Resistance mechanis of molecular targeted therapy and tumor micro environment as the immune-checkpoint inhibitor's biomarker

• Project/Area Number: 16K21506
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor diagnostics; Medical genome science
• Research Institution: Kindai University
• Principal Investigator: HAYASHI Hidetoshi 近畿大学, 医学部, 講師 (10548621)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: バイオマーカー / 個別化医療 / 免疫チェックポイント阻害薬 / 免疫チェックポイント / 免疫チェックポイント阻害剤 / 分子標的治療薬

Outline of Final Research Achievements

The efficacy of PD-1 blockade in EGFR mutated NSCLC with different mechanisms of acquired resistance to EGFR-TKIs is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations.
Efficacy of nivolumab tended to increase as the PD-L1 expression level increased with cutoff values of 10% and 50%.The proportion of tumors with a PD-L1 level of10% or50% was higher among T790M-negative patients than among -positive patients. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level.

Research Products

• [Journal Article] Tumor Immune Microenvironment and Nivolumab Efficacy in EGFR Mutation-Positive Non-Small Cell Lung Cancer Based on T790M Status After Disease Progression During EGFR-TKI Treatment (2017)
  • Author(s): K. Haratani, H. Hayashi*, T. Tanaka, H. Kaneda, Y. Togashi, K. Sakai, K. Hayashi, S. Tomida, Y. Chiba, K. Yonesaka, Y. Nonagase, T. Takahama, J. Tanizaki, K. Tanaka, T. Yoshida, K. Tanimura, M. Takeda, H. Yoshioka, T. Ishida, T. Mitsudomi, K. Nishio and K. Nakagawa
  • Journal Title: Annals of Oncology Volume: in press Issue: 7 Pages: 1532-1539
  • DOI: 10.1093/annonc/mdx183
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 肺癌におけるEGFR遺伝子変異と免疫チェックポイント阻害薬 (2017)
  • Author(s): 林秀敏、光冨徹哉
  • Journal Title: 癌と化学療法 Volume: 未定
• [Presentation] EGFR遺伝子変異陽性非小細胞肺癌におけるEGFR-TKI耐性後T790M変異有無によるニボルマブ治療効果と腫瘍微小免疫環境の後向き検討 (2017)
  • Author(s): 原谷浩司、林秀敏、田中妙、金田裕靖、冨樫庸介、坂井和子、吉岡弘鎮、光冨徹哉、西尾和人、中川和彦
  • Organizer: 第15回日本臨床腫瘍学会学術集会