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J. Zhao
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.13 - NGS Sequencing Based Liquid / Tissue Biopsy Identified Coexistence of HER2 Amplification and Mutation in Advanced NSCLC Patients (ID 9737)
17:05 - 17:10 | Author(s): J. Zhao
- Abstract
- Presentation
Background:
Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.
Method:
We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).
Result:
We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.
Conclusion:
HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.
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P1.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 703)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.17-001 - The Optimal First-Line Treatment for Advanced Thymic Carcinomas (ID 7493)
09:30 - 09:30 | Author(s): J. Zhao
- Abstract
Background:
Thymic carcinomas (TC) are remarkably rare aggressive tumors. Due to this, the optimal first-line regimen in patients with advanced TC has not been clarified since the previous studies included a relatively small number of TC patients. The purpose of this study was to evaluate the optimal first-line regimen in patients with advanced TC.
Method:
We conducted a retrospective study in patients with advanced TC from 2006 to 2015. The primary end point of this study was to evaluate the objective response rate (ORR) and progression free survival (PFS) of different chemotherapy regimens. Age, gender, stage (IVa or IVb), radiation therapy after chemotherapy, resection of primary lesion, different chemotherapy regimens and cycles of chemotherapy were analyzed for significance on PFS. Multivariate Cox model was used to identify significant factors.
Result:
Sixty-seven patients with stage IV (Masaoka stage) TC were enrolled. Thirty-six patients were treated with paclitaxel-platinum regimen every 3 weeks for a maximum of six cycles. Thirty-one patients were treated with gemcitabine-platinum regimen every 3 weeks for a maximum of six cycles. Resections of primary lesion were performed in fourteen patients before chemotherapy. Thirty-three out of 67 patients were given radiation therapy after chemotherapy. Multivariate analysis demonstrated that different stages (HR = 2.47, P = 0.003), surgical resection (HR = 0.32, P= 0.0049) and radiation therapy after chemotherapy (HR = 0.32, P= 0.0001) were significantly associated with PFS. The ORR were 31% (11/36) and 29% (9/31) in paclitaxel-platinum regimen group and gemcitabine-platinum regimen group (P=0.89), respectively. The median PFS, 1-/2-year PFS rates in paclitaxel-platinum regimen group were 7.0 (95% CI 4.0–8.0) months, 26%/6% respectively compared to 12 months (95% CI 11.2–24.0), 48%/24% in gemcitabine-platinum regimen group (P=0.03). The median PFS, 1-/2-year PFS rates were 18.0 (95% CI 12.0–36.0) months/7.3(95% CI 5.0–11.3) months, 57%/31% and 33%/7% for patients with and without resection of primary lesion (P = 0.0302). The median PFS, 1-/2-year PFS rates were 13.0 (95% CI 11.3–17.0) months/4.3(95% CI 3.0–7.3)months, 52%/22% and 20%/7% for patients with and without radiation after chemotherapy (P = 0.0013). Major adverse event was grade 3–4 neutropenia in both paclitaxel-platinum regimen (27.7%) and gemcitabine-platinum regimen group (12.9%). Grade 1-2 sensory neuropathy and/or muscle pain were seen in 25.0% of patients treated with paclitaxel-platinum regimen.
Conclusion:
Both gemcitabine-platinum and paclitaxel-platinum regimen showed promising efficacy in advanced TC. Resections of primary lesion and radiation after chemotherapy might be an option for selected patients.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-021 - A Multicenter, Non-Interventional Study on Real World EGFR Testing and in Patients with IIIB/IV NSCLC in Northern China (ID 8897)
09:30 - 09:30 | Author(s): J. Zhao
- Abstract
Background:
EGFR mutation plays a dominant role in the precise treatment of non-small cell lung cancer (NSCLC), and EGFR-TKIs has been recommended for patients with positive EGFR-sensitive mutation as a standard regimen in clinical practice. In China, application of EGFR-TKIs without knowing EGFR mutation status has been a common phenomenon due to various reasons including the vast territory, uneven distribution of medical resources, differences level of testing technology and others. Therefore, we prospectively conducted a real-world investigation to understand the actual situation of EGFR testing in Northern China, and identify the underlying causes affecting EGFR detection, in order to provide references to improve the standardized treatment.( NCT02620657)
Method:
The patients with IIIB/IV NSCLC who were firstly diagnosed or postoperative recurrence between 2014-1-1 and 2014-12-31 in 28 research centers of Northern China were analyzed. The primary endpoint was testing rate，the secondary endpoints were factors affecting EGFR testing, EGFR mutation status, detection methods and the survival outcomes of patients.
