This article is more than 5 years old. Information may no longer be current.
Palbociclib plus letrozole prolongs PFS in advanced breast cancer
Click Here to Manage Email Alerts
The addition of palbociclib to letrozole extended PFS in women with previously untreated ER–positive, HER-2–negative advanced breast cancer, according to results of the double blind, placebo-controlled, randomized phase 3 PALOMA-2 study published in The New England Journal of Medicine.
However, the combination also increased the rate of myelotoxic effects.
“These findings confirm our initial observation on the importance of targeting CDK 4/6 in hormone receptor–positive breast cancer,” Richard S. Finn, MD, assistant professor of medicine at Geffen School of Medicine at UCLA, told HemOnc Today. “The open-label randomized phase 2 PALOMA-1 study showed an unprecedented 10-month improvement in PFS with the addition of palbociclib to letrozole with a predictable safety profile and served for the accelerated approval of the combination by the U.S. FDA. The PALOMA-2 study was a larger, double blind placebo-controlled study and remarkably confirmed the same degree of benefit — greater than 10 months — with the same safety profile. This will serve as the basis for the U.S. full approval and global registration.”
Although the incidence of neutropenia of any grade in the palbociclib–letrozole group was 79.5% in the current study, the incidence of febrile neutropenia was lower than 2%, Finn said.
“The most common abnormality is really a lowering of the white blood cell count but the incidence of serious infections is very low, less than 2%,” he said. “The drug is very well tolerated and other than neutropenia, side effects are low grade.”
Treatment of hormone receptor–positive breast cancer — the largest therapeutic subtype of the disease, accounting for more than 60% of all malignant neoplasms of the breast — has focused on targeting the ER–signaling pathway. However, resistance is common, and new approaches are needed.
Palbociclib is a small-molecule inhibitor that has shown an ability to inhibit the growth of ER–positive breast cancer cells, act synergistically with antiestrogens and reverse endocrine resistance. The drug became available in the United States in 2015 when it received accelerated approval and has been widely available since then, Finn said.
“With PALOMA-2, it will become available globally, although economics may limit its availability in some countries,” Finn said.
Finn and colleagues sought to replicate results of the phase 2 trial of palbociclib and letrozole in a phase 3 study.
The analysis included 666 postmenopausal women with ER–positive, HER-2–negative breast cancer who had not had prior treatment for advanced disease enrolled at 186 sites in 17 countries. Researchers randomly assigned patients 2:1 to receive letrozole with palbociclib (n = 444; median age, 62 years) or with placebo (n = 222; median age, 61 years).
PFS served as the study’s primary endpoint. Secondary endpoints included OS, objective response, duration of response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, safety and tissue biomarker assessments.
Median follow-up was 23 months.
The median PFS was 24.8 months (95% CI, 22.1 to not estimable) in the letrozole–palbociclib group, compared with 14.5 months (95% CI, 12.9-17.1) in the letrozole-only group (HR = 0.58, 95% CI, 0.46-0.72).
OS data were immature at the time of the analysis.
The most common grade 3 and grade 4 adverse events in the combination and placebo arms were neutropenia (66.4% vs. 1.4), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%) and fatigue (1.8% vs. 0.5%).
Febrile neutropenia occurred in 1.8% of women in the letrozole–palbociclib group and in none of the letrozole-only group.
In addition, 9.7% of patients in the letrozole–palbociclib group permanently discontinued treatments because of adverse events, compared with 5.9% of women in the letrozole-only group.
More patients in the letrozole–palbociclib arm experienced a severe toxicity (19.6% vs. 12.6%).
Fourteen deaths occurred during the treatment period — including 10 in the letrozole–palbociclib group (2.3%) and four in the letrozole-only group (1.8%) — one of which in the letrozole-only group was considered to be related to the study regimen.
These results confirm earlier findings that palbociclib with letrozole significantly prolongs PFS among postmenopausal women with ER–positive, HER-2–negative advanced breast cancer, and the adverse events associated with palbociclib “have been successfully managed with appropriate supportive care and dose reductions,” the researchers wrote.
“The clinical development of palbociclib and other CDK 4/6 inhibitors has moved quickly,” Finn said. “These findings are the result of a rational development plan based on preclinical observations made with palbociclib here at UCLA, which guided the success in the clinic.” – by Chuck Gormley
For more information :
Richard S. Finn, MD , can be reached at David Geffen School of Medicine at UCLA, 2825 Santa Monica Blvd, Suite 200, Santa Monica, CA 90404; email: rfinn@mednet.ucla.edu.
Disclosure: Pfizer funded this study. Finn reports no relevant financial disclosures. One other researcher reports employment with Pfizer at the time of the study.
Click Here to Manage Email Alerts