title: PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models.
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.
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.affiliation: Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Kodack
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Lars D
authors.initials: LD
authors.lastname: Engstrom
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Li
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: West
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Ruth W
authors.initials: RW
authors.lastname: Tang
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsaparikos
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Dac M
authors.initials: DM
authors.lastname: Dinh
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Hieu
authors.initials: H
authors.lastname: Lam
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Justine L
authors.initials: JL
authors.lastname: Lam
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Bhushankumar
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Bezwada
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Frias
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Lifshits
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sidra
authors.initials: S
authors.lastname: Mahmood
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Affolter
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Lappin
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Hovhannes
authors.initials: H
authors.lastname: Gukasyan
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Lee
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Shibing
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Ted W
authors.initials: TW
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.affiliation: Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA. Electronic address: tod.smeal@pfizer.com.
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D007769:Lactams; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C000590786:lorlatinib