2. Academic Validation
  3. 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: [email protected].
PMID: 26144315 DOI: 10.1016/j.ccell.2015.05.010
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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