CDK Inhibitor Triples PFS in Breast Cancer

Women with estrogen receptor (ER)–positive breast cancer who took an investigational drug targeting cyclindependent kinases 4 and 6 (CDK4/6) in combination with the aromatase inhibitor letrozole experienced a “dramatic and clinically meaningful effect,” researchers reported on December 5 at the 2012 Cancer Therapy and Research Center (CTRC) and American Association for Cancer Research (AACR) San Antonio Breast Cancer Symposium in Texas. Based on the positive results, these researchers expect to launch a phase III trial of the agent in 2013.

In the current phase II study, patients who took Pfizer's CDK4/6 inhibitor PD-0332991 with letrozole (Femara; Novartis) achieved a progression-free survival (PFS) period of 26.1 months compared with 7.5 months for patients who were treated with letrozole alone. “This was a welcome result,” commented Norman Sharpless, MD, deputy director of the Lineberger Comprehensive Cancer Center at the University of North Carolina (UNC) at Chapel Hill, who was not associated with the study. “A tripling of PFS in this disease is a great finding.”

CDKs, which participate in cell proliferation, tend to be overactive in cancer.

Richard Finn, MD, associate professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and the study's principal investigator, explained that the primary function of CDK4/6 is to phosphorylate the retinoblastoma (RB) protein, which ordinarily blocks early events in the cell cycle. Phosphorylation inactivates RB so that cells can continue to divide. In some cancers, however, CDK4/6 hypherphosphorylates RB, which can lead to uncontrolled cell growth.

By inhibiting CDK4/6, Pfizer's experimental drug prevents RB hyperphosphorylation. Moreover, Finn added, it has minimal side effects.

According to Finn, preclinical studies indicate that only ER-positive breast cancer cells had robust responses to PD-0332991. “ER positivity appears to be a marker for an intact RB pathway,” he said.

That's noteworthy, UNC's Sharpless added, given that RB loss occurs in roughly 10% of all cancers. “The drug won't work in patients who lack the RB pathway,” he noted, “so that gives us a good negative biomarker for who won't respond to treatment. What we need now is a better positive biomarker to identify those who might respond best in breast cancer and other cancer types.”

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