Format

Send to

Choose Destination
Cancer Cell. 2015 Jul 13;28(1):70-81. doi: 10.1016/j.ccell.2015.05.010. Epub 2015 Jul 2.

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

Author information

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.

PMID:
26144315
PMCID:
PMC4504786
DOI:
10.1016/j.ccell.2015.05.010
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center