Clinical significance of monitoring EGFR mutation in plasma using multiplexed digital PCR in EGFR mutated patients treated with afatinib (West Japan Oncology Group 8114LTR study)

9079 Background: First-line treatment of metastatic EGFR-mutated NSCLC relies on EGFR-TKIs. However, all patients (pts) eventually develop progression. Dual inhibition of EGFR with afatinib (A), an irreversible pan-erbB TKI, and cetuximab (C), an EGFR monoclonal antibody, has shown activity in EGFR-mutated pts with acquired resistance to TKIs, regardless of the T790M status. Methods: We conducted a phase II randomized trial in advanced NSCLC pts harboring an activating EGFR mutation, who had not received prior therapy. Pts were treated with A (40 mg/d) until progression alone or with C 500 mg/m² every 2 weeks during 6 months (mos) (beginning at D15 at 250 mg/m²). Primary endpoint was time-to-treatment failure (TTF) at 9 mos for pts with del19 and L858R mutations. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS). Prospective monitoring of the T790M mutation was performed on circulating tumoral DNA (ctDNA) by digital PCR. Results: Trial was stopped early due to futility analysis after 118 pts were enrolled (59 in each arm). Baseline characteristics were balanced between the 2 arms, and especially for the types of EGFR mutation (del19, 55.9 vs 50.8%; L858R, 39 vs 40.7%; others, 5.1 vs 8.5% in AC and A arms, respectively). Treatment-related AEs of any grades were similar, although there was an excess of grade 3 AEs in the AC arm (50 vs 37.3%), but no of grade 5. The excess in grade 3-5 AEs was essentially due to cutaneous (96.6 vs 81.4%), eyes (32.8 vs 27.1%), hematological (22.4 vs 15.3%) but not to digestive toxicities (89.7 vs 98.3%). Among the 117 pts included in the efficacy analysis, 9-months TTF was 63.3% (47.5-75.6) in arm A and 65.8% (50.1-77.66) in arm AC. Median TTF was 11.1 mos (8.3-not reached [NR]) and 10.8 mos (9.2-13.7) in arms A and AC, respectively. Median PFS was 11.1 mos (8.3-NR) and 12.8 mos (9.2-13.7), respectively. Median OS was 20.8 mos (17.5-NR) and NR (17-NR), respectively. Conclusions: Efficacy of AC was similar to that of A alone. These results don’t support further evaluation of this combination in this setting. Results of ctDNA monitoring will be reported during the meeting. Clinical trial information: NCT02716311.

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Abstract CT078: A prospective biomarker study using digital PCR method in EGFR-mutated, advanced lung adenocarcinoma patients treated with afatinib (West Japan Oncology Group 8114LTR)

10.1158/1538-7445.am2016-ct078 ◽

2016 ◽

Author(s):

Hiroaki Akamatsu ◽

Yasuhiro Koh ◽

Satoshi Morita ◽

Nobuyuki Yamamoto ◽

Kazuhiko Nakagawa

Keyword(s):

Lung Adenocarcinoma ◽

Digital Pcr ◽

Oncology Group ◽

Pcr Method ◽

Egfr Mutated

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1294P RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: Outcomes by EGFR mutation type

Annals of Oncology ◽

10.1016/j.annonc.2020.08.1608 ◽

2020 ◽

Vol 31 ◽

pp. S838 ◽

Cited By ~ 1

Author(s):

K. Nakagawa ◽

E. Nadal ◽

E.B. Garon ◽

M. Nishio ◽

T. Seto ◽

...

Keyword(s):

Egfr Mutation ◽

Metastatic Nsclc ◽

Egfr Mutated ◽

Mutation Type

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A phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected non-small-cell lung cancer with EGFR mutation (West Japan Oncology Group 11719L/ADJUST study)

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920987647 ◽

2021 ◽

Vol 13 ◽

pp. 175883592098764

Author(s):

Ryota Shibaki ◽

Hiroaki Akamatsu ◽

Terufumi Kato ◽

Kazumi Nishino ◽

Morihito Okada ◽

...

Keyword(s):

Lung Cancer ◽

Adjuvant Therapy ◽

Egfr Mutation ◽

Phase Ii Study ◽

Small Cell ◽

Small Cell Lung ◽

Resected Nsclc ◽

Egfr Mutated ◽

Doublet Chemotherapy ◽

Platinum Doublet

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with EGFR mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with EGFR-mutated NSCLC. Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with EGFR mutation. Accrued patients will be pathological stage II–IIIA with completely resected NSCLC and whose tumors have EGFR mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study. Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with EGFR mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.

