Novel Oral Agent plus Letrozole Improves Progression-free Survival in ER-positive Advanced Breast Cancer 

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The combination of letrozole plus a novel oral inhibitor of cyclin-dependent kinase 4/6 called PD 0332991 achieved an unprecedented improvement in progression-free survival among women with advanced estrogen receptor–positive/HER2-negative breast cancer. Median progression-free survival was 26.1 months among women treated with the combination vs 7.5 months for letrozole alone (P = .006), according to results of a randomized phase II study presented at the 2012 San Antonio Breast Cancer Symposium.1

PD 0332991 is a first-in-class oral selective inhibitor of cyclin-dependent kinase 4/6. The drug prevents cellular DNA synthesis.

Experts were excited about these results but agreed that further study is needed. Pfizer, marketer of PD 0332991, is planning a phase III trial of this combination.

Well Tolerated Drug

“The dramatic, significant, and clinically meaningful improvement in progression-free survival with the combination is very encouraging. Importantly, this novel drug is very well tolerated,” stated Richard S. Finn, MD, Associate Professor of Medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. “This study validates preclinical studies showing that the new compound has significant activity in breast cancer models and acts synergistically with hormonal therapy.”

The phase II study had two parts, and in both, women were randomly assigned 1:1 to receive letrozole plus PD 0332991 or letrozole alone. Part 1 enrolled 66 postmenopausal women with estrogen receptor–positive/HER2-negative advanced breast cancer. Part 2 enrolled 99 patients using the same eligibility criteria but also screened tumors for cyclin D1 amplification and/or loss of p16 by fluorescence in situ hybridization. For both parts of the trial, the primary endpoint was progression-free survival; secondary endpoints included response rate, overall survival, safety, and correlative biomarker studies.

Dr. Finn did not present any data on cyclin D1 amplification and loss of p16 because these biomarkers had no effect on results, based on retrospective review of the part 1 patients. The only biomarker required for selection of patients was estrogen receptor positivity, he added.

Earlier and Updated Reports

Interim results for progression-free survival in part 1 of the trial were presented at the IMPAKT Breast Cancer Conference in Brussels earlier in 2012. The combination significantly improved progression-free survival compared with letrozole alone (P = .006).

Dr. Finn updated these results at the San Antonio Breast Cancer Symposium based on a total of 165 patients enrolled in both parts 1 and 2. In this analysis, median progression-free survival was 26.1 months with the combination vs 7.5 months with letrozole alone, representing a 63% improvement in risk of progression (P < .001).

The combination was also superior to letrozole alone for secondary endpoints of response rate (45% for the combination vs 31% for letrozole alone in patients with measurable disease), and clinical benefit rate (70% vs 44%, respectively).

Neutropenia, leukopenia, anemia, and fatigue were the most common treatment-related adverse events reported with combination therapy. The neutropenia that patients experienced was generally uncomplicated and manageable, with no cases of febrile neutropenia.

The two treatment arms were well balanced at baseline for demographic and disease characteristics. Median age was about 63 years, about 95% had stage IV disease, about 50% had visceral metastases, and about 19% had bone-only metastases. About 70% had a recurrence less than 12 months after adjuvant therapy or had de novo advanced disease. About 50% had no prior systemic treatment for advanced disease.

Combination to Watch

Commenting on these results, Jennifer Litton, MD, breast medical oncologist at The University of Texas MD Anderson Cancer Center in Houston, said, “I can’t recall a phase II trial that has shown such significant early results with a drug that appears to be fairly well tolerated. This will be an exciting combination to watch.”  Acknowledging that not all phase II results hold up under phase III scrutiny, she said, “I am cautiously optimistic.” ■

Disclosure: Drs. Finn and Litten reported no potential conflicts of interest.


1. Finn RS, Crow JP, Lang I, et al: Results of a randomized phase 2 study of PD 0332991, a cyclin dependent kinase (cdk) 4/6 inhibitor in combination with letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S1-6. Presented December 5, 2102.