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
  • 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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