The combination of the investigational agent PD 0332991 and letrozole significantly improved median progression-free survival in patients with advanced estrogen receptor-positive breast cancer, according to results from this phase II study.

PD 0332991 is a novel oral selection inhibitor of cyclin-dependent kinase (CDK) 4/6 that prevents cellular DNA synthesis by blocking cell cycle progression. This compound is being developed by Pfizer, Inc. Previously published preclinical data suggested that CDK 4/6 inhibition may play a role in the treatment of some breast cancers.

The first part of this two-part, phase II study involved randomly assigning 66 postmenopausal women with metastatic estrogen receptor (ER)-positive breast cancer to either the combination of PD 0332991 and letrozole or to letrozole alone. The second part of the study involved 99 patients with ER-positive cancers determined by screening to have certain genomic alterations, specifically cyclin D1 amplification, p16 loss, or both.


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The results presented showed that progression-free survival was 26.1 months for those in the combination arm versus 7.5 months for those treated with letrozole alone. Among patients with measurable disease, the response rate was 45% with the combination treatment versus 31% with letrozole alone. The clinical benefit was 70% with the combination treatment and 44% with letrozole alone.

The combination of PD 0332991 was well tolerated. The most common adverse events were neutropenia, leukopenia, anemia, and fatigue. The lead author, Richard S. Finn, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, explained, “Importantly, this was uncomplicated neutropenia. There was no evidence of febrile neutropenia.”

Further, after retrospectively analyzing the biomarkers for cyclin D1 amplification or p16 loss, the researchers found that “ER positivity was the only biomarker we really needed to select patients who were most likely to benefit from PD 0332991,” he said.

“If these results are verified in a large, phase III study this could establish PD 0332991 as an important new treatment option for advanced ER-positive breast cancer in a frontline setting.”

This research was presented at the CTRC-AACR San Antonio Breast Cancer Symposium, held December 4-8, 2012.