Result:
Among 2809 patients, 2250(90.78%) were adenocarcinoma, 208(7.40%) were squamous carcinoma, 51(1.82%) were other pathologic types. Testing rate was 42.54%(1195/2809) and was significantly related to city level (first-tier cities vs. new first-tier cities vs. second-tier cities vs. third-tier and above cities : 69.04% vs. 38.08% vs. 34.05% vs. 14.11%, P < 0.001), smoking status (never smoking vs. ever smoking vs. smoking: 45.42% vs. 51.10% vs. 33.37%, P<0.001), ECOG PS(0 vs.1vs.2vs.≥3:47.93%vs. 44.48vs.34.89%vs.20.37%, P=0.011), pathological type (adenocarcinoma vs. squamous carcinoma: 44.94% vs.19.23%, P=0.003) and medical insurance situation (social basic medical insurance vs. new rural cooperative medical insurance vs. own expense: 44.98% vs. 36.49% vs. 29.55%, P=0.001). EGFR sensitive mutation rate was 46.44%, the most common subtype was 19Del(42.16%), followed by L858R(40.00%), Exon 20 insertions(1.62%) and other subtypes(16.20%). The most common methodology is ARMS(63.77%), the second common one is DNA sequencing(5.36%). The 1-year and 2-year survival rate in patients receiving EGFR testing was 73.6%and 51.9%, compared with 64.3% and 43.7% respectively in patients without EGFR testing.
Conclusion:
There were regional differences in EGFR testing rates among IIIB/IV NSCLC patients in Northern China. The intention of doctors and patients, medical insurance coverage and differences technical level are major factors affecting the testing rate of EGFR. Approaches should be taken to improve the situation, such as strengthening the training, expanding the coverage of medical insurance, and relying on commercial gene detection companies, and further standardize the molecularly pathological diagnosis and treatment of NSCLC.
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P3.01-036 - A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 9251)
09:30 - 09:30 | Author(s): J. Zhao
- Abstract
Background:
In the Phase III LUX-Lung (LL) 3 and LL6 trials, first-line afatinib significantly improved PFS vs platinum-doublet chemotherapy in patients with EGFRm+ NSCLC (independent review; LL3: 11.1 vs 6.9 months, HR=0.58; p=0.001; LL6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). In the Phase IIb LL7 trial, afatinib significantly improved PFS and TTF vs gefitinib in patients with EGFRm+ NSCLC harboring common EGFR mutations (PFS, independent review: 11.0 vs 10.9 months, HR=0.73; p=0.017; TTF: 13.7 vs 11.5 months, HR=0.73, p=0.0073). Here we report interim analysis results of a large Phase IIIb study of afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC.
Method:
In this Phase IIIb trial with a similar setting to ‘real-world’ practice, EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from centers in China, Hong Kong, India, Singapore and Taiwan and received afatinib 40mg/day until investigator-assessed progression or lack of tolerability. Primary endpoint: number of patients with serious adverse events (SAEs). Secondary endpoints included: number of patients with afatinib-related AEs; time to symptomatic progression (TTSP). Other assessments included PFS (investigator review).
