First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non–Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance

Yuxiang Ma, Xin Zheng, Hongyun Zhao, Wenfeng Fang, Yang Zhang, Jieying Ge, Lu Wang, Weicong Wang, Ji Jiang, Shaokun Chuai, Zhou Zhang, Wanhong Xu, Xiao Xu, Pei Hu, Li Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Introduction: AC0010 is a mutation-selective, third-generation EGFR tyrosine kinase inhibitor (TKI). This aim of this first-in-human phase I trial was to determine the maximum tolerated dose, recommended phase II dose, schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AC0010 in patients with advanced or recurrent NSCLC and acquired resistance to a first-generation EGFR TKI. Methods: Patients received escalating daily doses of AC0010 (50–600 mg) throughout 28-day cycles. A modified three-plus-three design was applied. Patients with EGFR T790M mutation were selected by dose expansion. Next-generation sequencing of plasma cell-free DNA was performed before and after treatment to determine mechanisms of anticancer activity and underlying acquired resistance. Results: Data from 52 patients were reported. Common treatment-emergent adverse events were diarrhea (75%), skin rash (48%), and increased alanine transaminase level (44%); adverse events of grade 3 or higher were seen for increased transaminase level (12%) and skin rash (4%). The maximum tolerated dose was not reached. When all evaluated doses and patients negative for T790M were included, the overall response rate was 36.5%. At daily doses of 350 mg or higher, the overall response rate was 50.0% and the median progression-free survival estimated by the Kaplan-Meier method ranged from 14.0 to 35.6 weeks across a daily dose level from 350 mg to 600 mg. On the basis of pharmacokinetics data analysis, twice-daily administration is recommended and 300 mg twice daily is suggested as the recommended phase II dose. The cell-free DNA sequencing results from 17 patients indicate that T790M allele frequency decreased significantly after treatment with AC0010 (from 2.24 at baseline to 0 with a partial response or stable disease [p <.001]). In patients with development of resistance to AC0010, BRAF V600E mutation, ROS1 fusion, MNNG HOS Transforming gene (c-Met), and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification were detected but EGFR C797S mutation was not detected. Conclusions: AC0010 had a well-tolerated safety profile and promising antitumor activity in patients with NSCLC with acquired resistance to a first-generation EGFR TKI, supporting its continued development.

Original languageEnglish (US)
Pages (from-to)968-977
Number of pages10
JournalJournal of Thoracic Oncology
Issue number7
StatePublished - Jul 2018
Externally publishedYes


  • EGFR
  • T790M
  • cell-free DNA
  • next-generation sequencing

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine


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