Investigational drug may overcome crizotinib resistance in lung cancers

The investigational drug PF-06463922 has the potential to become a new treatment option for patients who have lung cancer that harbors abnormalities in the ALK gene. These preclinical results were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts.

Approximately 3% to 5% of lung cancers harbor ALK gene abnormalities. Crizotinib (Xalkori) received FDA approval for the treatment of these lung cancers in August 2011. The drug blocks ALK protein kinase activity. Although robust responses to crizotinib are observed in lung cancers harboring ALK gene abnormalities, most of these cancers eventually become resistant to the effects of the drug. In many cases, resistance arises because of genetic mutations in ALK.

"Resistance to targeted therapies such as crizotinib is a major challenge when treating patients with cancer," said Tod Smeal, PhD, associate research fellow in the Oncology Research Unit at Pfizer Inc in San Diego, California. Pfizer is developing PF-06463922. “Our goal is to take advantage of everything we have learned about designing drugs that target kinases like ALK and the ways in which lung cancers become resistant to crizotinib to develop the best next-generation ALK inhibitor we can.

"Our preclinical studies suggest that we are making progress toward achieving our goal: PF-06463922 has potent ALK-inhibiting activity, it is capable of inhibiting all the crizotinib-resistant ALK mutants so far detected in patients, and it can efficiently access the brain. We are excited about these preclinical results and very hopeful that they will translate into meaningful responses in the clinic."

After carefully designing PF-06463922, Smeal and colleagues first showed in cell assays that it potently inhibited the activity of ALK and all eight of the mutant forms of ALK known to cause resistance to crizotinib in patients with lung cancer. They then showed that PF-06463922 inhibited the growth of tumors harboring three of the crizotinib-resistant ALK mutants, including the most resistant ALK mutant, G1202R, in mice.

Further analysis indicated that PF-06463922 readily entered the brains of mice, rats, and dogs. In mice, levels of PF-06463922 in the brain were 20% to 30% of the levels of the investigational drug in the brain. This is potentially clinically relevant because a significant number of lung cancer patients will develop brain metastasis during the course of their disease, according to Smeal, although he noted that it will be important to see if these results in animals hold true in humans.

Smeal and colleagues also found that PF-06463922 potently inhibited the protein ROS1, a close relative of ALK recently implicated in a number of cancer types, including some lung and brain cancers. Further, PF-06463922 had antitumor effects in two mouse models of cancers driven by ROS1 gene abnormalities, leading the researchers to suggest that PF-06463922 has potential as a treatment for this subgroup of cancers, in addition to its promise as a new treatment for ALK-driven cancers.

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