The experimental CDK-inhibitor palbociclib, when combined with the aromatase inhibitor letrozole, significantly extended progression-free survival in women with HER2-/ER+ breast cancer compared with letrozole alone, according to the final results from a phase II clinical trial of the drug.
In postmenopausal women with locally advanced or metastatic HER2−/ER+ breast cancer, treatment with the experimental drug palbociclib and the aromatase inhibitor letrozole nearly doubled progression-free survival (PFS) versus treatment with letrozole alone, according to final results from the phase II PALOMA-1 trial. Researchers presented the findings on April 6 at the American Association for Cancer Research Annual Meeting 2014 in San Diego, CA.
Under development at Pfizer, palbociclib (PD 0332991) is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. It is thought to block cell-cycle progression.
The median PFS for women in the palbociclib plus letrozole group was 20.2 months, compared with 10.2 months for women taking letrozole alone, the researchers said.
“The magnitude of benefit is really remarkable for this population,” said Richard Finn, MD, the study's principal investigator and an associate clinical professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dennis Slamon, MD, PhD, director of the Revlon/UCLA Women's Cancer Research program, was the study's senior author.
Researchers have long sought therapies to target CDKs, which become overactive in many cancers. To date, no CDK inhibitors have been approved by the FDA.
However, in 2013, palbociclib received the FDA's “breakthrough therapy” designation, designed to expedite the review and approval process. The FDA based its decision largely on interim findings, reported in December 2012, suggesting the drug offered a clinical advantage over existing treatments. In addition, side effects of the drug, which included neutropenia, leukopenia, fatigue, and anemia, were all manageable, Finn said.
The randomized trial consisted of two parts, with 66 women enrolled in the first part and 99 in the second. Patients in the first part, on which the 2012 interim results were based, were postmenopausal women with locally advanced or metastatic inoperable HER2−/ER+ breast cancer. The second part of the trial, which was accruing patients when the interim results were reported, enrolled patients with HER2−/ER+ disease who also had amplification of the oncogene CCND1 and/or loss of p16, a tumor-suppressor protein. Palbociclib showed benefits for patients with and without those alterations, but Finn noted that patients without those biomarkers may derive greater benefit.
Most patients in the trial are still alive, which means there have been too few deaths to determine overall survival statistics. However, based on 61 deaths, the overall survival for women treated with palbociclib plus letrozole was 37.5 months, compared with 33.3 months for those treated with letrozole alone.
Finn said that researchers investigated ER+ breast cancer because preclinical studies suggested that population was most likely to benefit from the drug. However, he noted that other cancers may also respond well to palbociclib. “I have a strong sense this drug will have activity in various malignancies,” he said.
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