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New agent, letrozole combination improved PFS in advanced breast cancer
SAN ANTONIO — A novel cyclin dependent kinase inhibitor was associated with increases in PFS in patients with ER-positive and HER-2–negative breast cancer, according to findings presented here.
The novel agent, known as PD0332991 (PD 991, Pfizer Oncology), aims at a new target in oncology, according to presenter Richard S. Finn, MD, associate professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. He said inhibition of cyclin dependent kinase 4/6 activity prevents cellular DNA synthesis by prohibiting progression of the cell cycle from the G1 to S phase. In preclinical studies, the investigational drug demonstrated activity in certain ER subtypes and showed synergistic activity with tamoxifen.
The current phase 1/2 study investigated the efficacy of 125 mg of the drug (administered daily, 3 weeks on, 1 week off) plus letrozole (Femara, Novartis Pharmaceuticals) 2.5 mg daily.
Part 1 of the study enrolled postmenopausal women with ER-positive/HER-2–negative advanced disease. Part 2, besides ER-positive/HER-2–negative as eligibility criteria, screened for CCND1 amplification and/or loss of p16 by fluorescent in situ hybridization, according to Finn. There were 165 patients overall, 84 of whom received the study drug plus letrozole and 81 of whom received letrozole alone.
Results of an intention-to-treat analysis indicated an overall 34% objective response rate in the study drug group and a 26% rate in the letrozole alone group. Among patients with measurable disease, the combination group yielded an objective response rate of 45% vs. 31% for the letrozole group.
Regarding the PFS curve, Finn highlighted a “dramatic, significant and clinically meaningful improvement in the cohort treated with PD 991.”
“Importantly, this drug is very well tolerated,” he said. “Leukopenia, neutropenia and anemia occurred, but they were mostly low grade and generally manageable with dose reductions.”
Finn said a phase 3 study of the drug is planned for early 2013.
For more information:
Finn RS. #S1-6. Presented at: the 2012 CTRC-AACR San Antonio Breast Cancer Symposium; Dec. 4-8, 2012; San Antonio.
Disclosure: Finn reports receiving research funding from Pfizer.
Perspective
Back to TopThere are not too many of these novel compounds that have made it to the clinic. These data suggest this is an agent that is worthy of continued study in breast cancer because of the significant improvement in PFS. I am enthusiastic that they will be proceeding shortly with a phase 3 trial. I was impressed because the investigators are looking at combining targeted drugs with hormonal treatment. The positive aspect of this is that there was very little toxicity added when the novel agent was introduced.
One thing to clarify from the presentation was that they had two groups. The first was all-comers and then they took patients with a particular abnormality, but then they lumped everything together for the analysis. It would be nice in follow-up to see if the mutation status makes any difference or not.
Perspective
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Pre-clinical studies have shown that the inhibition of the cell-cycle regulatory proteins CDK4/6 can prevent DNA cellular synthesis by inhibiting cell cycle progression. The ER-positive luminal A subtype of breast cancer was found to be particularly sensitive to the CDK4/6 inhibitor PD0332991, and synergistic activity was found in vitro when this novel agent was combined with tamoxifen. Based upon these observations, Finn and colleagues performed a randomized phase 2 trial of letrozole alone vs. letrozole plus PD0332991 in patients with advanced ER-positive, HER-2–negative breast cancer. Sixty-six ER-positive patients were entered in part 1 of the trial, and 99 patients with CCND1 amplification or loss of p16 in addition to ER positivity were entered in part 2 of the study. In the combined group of 165 patients, those who received letrozole plus PD0332991 had a longer PFS (26.1 months vs. 7.5 months) and a higher response rate in patients with measurable disease (45% vs 31%) compared with the patients treated with letrozole alone, though at the expense of a greater risk of neutropenia, anemia and fatigue. No predictor of response other than ER positivity was found. Whether the encouraging results of this small trial reflect the true promise of this approach will be tested in a phase 3 trial scheduled to begin in 2013.