(ChemotherapyAdvisor) – Adding the investigational cyclin-dependent kinase (CDK) inhibitor PD 0332991 to letrozole therapy significantly prolongs progression-free survival (PFS) among women with advanced estrogen receptor-positive (ER+) breast cancer, according to data from a randomized phase 2 clinical trial, presented during the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS).

“The combination of PD 0332991 and letrozole is well tolerated and shows encouraging clinical benefit, confirming the sensitivity of ER+ BC to PD 0332991,” reported lead author Richard S. Finn, MD, associate professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

PD 0332991, an investigational oral selective inhibitor of CDK 4/6 under development by Pfizer Inc., blocks cell cycle progression in effort to prevent DNA synthesis, Dr. Finn and his coauthors noted.

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The authors’ two-part phase 2 study first enrolled 66 postmenopausal women diagnosed with ER+/HER2- advanced breast cancer, randomizing them to receive either letrozole alone (2.5 mg every day) or letrozole plus PD 0332991 (L+P; 125 mg every day, on a schedule of 3 weeks on treatment followed by 1 week off treatment). For Part 2 of the study, 99 additional patients with ER+ breast cancers harboring genomic alterations (cyclin D1 amplification and/or p16 loss) were enrolled.

Preliminary results from Part 1 of the study were previously reported in May 2012, and showed better median PFS among patients who received L+P than among patients in the letrozole-only study arm (HR 0.35, 95% CI, 0.17-0.72; P=0.006), the researchers noted.

“With the additional 99 patients randomized in Part 2 (n=165), the statistically significant improvement in median PFS (26.2 vs. 7.5 months, respectively) continues to be observed” among L+P patients (HR 0.32, 95% CI, 0.19-0.56; P<0.001), they reported.

The response rate for the 84 patients in the L+P study arm was 31%, compared to 26% for the 81 patients in the letrozole-only arm, Dr. Finn and coauthors reported. The clinical benefit rates were 68% and 44%, respectively.

“ER positivity was the only biomarker we really needed to select patients who were most likely to benefit from PD 0332991,” Dr. Finn reported.

The combination treatment was well tolerated and there was “no evidence of febrile neutropenia,” he noted. “The most commonly reported treatment-related AEs in the combination arm were neutropenia, leucopenia, anemia, and fatigue.”

A phase 3 trial is scheduled to begin in 2013.

SABCS Meeting Website