The FDA granted accelerated approval to palbociclib for the treatment of estrogen receptor–positive, HER2-negative metastatic breast cancer in postmenopausal women who have not yet received endocrine-based therapy. Palbociclib is the first cell cycle–targeting CDK 4/6 inhibitor to reach the market.

The first of a novel class of cell cycle–targeting cancer medicines passed muster in early February, when Pfizer's palbociclib (Ibrance) won accelerated FDA approval. Palbociclib is indicated for use in combination with letrozole as a first-line hormonal therapy in postmenopausal women with locally advanced or metastatic HER2-negative, estrogen receptor (ER)–positive breast cancer. However, the drug still must prove that it prolongs overall survival.

Antiestrogens such as letrozole are the mainstay for treating this type of breast cancer, but tumor resistance is common and additional therapies are sorely needed. Palbociclib represents a new generation of medicines designed to rein in an out-of-control cell cycle.

The Pfizer pill selectively inhibits cyclin-dependent kinases (CDK) 4 and 6, which normally trigger cell growth and division. Two other CDK4/6 inhibitors—one from Novartis (LEE 001) and one from Eli Lilly (LY 2835219)—are also in clinical testing for breast tumors and other cancers.

Palbociclib's expedited FDA approval and designation as a “breakthrough therapy” were granted based on evidence that it doubled progression-free survival (PFS) in older women with advanced HER2-negative, ER-positive breast cancer. In the phase II PALOMA-1 study, women receiving the palbociclib–letrozole combination had a median PFS of 20.2 months, compared with 10.2 months in those who took letrozole alone. The final results were published in January (Lancet Oncol 2015;16:25–35).

Common side effects of palbociclib, including low white blood cell counts and upper respiratory infections, were “predictable and manageable,” the study authors reported.

However, the authors acknowledged the trial's limitations, such as its open-label design and reliance on investigators' assessments of tumor progression, rather than on assessments by a central panel of independent reviewers. Furthermore, PFS is a surrogate endpoint, so it is unclear whether palbociclib extends overall survival; PALOMA-1 did not track participants long enough to answer that.

The FDA's decision came with the caveat that continued approval of palbociclib “may be contingent upon verification and description of clinical benefit in an ongoing confirmatory trial.” Pfizer's phase III replication trial, PALOMA-2, is now under way, with final results due in October 2016.

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