Pfizer Inc. has presented randomized phase II data that showed PD-0332991 (PD-991) in combination with letrozole significantly extended progression free survival (PFS) compared with letrozole alone in post-menopausal patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer. For patients treated with the combination of PD-991 plus letrozole, median PFS was 26.1 months, a statistically significant improvement compared to the median PFS in women who received letrozole alone, which was 7.5 months (HR=0.37 [95% CI: 0.21, 0.63]; P <0.001).

These data were presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS).

“These results are especially important because of the magnitude of clinical effect observed and the fact that PD-991 represents a potential first-in-class compound. Based on these positive phase II data, Pfizer is planning to open a randomized phase III study of PD-991 in this patient population in 2013,” said Dr Mace Rothenberg, senior vice president of clinical development and medical affairs for Pfizer’s Oncology Business Unit. “We are working with regulatory authorities to advance the development of this promising compound in the most expeditious and responsible way.”

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide. Estrogen receptor positive, HER2- breast cancer represents approximately 60 per cent of all cases of breast cancer. Despite currently available treatments, survival rates for advanced or metastatic breast cancer remain low.

The focus of phase II evaluation of PD-991 was to measure the clinical activity of PD-991 in combination with letrozole versus letrozole alone in post-menopausal women with ER+, HER2- locally advanced or metastatic breast cancer. In Part 1, 66 patients were enrolled. Preliminary results were presented in May 2012 at the IMPAKT Breast Cancer Conference in Brussels, Belgium, and showed statistically significant improvement in median PFS in the PD-991 plus letrozole arm versus the letrozole arm. Part 2 enrolled 99 additional patients whose tumors were selected for presence of biomarkers: cyclin D1 amplification and/or p16 loss. The results presented here at SABCS reflect the combined interim data analysis of parts 1 and 2 of the phase II evaluation.

In patients with measurable disease, the objective response rate was 45 per cent for those women who received PD-991 plus letrozole versus 31 per cent for those who received letrozole alone. The clinical benefit rate (defined as complete response plus partial response plus stable disease for =24 weeks) was 70 per cent versus 44 per cent, respectively. The differences observed in the objective response rate and clinical benefit rate were statistically significant. The most frequently reported treatment-related Grade 3/4 adverse events (AEs) in patients who received the combination therapy were neutropenia, leucopenia, anemia and fatigue.

Both Part 1 and Part 2 of this phase II evaluation are ongoing but no longer enrolling new patients. Final efficacy and safety data are expected to be presented at a future medical congress.

“In demonstrating very strong efficacy and a manageable tolerability profile, these new data represent a potential major advancement in breast cancer clinical research and our continued efforts to identify new medicines that target patients most likely to have an optimal response,” said Dr Richard S Finn, associate professor of Medicine, Revlon/UCLA Women’s Cancer Research Programme at Jonsson Comprehensive Cancer Centre, UCLA, and lead investigator of the phase II trial. “The oncology community is looking forward to the further evaluation of PD-991 in the planned phase III trial and very interested in the potential for this novel CDK 4 and 6 inhibitor to improve the treatment landscape for patients with advanced breast cancer.”

PD-991 is an investigational, oral and selective inhibitor of the CDK 4 and 6 kinases. CDK 4 and 6 are two closely related kinases that enable tumor cell progression during phase G1 to phase S in the cell cycle. This progression is necessary for DNA replication and cell division. Inhibition of CDK 4 and 6 has been shown to prevent the deactivation of retinoblastoma, a tumour suppressor protein, and interfere with tumor cell progression. In pre-clinical studies, PD-991 was shown to be an inhibitor of cell growth and a suppressor of DNA replication by preventing cells from entering S phase.

In addition to breast cancer, PD-991 is currently being evaluated through Pfizer-sponsored and investigator-initiated research in other cancers, including liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, multiple myeloma, and mantle cell lymphoma.

Pfizer Oncology is committed to the discovery, investigation and development of innovative treatment options to improve the outlook for cancer patients worldwide.