Virtual Library

Start Your Search

K. Yamada



Author of

  • +

    MINI 31 - ALK (ID 158)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • +

      MINI31.09 - Association of Crizotinib Toxicity with Pharmacokinetics and Pharmacogenomics in Non-Small Cell Lung Cancer Harboring ALK Fusion Gene (ID 464)

      18:30 - 20:00  |  Author(s): K. Yamada

      • Abstract
      • Presentation
      • Slides

      Background:
      Crizotinib, a standard care for advanced ALK-positive NSCLC, is a substrate for ABCB1-encoded P-glycoprotein, and is primarily metabolized by CYP3A4/5. The most common adverse events (AEs) are visual disorder, gastrointestinal disorders, and elevated transaminase levels. Serious AEs such as grade (Gr) ≥ 3 elevated transaminase levels and interstitial lung disease (ILD) occasionally develop.

      Methods:
      ALK-positive NSCLC patients were enrolled in cohort A (enrollment before starting crizotinib therapy) or cohort B (enrollment during crizotinib therapy). Trough concentrations of crizotinib at steady state were measured using LC/MS/MS and ABCB1 polymorphisms were analyzed. We evaluated clinically significant AEs, defined as Gr 4 hematological toxicity, Gr ≥ 3 non-hematological toxicity, or any ILD. AEs during 8 weeks were also evaluated prospectively on the patients enrolled in cohort A.

      Results:
      A total of 78 patients at 17 institutions were enrolled. In cohort A (n = 47), AEs which occurred in more than 40% of patients during 8 weeks were ALT increased (75.0%), visual disorder (47.2%), anorexia (45.5%), nausea (45.5%), and AST increased (43.2%). In both cohorts (n = 75), 26 clinically significant AEs (n = 25) were observed: Gr ≥ 3 elevated transaminase level (14.7%), ILD (4.0%), Gr 4 neutropenia (4.0%), Gr 3 thromboembolic event (4.0%), Gr 3 esophagitis (2.6%), and Gr 3 QTc prolongation (2.6%). There was one treatment-related death (1.3%) due to ILD. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance (38.4% vs. 19.2%, respectively; p = 0.09). Blood samples for trough concentrations of crizotinib at steady state were collected from 63 patients. The geometric mean of trough concentrations were 396 (95% CI, 325-483) ng/ml in male and 395 (95% CI, 329-474) ng/ml in female, respectively (p=0.569, Mann-Whitney U test). No clinical factors including gender, weight, body surface area, and age which influenced trough concentrations or AEs of crizotinib were identified. Moreover, the trough concentration of crizotinib was not significantly different between patient with clinically significant and without (429 [95% CI, 361-509] ng/ml vs. 378 [95% CI, 313-456] ng/ml, respectively [p=0.365]).

      Conclusion:
      In this multicenter study, we observed crizotinib AEs as previously reported. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance. Furthermore, we will present the association of clinically significant AEs and trough concentration with ABCB1 polymorphism.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      P2.04-091 - Digital PCR Analysis of Plasma Cell-Free DNA as a Noninvasive Detection of the Drug Resistance Mechanisms in EGFR Mutant NSCLC (ID 2613)

      09:30 - 17:00  |  Author(s): K. Yamada

      • Abstract
      • Slides

      Background:
      Although the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have shown dramatic effects against EGFR mutant non-small-cell lung cancer (NSCLC), patients demonstrate resistant by various mechanisms, such as second-site point mutation that substitutes methionine for threonine at position 790 (T790M) in EGFR, and amplification of mesenchymal-epithelial transition (MET) proto-oncogene and human epidermal growth factor receptor 2 (HER2). With the development of overcoming resistance to EGFR-TKIs, identification of the mechanisms of drug resistance is urgently needed. However, tumor samples for detecting the resistant mechanisms were not easily available in patients with EGFR mutation-positive NSCLC relapsed after EGFR-TKIs treatment. Here, we examined the correlation of T790M mutation, activating EGFR mutations, HER2 amplification, and MET amplification in relapsed NSCLC patients between plasma and tumor samples using digital PCR assay as an alternative and noninvasive method.

      Methods:
      A total of 18 patients obtained pairs of tumor and blood samples after resistance to EGFR-TKI treatment were enrolled in this study. T790M mutation, activating EGFR mutations, MET amplification, and HER2 amplification in relapsed NSCLC patients after EGFR-TKIs treatment were analyzed by digital PCR.

      Results:
      Digital PCR analysis of T790M mutation in plasma had a sensitivity of 81.8% and specificity of 85.7%, with the overall concordance between plasma and tissue samples 83.3%. Analysis of primary active mutation in plasma showed inconsistent results with lower sensitivity of 66.7% and concordance of 70.6% compared to those of T790M mutation. MET gene copy number gain of tumor DNA by digital PCR was observed in three patients. Of these patients, one patient exhibited positive for MET amplification by FISH, whereas no patient demonstrated MET and HER2 copy number gain in plasma DNA.

      Conclusion:
      Digital PCR analysis in plasma is feasible and accurate method for detecting the T790M mutation in NSCLC resistance to EGFR-TKIs treatment.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
    • +

      P3.01-068 - Phase II Study of S-1 plus Bevacizumab for Pretreated Patients with Non-Squamous NSCLC (ID 677)

      09:30 - 17:00  |  Author(s): K. Yamada

      • Abstract
      • Slides

      Background:
      The additional effects of bevacizumab (B) as first-line chemotherapy for non-squamous non-small cell lung cancer (Non-sq NSCLC) have been established. However, the efficacy of B in a second-line setting or further has not been clarified. It has recently become clear that S-1 (S), an oral fluoropyrimidine, is effective for advanced NSCLC, and S is now used with platinum as one of the standard forms of first-line chemotherapy. Furthermore, preclinical findings have suggested that the combination of S plus B is a promising treatment option.

      Methods:
      Non-sq NSCLC patients with an ECOG performance status of 0-2, and who had undergone prior platinum-based chemotherapy regardless of the use of B, were eligible for the study. S (80 mg/m[2]) was administered orally twice daily for 14 days, and B (15 mg/kg) on day 1 every 3 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS), and the planned sample size was 28 patients.

      Results:
      Between March 2012 and June 2014, 28 patients (14 males and 14 females; median age 62 years; PS 0/1/2: 21/7/0; Ad/Other: 26/2, EGFR mutation positive/wild type 12/16) were accrued from 4 centers in Japan. All 28 patients were included in analysis of efficacy and toxicity. With a median follow-up of 9.3 months, the median PFS was 3.2 months (95% CI: 2.2-4.0 months). Patients who had not received prior pemetrexed or who had shown a good response to prior chemotherapy tended to have a longer PFS (5.3 and 5.0 months, respectively), although this was not statistically significant. An objective response was observed in 4 patients (PR; 4, SD; 20, PD 4), the response rate and disease control rate being 14.3% and 85.7%, respectively. The treatment was well tolerated, the most common treatment-related side effects being anorexia (75%) and fatigue (68%).

      Conclusion:
      This is the first report to evaluate the efficacy and safety of SB. Although SB seems to have a higher tumor reduction effect than S alone for previously treated Non-sq NSCLC, this study failed to meet its primary endpoint. SB is well tolerated and no new toxicities were observed.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.