A promising hope...

• Combination improved progression-free survival and was well tolerated.
• Investigational agent is an oral selective inhibitor of cyclin-dependent kinase 4/6.

SAN ANTONIO — 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 phase II results presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held here Dec. 4-8.

“We are very encouraged by this improvement in progression-free survival,” said Richard S. Finn, M.D., associate professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. 

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

In the first part of this two-part, phase II study, Finn and colleagues randomly assigned 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 and/or p16 loss, according to Finn. 

Results showed that progression-free survival was 26.1 months for those in the combination arm versus 7.5 months for patients treated with letrozole alone. There was also a 45 percent response rate with the combination treatment versus 31 percent with letrozole alone in patients with measurable disease. The clinical benefit rate was 70 percent with the combination treatment and 44 percent with letrozole alone.

The combination of PD 0332991 and letrozole was also well tolerated. The most common adverse events were neutropenia, leukopenia, anemia and fatigue. “Importantly, this was uncomplicated neutropenia,” Finn said. “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.”