Advancements in ALK Inhibitors: The Emergence of PF-06463922 as a Promising Therapeutic for Overcoming Resistance in Lung Cancer

The abstract discusses the development and efficacy of a new ALK/ROS1 inhibitor, PF-06463922, which is designed to combat resistance to the first-generation ALK inhibitor, crizotinib (XALKORI), in non-small cell lung cancer (NSCLC) patients. This novel compound has shown to be potent and selective against all known acquired mutations that confer resistance to XALKORI. Importantly, it can penetrate the blood-brain barrier, which is crucial given the prevalence of brain metastases in these patients.

In vitro studies have demonstrated that PF-06463922 inhibits the catalytic activity of ALK and its mutant forms with high potency, as well as the growth of NSCLC cells with ALK fusions. In vivo, the compound has shown significant tumor reduction in mice with various ALK fusions at low concentrations, along with increased apoptosis and reduced cell proliferation in tumors.

Furthermore, PF-06463922 has been shown to achieve substantial brain exposure and to significantly regress brain tumors in mice with orthotopic brain tumor implants. The compound's antitumor effects are dose-dependent and are linked to the inhibition of ALK phosphorylation and its downstream signaling pathways.

The research indicates that PF-06463922 is the most potent ALK inhibitor reported to date, with potential for treating ALK fusion-positive cancers, especially in patients who have relapsed after XALKORI therapy due to ALK kinase domain mutations or brain metastases. The study was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2013.