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Phase I/II Study of Osimertinib With Bevacizumab in EGFR-mutated, T790M-positive Patients With Progressed EGFR-TKIs: West Japan Oncology Group 8715L (WJOG8715L)

Clinical Lung Cancer ◽

10.1016/j.cllc.2019.03.002 ◽

2019 ◽

Vol 20 (4) ◽

pp. e492-e494 ◽

Cited By ~ 3

Author(s):

Hiroaki Akamatsu ◽

Shunsuke Teraoka ◽

Satoshi Morita ◽

Nobuyuki Katakami ◽

Motoko Tachihara ◽

...

Keyword(s):

Phase I ◽

Oncology Group ◽

Egfr Mutated ◽

Egfr Tkis

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Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR -mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI

Lung Cancer ◽

10.1016/j.lungcan.2015.06.021 ◽

2015 ◽

Vol 89 (3) ◽

pp. 357-359 ◽

Cited By ~ 45

Author(s):

Samuel J. Klempner ◽

Lyudmila A. Bazhenova ◽

Fadi S. Braiteh ◽

Petros G. Nikolinakos ◽

Kyle Gowen ◽

...

Keyword(s):

Second Generation ◽

Egfr Mutation ◽

Ret Rearrangement ◽

Nsclc Patients ◽

Egfr Mutated ◽

Egfr Tki

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Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8501-8501

Author(s):

Hirohito Tada ◽

Tetsuya Mitsudomi ◽

Takeharu Yamanaka ◽

Kenji Sugio ◽

Masahiro Tsuboi ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Egfr Mutation ◽

Disease Free Survival ◽

Small Cell ◽

Stage Ii ◽

Small Cell Lung ◽

Significant Difference ◽

Egfr Mutated

8501 Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy. Clinical trial information: UMIN000006252.

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Cell membrane based biomimetic nanocomposites for targeted therapy of drug resistant EGFR-mutated lung cancer

Nanoscale ◽

10.1039/c9nr05791a ◽

2019 ◽

Vol 11 (41) ◽

pp. 19520-19528 ◽

Cited By ~ 9

Author(s):

Pengying Wu ◽

Dongtao Yin ◽

Jiaming Liu ◽

Huige Zhou ◽

Mengyu Guo ◽

...

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Targeted Therapy ◽

Cell Membrane ◽

Cancer Cell ◽

Egfr Mutation ◽

Drug Resistant ◽

Egfr Mutated

A cancer cell membrane-based biomimetic strategy was developed by loading doxorubicin and icotinib to overcome drug-resistance of EGFR-mutation lung cancer.

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R-Score: A New Parameter to Assess the Quality of Variants’ Calls Assessed by NGS Using Liquid Biopsies

Biology ◽

10.3390/biology10100954 ◽

2021 ◽

Vol 10 (10) ◽

pp. 954

Author(s):

Roberto Serna-Blasco ◽

Estela Sánchez-Herrero ◽

María Berrocal Renedo ◽

Silvia Calabuig-Fariñas ◽

Miguel Ángel Molina-Vila ◽

...

Keyword(s):

Egfr Mutation ◽

False Negative ◽

Digital Pcr ◽

Liquid Biopsies ◽

Molecular Alterations ◽

Significant Linear Correlation ◽

Molecular Landscape ◽

Nsclc Patients ◽

Next Generation Sequencing Ngs

Next-generation sequencing (NGS) has enabled a deeper knowledge of the molecular landscape in non-small cell lung cancer (NSCLC), identifying a growing number of targetable molecular alterations in key genes. However, NGS profiling of liquid biopsies risk for false positive and false negative calls and parameters assessing the quality of NGS calls remains lacking. In this study, we have evaluated the positive percent agreement (PPA) between NGS and digital PCR calls when assessing EGFR mutation status using 85 plasma samples from 82 EGFR-positive NSCLC patients. According to our data, variant allele fraction (VAF) was significantly lower in discordant calls and the median of the absolute values of all pairwise differences (MAPD) was significantly higher in discordant calls (p < 0.001 in both cases). Based on these results, we propose a new parameter that integrates both variables, named R-score. Next, we sought to evaluate the PPA for EGFR mutation calls between two independent NGS platforms using a subset of 40 samples from the same cohort. Remarkably, there was a significant linear correlation between the PPA and the R-score (r = 0.97; p < 0.001). Specifically, the PPA of samples with an R-score ≤ −1.25 was 95.83%, whereas PPA falls to 81.63% in samples with R-score ≤ 0.25. In conclusion, R-score significantly correlates with PPA and can assist laboratory medicine specialists and data scientists to select reliable variants detected by NGS.

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