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

Helen Y Zou1, Luc Friboulet2, David P Kodack3

  • 1Pfizer World Wide Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA.

Cancer Cell
|July 7, 2015
PubMed

Insights

PF-06463922, a novel anaplastic lymphoma kinase (ALK)/ROS1 inhibitor, shows potent activity against ALK mutations and brain metastases in preclinical models. This drug offers a promising new treatment option for ALK-driven lung cancers, especially in relapsed or brain metastatic cases.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Anaplastic lymphoma kinase (ALK) and ROS1 fusions drive certain lung cancers.
  • Existing ALK inhibitors face challenges with resistance mutations and brain metastases.
  • Novel therapeutic strategies are needed for advanced ALK-driven non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To evaluate the preclinical efficacy and safety of PF-06463922, a novel ALK/ROS1 inhibitor.
  • To assess PF-06463922's activity against known ALK resistance mutations.
  • To determine PF-06463922's effect on brain metastases and overall survival in preclinical models.

Main Methods:

  • In vitro biochemical and cellular assays to determine potency against ALK/ROS1 and mutations.
  • In vivo studies using patient-derived xenografts and genetically engineered mouse models.
  • Pharmacokinetic and safety assessments in preclinical species.

Main Results:

  • PF-06463922 demonstrated superior potency against a broad spectrum of ALK mutations, including G1202R.
  • Significant regression of EML4-ALK-driven brain metastases was observed.
  • PF-06463922 exhibited favorable selectivity and safety profiles in preclinical evaluations.

Conclusions:

  • PF-06463922 is a potent, brain-penetrant ALK/ROS1 inhibitor with promising preclinical data.
  • It shows potential efficacy in patients with ALK-driven lung cancers, including those with resistance mutations or brain metastases.
  • Further clinical investigation of PF-06463922 is warranted for ALK-positive NSCLC treatment.

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