Treatment with palbociclib combined with letrozole resulted in significantly improved progression-free survival (PFS) compared with letrozole alone in patients with hormone receptor-positive metastatic breast cancer, according to a phase 2 trial presented at the American Association of Cancer Research Annual Meeting in San Diego, CA, on April 6, 2014.

Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6.

The study design comprised 2 parts. In part 1, researchers recruited 66 postmenopausal patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and, in part 2, they recruited 99 postmenopausal patients with the same diagnosis who had been found to have CCND1 amplification and/or loss of p16, which are markers of sensitivity to palbociclib. Patients continued to receive medication until disease progression, unacceptable toxicity, or withdrawal from the study, and their tumors were assessed every 2 months.1

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PFS in patients treated with palbociclib plus letrozole was almost double that of patients treated with letrozole alone: 20.2 versus 10.2 months (P=0.0004). There was a 51% reduction in the risk of disease progression in patients who received palbociclib.1

RELATED: Breast Cancer Resource Center

“This study grew out of a strong initial preclinical observation made a few years ago that hormone receptor-positive breast cancer cells are dependent on CDK-4/CDK-6 for their growth, and that these cancers are sensitive to inhibition of CDK-4/CDK-6,” said lead researcher Richard S. Finn, MD, associate professor of medicine at the University of California in Los Angeles.

The risk for disease progression did not decrease further in patients who were recruited in part 2 of the study, whose tumors had the molecular targets specific for the drug: risk decreased by 70% for those in part 1, compared with 49% for those in part 2. “The challenge with any targeted drug is identifying patients who are dependent on the target,” said Dr. Finn. “Having an intact Rb pathway seems to be the most critical factor for this drug to be effective, because most hormone-positive tumors are dependent on this pathway.”

Overall survival was 37.5 months in patients treated with palbociclib and letrozole and 33.3 months in patients treated with letrozole alone, a difference that was not significant.1

“A small lead-in phase 1 study conducted prior to this phase 2 trial showed that palbociclib and the antiestrogen drug letrozole could be given safely as a combination, with manageable side effects,” said Dr. Finn. The most common adverse events associated with palbociclib treatment were neutropenia, leukopenia, fatigue, and anemia. “It is important that we not only improve the efficacy of the compound, but also that we do not add an undue burden in toxicity, and we are happy that the drug was well tolerated overall.”

Two important reasons for the success of this trial, Dr. Finn explained, were that hormone receptor-positive/HER2-negative patients are more likely than other patients to benefit from palbociclib and that the compound is highly specific in its ability to block CDK-4 and CDK-6, leading to less toxicity.

Palbociclib is being tested in phase 3 trials in combination with letrozole (PALOMA-2) and fulvestrant (PALOMA-3) for late-stage, metastatic breast cancers, and in combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.


  1. Finn RS, Crown JP, Lang I, et al. Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) [Abstract CT101]. Presented at the American Association for Cancer Research, San Diego, CA, April 6, 2014.