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Kazuto Nishio
Author of
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-18 - A Multicenter Prospective Biomarker Study to Explore Mechanisms of Afatinib Resistance Based on Digita PCR and Next-Generation Sequencing (ID 12187)
16:45 - 18:00 | Author(s): Kazuto Nishio
- Abstract
Background
Afatinib is an oral irreversible blocker of ErbB-family kinases and shows a pronounced anti-tumor efficacy for advanced non–small cell lung cancer (NSCLC) positive for activating mutations of EGFR. We applied digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) to explore mechanisms of afatinib resistance.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations. Tumor and plasma samples were collected before afatinib treatment and after treatment failure with disease progression (systemic progressive disease, SPD). DNA from the samples was analyzed by dPCR and NGS.
4c3880bb027f159e801041b1021e88e8 Result
Thirty-five patients were enrolled, with a median follow-up time of 15.8 months. Among 25 patients with SPD, tumor, plasma, or both samples were available for 18, 23, and 16 individuals, respectively. dPCR and NGS detected EGFR T790M mutation in 13 (56.5%) and 11 (47.8%) of 23 plasma samples at SPD, with sensitivity and specificity compared with tumor samples being 83.3% and 70.0% (dPCR) and 50.0% and 70.0% (NGS), respectively. Applying the ratio of the number of T790M alleles to that of activating mutations (T/A) for determination of the T790M positivity improved the sensitivity and specificity of plasma analysis compared with tumor analysis to 83.3% and 100% (dPCR) and 57.1% and 100% (NGS), respectively. Among 25 patients with SPD, the T790M mutation of EGFR alone (n = 11), copy number gain (CNG) of NRAS (n = 1), CNG of MET (n = 1), CNG of EGFR plus T790M (n = 1), and CNG and E545K of PIK3CA plus T790M of EGFR (n = 1) were identified by NGS as putative resistance mechanisms against afatinib. No tumor showed transformation to small cell carcinoma. Median progression-free survival was longer in patients with than in those without T790M at SPD (15.1 versus 10.9 months, P =0.25). Median time to SPD was much longer in patients with than in those without T790M at SPD (17.9 versus 10.9 months, P =0.18).
8eea62084ca7e541d918e823422bd82e Conclusion
Assessment of T/A ratio with dPCR or NGS improved specificity of plasma analysis for determination of T790M positivity compared with tumor analysis. dPCR and NGS analysis in tumor and plasma samples shed light on exploring mechanisms of afatinib resistance.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-45 - Multifactorial Gene Alterations in EGFR Bypass Pathway are Induced by Afatinib in T790M-Mutant NSCLC Resistant to Osmertinib (ID 13247)
12:00 - 13:30 | Author(s): Kazuto Nishio
- Abstract
Background
The 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was developed to target the EGFR T790M resistance mutation in non-small cell lung cancer patients resistant to 1st or 2nd generation EGFR-TKIs. Although some mechanisms of acquired resistance to 3rd generation EGFR-TKI such as EGFR C797S mutation have been reported, the effect and resistant mechanisms to afatinib followed by osmertinib has not been well-known.
a9ded1e5ce5d75814730bb4caaf49419 Method
Nine patients with EGFR T790M-mutant NSCLC resistance to 3rd generation EGFR-TKI were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. Mutation profile and tumor mutation burden (TMB) in plasma cell free DNA (cfDNA) were analyzed by CAPP-seq.
4c3880bb027f159e801041b1021e88e8 Result
The objective response rate and median progression-free survival of afatinib were 0% and 2.0 months, respectively. At the time of 4 weeks after treatment, four patients developed disease progression and five patients showed stable disease. A total of 36 somatic mutations or amplification were detected in plasma cfDNA before afatinib treatment; EGFR activating mutations in 8 patients, T790M mutation in 4, TP53 mutations in 6, PIK3CA mutations in 3, BRAF mutations in 3, MET amplification in 3, CTNNB1 mutations in 2, ERBB2 mutations in 2, C797S mutation in 1, SMAD4 mutation in 1, EGFR minor mutation in 1, KRAS mutation in 1, and APC mutation in one patient. EGFR C797S mutation in cfDNA was detected during afatinib treatment in two cases. In the patients having stable disease at 4 weeks after treatment, mutant allele frequency and TMB tended to decline once, and then increased in association with disease progression.
8eea62084ca7e541d918e823422bd82e Conclusion
Detection of mutant allele frequency and TMB of ctDNA by CAPP-seq could monitor the effectiveness and resistance to afatinib. Resistant mechanisms to afatinib might be characterized by multifactorial bypass pathway activation.
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P3.01-75 - RELAY+, an Exploratory Study of Gefitinib with Ramucirumab in Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC (ID 12637)
12:00 - 13:30 | Author(s): Kazuto Nishio
- Abstract
Background
RELAY is a randomized, double-blind phase 1b/3 study investigating the efficacy and safety of the addition of ramucirumab (a human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor (VEGF) Receptor 2) to erlotinib (an EGFR TKI) in treatment-naïve EGFR-mutant metastatic NSCLC. Results from the Phase 1b cohort showed that combining ramucirumab with erlotinib was safe with encouraging clinical activity and a median PFS of 17.1mo (Reck et al., Clinical Lung Cancer 2017). While enrolment for the RELAY Phase 3 cohort has been completed, the RELAY+ cohort was recently added to explore the safety and efficacy of the combination of ramucirumab with gefitinib, a frequently used EGFR TKI in East Asia.
a9ded1e5ce5d75814730bb4caaf49419 Method
RELAY+ is an open-label, 2-period, single-arm exploration of the efficacy and safety of the addition of ramucirumab to gefitinib in previously untreated East-Asian patients with EGFR mutation-positive metastatic NSCLC (Period 1) and of ramucirumab to osimertinib in patients whose disease progressed in Period 1 and harbors the T790M mutation (Period 2). The trial is planned to be conducted in Japan, Taiwan and South-Korea and is currently open for enrollment. Approximately 80 patients will be enrolled.
In Period 1 patients will receive ramucirumab (10mg/kg) every two weeks and gefitinib (250mg/day) until disease progression, unacceptable toxicity or other withdrawal criteria are met. The study objectives are to determine the 1-yr PFS rate, safety and patient reported outcomes (Lung Cancer Symptom Scale and EQ-5D-5L]). In Period 2 the efficacy and safety of ramucirumab (10mg/kg) every two weeks with osimertinib (80mg/day) will be explored.
Both RELAY+ and RELAY participants will be enrolled in a liquid biopsy exploratory substudy. ctDNA (circulating tumor DNA) from plasma samples will be used for ddPCR (droplet digital PCR) and NGS (Next Generation Sequencing) to characterize mechanisms of acquired resistance and to test the hypothesis if the addition of ramucirumab to an EGFR TKI delays or modifies the emergence of EGFR TKI resistance.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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P3.01-96 - Clinical Characteristics of Non–Small Cell Lung Cancer Harboring Mutations in Exon 20 Of EGFR or HER2 (ID 11715)
12:00 - 13:30 | Author(s): Kazuto Nishio
- Abstract
Background
Unlike common epidermal growth factor receptor gene (EGFR) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non–small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene (HER2) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited.
a9ded1e5ce5d75814730bb4caaf49419 Method
Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon-20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel.
4c3880bb027f159e801041b1021e88e8 Result
Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR), and 12 patients harbored EGFR exon-20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2.
8eea62084ca7e541d918e823422bd82e Conclusion
Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2, and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations.
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