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Positive Results Reported for Palbociclib Plus Letrozole in Patients With Advanced Breast Cancer

Combo therapy prolongs survival in mid-stage trial

Positive results have been reported from the PALOMA-1 trial, a randomized phase II study of palbociclib (Pfizer) in combination with the aromatase inhibitor letrozole (Femara, Novartis). The study achieved its primary endpoint by significantly prolonging progression-free survival (PFS) compared with letrozole alone in postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.

For women treated with the combination of palbociclib plus letrozole, the median PFS was 20.2 months, a statistically significant improvement compared with the 10.2 months of PFS in women who received letrozole alone (hazard ratio [HR], 0.488; P = 0.0004).

An initial assessment of overall survival (OS), a secondary endpoint, was also performed. A median OS of 37.5 months was observed in the combination-treatment arm versus 33.3 months for those who received letrozole alone — a difference of 4.2 months (HR, 0.813). This difference was not statistically significant.

The new data were presented April 6 at the American Association of Cancer Research (AACR) Annual Meeting 2014 in San Diego, California.

PALOMA-1 was a phase II trial designed to assess PFS in post-menopausal women with ER-positive, HER2-negative advanced breast cancer receiving palbociclib (125 mg once daily for 3 out of 4 weeks in repeated cycles) in combination with letrozole versus letrozole alone (2.5 mg once daily on a continuous regimen).

The trial consisted of two parts. Part 1 enrolled 66 patients with ER-positive, HER2-negative advanced breast cancer, and part 2 enrolled 99 additional patients whose tumors were selected for the presence of biomarkers (i.e., cyclin D1 amplification and/or p16 loss). The study’s final results showed that statistically significant improvement in PFS was achieved for the study arm (palbociclib plus letrozole) in both part 1 and part 2.

Palbociclib is an investigational oral targeted agent that selectively inhibits cyclin-dependent kinases (CDKs) 4 and 6 to regain cell cycle control and to block tumor cell proliferation.

Loss of cell cycle control is a hallmark of cancer, and CDK 4 and 6 are overactivated in numerous cancers, leading to the loss of proliferative control. CDK 4 and 6 are key regulators of the cell cycle that triggers cellular progression from the growth phase (G1) into phases associated with DNA replication. CDK 4 and 6, whose activity is often increased in ER-positive breast cancer, are key downstream targets of ER signaling in that disease. Preclinical data suggest that dual inhibition of CDK 4/6 and ER signaling is synergistic and can stop the growth of ER-positive breast cancer cell lines in the G1 phase.

Source: Pfizer; April 6, 2014.

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