Result:
At data cut-off (13 Feb 2017) 479 patients were treated with afatinib (median age: 59.0 years; female: 52.4%; common [(Del19 and/or L858R) with or without uncommon]/uncommon only EGFR mutations: 86.0%/14.0%; ECOG PS 0/1: 19.8%/78.1%; brain metastases: 19.2%; 0/1/≥2 lines of prior chemotherapy: 59.7%/30.1%/10.2%. 24.8% of patients required dose reductions to 30mg; 6.1% had further reductions to 20mg. Median (range) treatment time was 9.7 months (0.2–38.6). SAEs were reported in 115 (24.0%) patients and afatinib-related SAEs in 29 (6.1%) patients. Grade ≥3 afatinib-related AEs occurred in 122 (25.5%) patients; diarrhea (n=50; 10.4%) and rash/acne (n=38; 7.9%) were the most common (≥5%). 18 (3.8%) patients discontinued treatment due to afatinib-related AEs. Median TTSP (15.3 months [95% CI: 13.4–17.5]) was 3 months longer than PFS (12.1 months [10.8–13.7]), suggesting afatinib may be continued beyond progression, and both were longer in patients with common (with/without uncommon) vs uncommon only EGFR mutations (PFS: 12.6 vs 9.1; TTSP: 15.8 vs 10.0 months).
Conclusion:
The safety data of afatinib from this interim analysis of a large-scale population of EGFR TKI-naïve EGFRm+ NSCLC patients are consistent with LL3/6/7 and confirm that most afatinib-related AEs are manageable and result in few treatment discontinuations. Afatinib also demonstrated encouraging efficacy in patients with common and uncommon EGFR mutations. Data from larger patient populations will be evaluated in further analyses of this trial.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-003 - ABCB1 3435C≫T Polymorphism Influences the Toxicity and Clinical Outcome of Patients with Taxane-Based Chemotherapy (ID 8071)
09:30 - 09:30 | Author(s): J. Zhao
- Abstract
Background:
Taxane-based chemotherapy including paclitaxel, docetaxel, paclitaxel-albumin was wildly used in solid tumors. ABCB1 (P-glycoprotein, multidrug resistance 1) is a trans-membrane protein that acts as an energy-dependent drug efflux pump for chemotherapeutic drugs, including taxanes. In addition, ABCB1 has been suggested to have a role in the prediction of treatment response and toxicity of chemotherapy in breast cancer, gastric cancer et.al. In this retrospective study, we explore the influence of ABCB1 polymorphism on toxicity and taxane-based chemotherapy.
Method:
118 patients (lung cancer 103, others 15) with taxane-based chemotherapy (paclitaxel 56 cases, docetaxel 55 cases, paclitaxel-albumin 7 cases) treatment were included in this study. Fluorescence in situ hybridization (FISH) was used for ABCB1 polymorphism detection. Statistical analysis was performed using SPSS 20.0.
Result:
The frequency of the ABCB1 3435 site homozygous mutation (TT genotype), heterozygous mutation (TC genotype) and wild type (CC genotype) was 11.0%(13/118) , 45.8%(54/118) and 43.2%(51/118) respectively. The occurrence of neurotoxicity was higher in patients had TT genotype (62.9%) compared with patients had TC (25.9%) and CC genotype (37.3%)(P=0.310). Especially in the docetaxol subgroup, the difference of chemotherapy-induced neurotoxicity was statistically significant (TT 75.0%, TC 9.5%, CC 11.5%, P=0.007). There was not significant difference between the three ABCB1 genotypes with regarding to other chemotherapy-induced toxicity, including diarrhea, constipation, leukocytes, neutrophils, anemia and thrombocytopenia. For non-small cell lung cancer (NSCLC) patients in this study, patient harboring ABCB1 3435 site CC genotype had longer median progression free survival (PFS) (5.1 months) than TC genotype (4.7 months) and TT genotype (2.6 months)(P=0.42). Especially in the paclitaxel subgroup (n=21), the median progression was significantly longer in patients with CC genotype when compared with TC and TT genotype (9.8 months vs. 4.5 months vs. 1.6 month, P=0.06). We failed to find the difference in either response rate or disease control rate between the different genotype, even in subgroup analysis.
Conclusion:
ABCB1 3435 site polymorphism is associated with neurotoxicity of taxane-based chemotherapy. It can also predict clinical outcomes for NSCLC.
