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Palbociclib plus letrozole extended PFS in metastatic breast cancer
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The addition of palbociclib to letrozole during first-line treatment significantly extended PFS in post-menopausal patients with ER-positive, HER-2–negative advanced breast cancer, according to final results of a randomized, open-label, phase 2 trial presented at the American Association for Cancer Research annual meeting.
Palbociclib (PD-0332991, Pfizer), an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, prevents DNA synthesis by blocking cell cycle progression. Results of preclinical studies showed HR-positive breast cancer cells are dependent on CDK-4/6 for growth, and a phase 1 study showed the combination of palbociclib and the antiestrogen drug letrozole appeared to be a safe, effective combination.
Richard S. Finn
“Critical to moving a new drug into cancer medicine is identifying a population that might respond. We know we might have the best drug, but if we don’t get it to the right people, you might not see benefit,” Richard S. Finn, MD, associate professor of medicine at University of California, Los Angeles, said during a press conference. “We identified a subpopulation of breast cancer patients — hormone receptor-positive, HER-2–negative breast cancer patients — who are most likely to benefit.”
The PALOMA-1 study included 165 postmenopausal patients with HR-positive, HER-2–negative metastatic breast cancer. Ninety-nine of the patients had disease that tested positive for alterations in the D1 and/or p16 genes, both of which are markers of sensitivity to palbociclib.
Finn and colleagues randomly assigned half of the patients to receive palbociclib 125 mg once daily for 3 weeks followed by 1 week off, plus 2.5 mg letrozole daily. The remainder of the patients received letrozole alone.
Patient characteristics were similar in both arms, and about one-third of patients overall underwent prior hormonal therapy in the adjuvant setting.
PFS served as the primary endpoint. Researchers assessed patients every 2 months. Treatment continued until unacceptable toxicity, disease progression or patient withdrawal from the study.
Patients who received palbociclib demonstrated significantly longer median PFS than those assigned to letrozole alone (20.2 months vs. 10.2 months; HR=0.488; 95% CI, 0.319-0.748), translating to a 51% reduced risk for progression with the addition of palbociclib.
Researchers observed the benefit among patients who tested positive for D1 and/or p16 alterations (HR=0.508; 95% CI, 0.303-0.853) and those who did not (HR=0.299; 95% CI, 0.156-0.572).
The initial OS analysis, performed after 61 events occurred, suggested patients assigned to palbociclib plus letrozole survived longer than those who received letrozole alone (37.5 months vs. 33.3 months; HR=0.813; P=.2105), although the difference was not statistically significant.
“Survival events in ER-positive breast cancer take time to evolve,” Finn said. “A first look at the survival data is very encouraging, and we’ll continue to follow that over time.”
The most common adverse events reported in the combination arm were neutropenia, leukopenia, fatigue and anemia.
A phase 3 double blind, placebo-controlled study designed to validate these findings is underway, Finn said.
For more information:
Finn RS. Abstract #CT101. Presented at: AACR Annual Meeting; San Diego; April 5-9, 2014.
Disclosure: The study was supported by Pfizer. Finn reports no relevant financial disclosures.