Phase I safety and pharmacokinetic study of YM155, a potent selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer

Cancer Chemother Pharmacol. 2020 Aug;86(2):211-219. doi: 10.1007/s00280-020-04112-1. Epub 2020 Jul 8.


Purpose: This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC).

Methods: The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed.

Results: Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8 mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients.

Conclusion: Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC.

Trial registration: UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).

Keywords: Anti-apoptotic agent; EGFR-mutant NSCLC; Phase I study; Survivin inhibitor; YM155.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Drug Resistance, Neoplasm / drug effects*
  • ErbB Receptors / antagonists & inhibitors
  • Erlotinib Hydrochloride / administration & dosage
  • Female
  • Follow-Up Studies
  • Humans
  • Imidazoles / administration & dosage
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Naphthoquinones / administration & dosage
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology*
  • Survivin / antagonists & inhibitors*


  • BIRC5 protein, human
  • Imidazoles
  • Naphthoquinones
  • Protein Kinase Inhibitors
  • Survivin
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • sepantronium

Associated data

  • UMIN-CTR/UMIN000031912