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J. He



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    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 09.06 - A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC (ID 8995)

      11:55 - 12:05  |  Author(s): J. He

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).

      Method:
      This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.

      Result:
      As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.

      Conclusion:
      These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-008 - Non-Invasive Diagnosis of Solitary Pulmonary Nodules Using High-Throughput Targeted DNA Methylation Sequencing of Circulating Tumor DNA (ID 9178)

      09:30 - 09:30  |  Author(s): J. He

      • Abstract

      Background:
      It remains a great challenge to differentiate solitary pulmonary nodules which might cause excessive medical care and unnecessary psychological burden. Disadvantages of previous image-based or invasive methods call for better diagnostic tools .

      Method:
      Based on several cohorts, we performed methylation profiling by high throughput bisulfite DNA sequencing in tissue samples to learn methylation patterns that differentiate cancerous from benign lesions by in-depth data mining. Then we filtered out methylation patterns exhibiting high background in cfDNA for plasma sample classification. Notably, given the usual low amount of ctDNA in plasma, we developed an ultra-sensitive library preparation method (AnchorIRIS[TM]) to perform targeted bisulfite DNA sequencing from as low as 1 ng of cell free DNA (cfDNA) or 1 mL of plasma.

      Result:
      In the training set (n = 230) which includes 129 malignant specimens with different subtypes (invasive adenocarcinoma, MIA, AIS, squamous carcinoma, small cell and large cell lung cancer) as well as 101 benign specimens in different categories (hamartoma, granuloma/tuberculosis, inflammation and infections), we were able to achieve a preliminary sensitivity of 94.3% ± 4.3% for identification of maglignacies, with a preliminary specificity of 93.6% ± 4.9% against all benign specimens. From an independent validation set of 145 plasma samples, this assay obtained a preliminary sensitivity of 78.5% and a preliminary specificity of 83.3% for differentiating patients with malignant tumor (n = 79) from patients with benign lesions and asymptomatic normal individuals (n = 66). Specifically, our assay is demonstrated to be highly sensitive towards early-stage lung cancer detection, with a preliminary sensitivity of 71.1% in 38 patients with stage Ia lung cancer and 87.5% in 16 patients with stage Ib lung cancer. To further confirm the clinical application of this model, an additional validation study was carried out in an independent center. Our assay obtained an overall sensitivity of 89.2% for 37 malignant tissue samples, particularly with a sensitivity of 100% for adenocarcinoma, and an overall specificity of 85.7% for 21 benign tissue samples. For plasma samples, our assay achieved a sensitivity and a specificity of 80% and 66.7% respectively for 20 malignant and 3 benign samples.

      Conclusion:
      We have developed a highly sensitive blood based non-invasive diagnostic assay for differentiation of solitary pulmonary nodules, which can aid clinical decisions for patients with a CT scan positive for lung nodules. To the best of our knowledge, this is the first study to examine the diagnostic value of high throughput targeted DNA methylation sequencing for early stage lung cancer.