Next-generation PI3 Kinase Inhibitor Demonstrated Early Efficacy, Safety

April 7, 2013

GDC-0032, a potent, next-generation PI3 kinase inhibitor, demonstrated early signs of efficacy for patients with cancers driven by mutations in the PI3 kinase alpha gene, according to first in-human results presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“We’ve shown that this novel agent is well tolerated,” said Dejan Juric, M.D., lead investigator of the study at the Termeer Center for Targeted Therapies at Massachusetts General Hospital in Boston. “We’ve shown that the safety profile is favorable and that the side effects are predictable. Early results show that the drug has very promising activity, particularly in tumors that have activating mutations in PI3 kinase alpha.”

GDC-0032, which is being developed by Genentech, a member of the Roche Group, targets a family of molecules called PI3 kinases. The drug is distinguished by its enhanced in-vitro activity against the mutant form of the family member called PI3 kinase alpha, which is known to be present in approximately 40 percent of hormone receptor-positive breast cancers.

“We currently have no approved therapies that directly target this critically important component of cancer cells,” Juric said.

This phase Ia, multicenter, open-label study included 34 patients with locally advanced or metastatic solid tumors who received a once-daily dose of GDC-0032. Researchers tested five dosing cohorts: 3 mg, 5 mg, 8 mg, 12 mg and 16 mg.

The drug was well tolerated, and side effects consisted of hyperglycemia, diarrhea, fatigue and nausea. The only study-related grade 4 adverse event was hyperglycemia in the 16-mg dose cohort, according to Juric.

“Those are very common and predictable side effects,” he said. “In particular, hyperglycemia is a so-called ‘on-target’ side effect because PI3 kinase alpha plays an important role in glucose metabolism. All agents that effectively block PI3 kinase alpha lead to some level of glucose elevation.”

The results also showed that four of six patients with breast cancers driven by a PI3 kinase alpha mutation had a partial response according to RECIST criteria, which is an objective measure of tumor shrinkage, according to Juric. In addition, the researchers observed a partial response in one patient with lung cancer driven by a PI3 kinase alpha mutation, as well as objective tumor shrinkage in a patient with HER2-amplified breast cancer.   

“This trial is an important step forward in getting us closer to developing an agent that shuts down PI3 kinase alpha effectively,” Juric said. “It is impressive how frequently PI3 kinase alpha mutations are found in human cancers. This is one of the first agents to have shown selectivity and encouraging signs of efficacy when we target that particular mutation.”

Media Contacts: Katie Marquedant, (617) 726-0337,
Sue McGreevey, (617) 724-2764,