Share this article on:

Metastatic Breast Cancer: PD 0332991 + Letrozole Triples PFS

Carlson, Robert H.

doi: 10.1097/01.COT.0000427377.71323.44
PD 0332991

PD 0332991

SAN ANTONIO—Combining an inhibitor of the cyclin-dependent kinase 4/6 with an aromatase inhibitor produced a dramatic improvement in progression-free survival in patients with metastatic breast cancer in a study reported here at the CTRC-AACR San Antonio Breast Cancer Symposium.

The combination of the novel oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor PD 0332991 and the oral non-steroidal aromatase inhibitor letrozole was tested against letrozole alone in the Phase II trial of women with metastatic estrogen receptor (ER)-positive breast cancer (Abstract S1-6). Median progression-free survival in the trial was 26.1 months for the combination study arm compared with 7.5 months in the letrozole-alone arm.

“PD 0332991 combined with letrozole provides a dramatic and unprecedented improvement in progression-free survival in this population,” said the study's first author, Richard S. Finn, MD, Associate Professor of Medicine at UCLA's Jonsson Comprehensive Cancer Center.



Among patients with measurable disease, 45 percent receiving the combination had confirmed responses, compared with 31 percent with letrozole alone. Clinical benefit rates, defined as tumor shrinkage and/or stable disease for a minimum of six months, were 70 and 44 percent, respectively.

Finn called the low toxicity profile of the combination regimen “striking,” with the most common adverse events being uncomplicated neutropenia, leukopenia, anemia, and fatigue, and with no evidence of febrile neutropenia.

ER positivity was the only biomarker that identified patients most likely to benefit from PD 0332991, the researchers reported.

PD 0332991 is a novel oral selective inhibitor of cyclin dependent kinase 4/6 (CDK4/6), which prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. Preclinical studies identified cells with elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991. Synergistic activity was also seen in vitro when PD 0332991 was combined with tamoxifen.

The preclinical work was conducted at the Translational Oncology Research Laboratory, directed by Dennis Slamon, MD, senior author of the study and Director of the Revlon/UCLA Women's Cancer Research Program.

The clinical studies were sponsored by Pfizer Inc. In the first part of the Phase II study, 66 patients were randomly assigned to receive letrozole at 2.5 mg daily plus PD 0332991 at 125mg daily, or to letrozole alone, with each group treated three weeks on and one week off. Finn said preliminary results showed significant improvement in median progression-free survival for the patients on the combination regimen.

Ninety-nine patients with the same eligibility criteria as in part 1 but also selected for cyclin D1 amplification and/or p16 loss were then enrolled in the second part of the study. The results of both parts of the study, totaling 84 combination patients and 81 letrozole-alone patients, were combined for the SABCS presentation. A Phase III trial is planned for later in 2013, Finn said.

Back to Top | Article Outline

Anti-Metastatic Effect?

From the audience during the question-and-answer period, Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs and Medical Director of the Breast Center at Memorial Sloan-Kettering Cancer Center, suggested that there might be an effect of this new compound on metastatic disease: “When one sees a disconnect between progression-free survival and response rate, one must think that maybe there is an effect on metastasis or new sites of disease,” he said. “This pathway clearly relates to many mechanisms of metastasis. Have you divided that out—are you having an anti-metastatic effect?”

Finn responded that although he agreed that there could be a potential mechanism that hasn't been teased out of the results yet, inducing cell cycle arrest and having a cytostatic effect could apply to both a metastatic site and a measureable site.

Another question from the audience was why the control group had such a low progression-free survival compared to historical data.

Finn said the control patients were a heterogeneous group, with some never having been treated previously while others had prior endocrine treatment. Regardless, he said, “the magnitude of benefit was so significant, this is clearly a signal that this molecule has a role in this disease.”

© 2013 Lippincott Williams & Wilkins, Inc.
Home  Clinical Resource Center
Current Issue       Search OT
Archives Get OT Enews
Blogs Email us!