1. Academic Validation
  2. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

  • Cancer Cell. 2015 Jul 13;28(1):70-81. doi: 10.1016/j.ccell.2015.05.010.
Helen Y Zou 1 Luc Friboulet 2 David P Kodack 3 Lars D Engstrom 1 Qiuhua Li 1 Melissa West 1 Ruth W Tang 1 Hui Wang 1 Konstantinos Tsaparikos 1 Jinwei Wang 1 Sergei Timofeevski 1 Ryohei Katayama 4 Dac M Dinh 1 Hieu Lam 1 Justine L Lam 1 Shinji Yamazaki 1 Wenyue Hu 1 Bhushankumar Patel 3 Divya Bezwada 3 Rosa L Frias 2 Eugene Lifshits 2 Sidra Mahmood 2 Justin F Gainor 2 Timothy Affolter 1 Patrick B Lappin 1 Hovhannes Gukasyan 1 Nathan Lee 1 Shibing Deng 1 Rakesh K Jain 3 Ted W Johnson 1 Alice T Shaw 2 Valeria R Fantin 1 Tod Smeal 5
Affiliations

Affiliations

  • 1 Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
  • 2 Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
  • 3 Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 4 Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
  • 5 Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA. Electronic address: tod.smeal@pfizer.com.
Abstract

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

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