efficacy ◽

Genetic Alterations ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Egfr Mutant ◽

Egfr Tki ◽

Egfr Tkis ◽

Gene Alterations

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

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MA15.09 Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR Mutant Advanced NSCLC Patients Treated with First-Line EGFR-TKIs

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.08.445 ◽

2018 ◽

Vol 13 (10) ◽

pp. S409-S410

Author(s):

C. Su ◽

T. Jiang ◽

J. Zhao ◽

X. Li ◽

C. Zhou

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Predictive Value ◽

Advanced Nsclc ◽

Dynamic Monitoring ◽

First Line ◽

Egfr Mutant ◽

Nsclc Patients ◽

Egfr Tkis

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Dynamic monitoring and predictive value of circulating tumor cells in EGFR mutant advanced NSCLC patients treated with first-line EGFR-TKIs.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e21045 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e21045-e21045

Author(s):

ChunXia Su ◽

Tao Jiang ◽

Jing Zhao ◽

Chao Zhao ◽

Xuefei Li ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Predictive Value ◽

Advanced Nsclc ◽

Dynamic Monitoring ◽

First Line ◽

Egfr Mutant ◽

Nsclc Patients ◽

Egfr Tkis

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P3.02b-095 Tracing Spatiotemporal T790M Heterogeneity in Patients with EGFR-Mutant Advanced NSCLC after Acquired Resistance to EGFR TKIs

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2016.11.1762 ◽

2017 ◽

Vol 12 (1) ◽

pp. S1249

Author(s):

Yi-Chen Zhang ◽

Can Pi ◽

E-E Ke ◽

Zhi-Hong Chen ◽

Jian Su ◽

...

Keyword(s):

Advanced Nsclc ◽

Acquired Resistance ◽

Egfr Mutant ◽

Egfr Tkis

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Association of allele frequency of EGFR mutation with efficacy of EGFR TKIs in advanced non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20678 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20678-e20678 ◽

Cited By ~ 1

Author(s):

Xiang-Meng Li ◽

Jin-Ji Yang ◽

Yi-Long Wu

Keyword(s):

Lung Cancer ◽

Allele Frequency ◽

Advanced Nsclc ◽

Initial Response ◽

Small Cell ◽

Small Cell Lung ◽

High Group ◽

Significant Difference ◽

Egfr Mutant ◽

Egfr Tkis

e20678 Background: Next-generation sequencing (NGS) is beneficial to precision medicine. However, it remains elusive whether the epidermal growth factor receptor ( EGFR) mutant allele frequency (MAF) tested by NGS is predictive for tyrosine kinase inhibitors (TKIs) therapy in advanced non-small-cell lung cancer (NSCLC). Methods: We enrolled 194 advanced NSCLC EGFR mutant patients receiving erlotinib or gefitinib orally. A total of 196 baseline tissue samples from a phase III clinical trial (CTONG 0901; clinicaltrials.gov No.NCT01024413) between July 2009 and 2014 were analyzed by a panel of 168 lung cancer-related genes NGS. The median EGFR MAF was 25.8% (range, 1.4%-86.2%). Patients were divided into MAF low group (1.4%-25.8%) and high group (25.8%-86.2%). We defined PFS as the time of randomization to confirmed disease progression or death from any cause. OS was calculated from randomization to the last visit or death from any cause. Tumor response was assessed by investigators according to RECIST version 1.1. Survival was estimated using the Kaplan-Meier method. The relationship between the response of TKIs and EGFR MAF were evaluated by Pearson Chi-square test or Fisher’s exact test. Results: The median age was 58.7 years (range,31.2- 85.1), 92 (47.4%) were male, 41(21.1%) were smokers,189 (97.4%) had adenocarcinoma, 105 (54.1%) patients were identified as carrying EGFR exon 19 deletion, while one patient with the co-existence of T790M mutation. 85 (43.8%) patients harbored EGFR exon 21 L858R mutation. After 5 weeks of treatment, the initial response was assessed. No significant difference was observed in initial response between the high and low groups ( P = 0.502). The difference in best response to EGFR-TKIs between the groups was not significant ( P = 0.557). Objective response rate (ORR) was 56.2% and 57.5% respectively. There was no significant difference in median PFS [11.2 (95% CI,10.0 -12.3) vs 12.4 (95% CI,10.3-14.5) months, P = 0.509] between the groups. The high group was not significantly superior to the low group in median OS[20.5 (95% CI,18.0-23.0) vs 23.1 (95% CI,19.3-27.0) months, P = 0.500]. Conclusions: EGFR mutant allele frequency tested by NGS is not associated with the efficacy of EGFR TKIs in advanced NSCLC.

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Comprehensive Analysis of EGFR-Mutant Abundance and Its Effect on Efficacy of EGFR TKIs in Advanced NSCLC with EGFR Mutations

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2017.06.006 ◽

2017 ◽

Vol 12 (9) ◽

pp. 1388-1397 ◽

Cited By ~ 15

Author(s):

Xuefei Li ◽

Weijing Cai ◽

Guohua Yang ◽

Chunxia Su ◽

Shengxiang Ren ◽

...

Keyword(s):

Advanced Nsclc ◽

Comprehensive Analysis ◽

Egfr Mutations ◽

Egfr Mutant ◽

Egfr Tkis

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MET second-site mutations in EGFR-mutant, MET-amplified non-small cell lung cancer after resistance to combinatorial targeted therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20730 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20730-e20730

Author(s):

Jia-Tao Cheng ◽

Jinji Yang ◽

Yilong Wu

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Genetic Alterations ◽

Subsequent Treatment ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Mutant

e20730 Background: MET second-site mutations were previously reported in a few cases of MET-amplified or exon 14-mutant advanced non-small-cell lung cancer (NSCLC) treated with MET inhibitors. However, both the frequency of MET second-site mutations and clinical outcome of patients with such genetic alterations have not been investigated, particularly in EGFR-mutant, MET-amplified advanced NSCLC treated with combinatorial targeted therapy. Methods: Retrospectively, from November 2016 to January 2019, 22 patients with EGFR-mutant, MET-amplified advanced NSCLC had sufficient tumor samples after resistance to a combinatorial therapy with both EGFR and MET inhibitors. All tissue samples were detected using Next-generation sequencing (NGS). The progression-free survival (PFS) was calculated the start of subsequent treatment to progressive disease or death from any cause. The overall survival (OS) was calculated from the start of subsequent treatment to death from any cause. Last follow-up was on January 31, 2019. Results: Five kinds of MET second-site mutations were found in 7 patients: D1246N D1228N, D1228H, D1231Y and Y1230H. The frequency of MET second-site mutations was 31.8% (7/22). The median PFS and OS were 3.7 (95%CI: 1.13-6.3) months and 6.9 (95%CI: 0.2-13.7) months respectively. The ORR of EGFR TKIs plus cabozantinib for suchsecond-site mutaant patients was 50% (2/4). However, the ORR of other treatments was 0% (0/3), Two of them received single agent cabozantinib, and PFS was 0.7 and 1.7 months respectively. One had a PFS of 2.5 months with pemetrexed/carboplatin plus bevacizumab. Conclusions: MET second-site mutation might be one of the commonly-seen molecular mechanisms of acquired resistance to combinatorial targeted therapy in EGFR-mutant, MET-amplified advanced NSCLC. Patients with such mutations could respond to cabozantinib plus EGFR TKI. Further more investigations are warranted to improve the efficacy.

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