Patients with ER-positive, HER2-negative advanced breast cancer had significant delays in progression when palbociclib was added to letrozole treatment, according to the double-blind PALOMA-2 study.
Patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer had significant delays in progression when treated with the combination of letrozole and an inhibitor of CDK4 and CDK6, palbociclib, compared with letrozole alone, according to the double-blind PALOMA-2 study published today in the New England Journal of Medicine. However, treatment with the combination also resulted in higher rates of myelotoxic effects.
“PALOMA-2 confirmed our earlier findings that palbociclib combined with letrozole results in significantly longer progression-free survival than that with letrozole alone among postmenopausal women with ER-positive, HER2-negative advanced breast cancer and provides additional evidence regarding the efficacy and safety of inhibition of CDK4 and CDK6 as first-line treatment,” wrote researchers led by Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles.
The study looked at 666 postmenopausal women with ER-positive, HER2-negative disease who had no prior treatment for advanced disease and randomly assigned them 2:1 to palbociclib plus letrozole or placebo plus letrozole. The primary endpoint was investigator-assessed progression-free survival.
Adding palbociclib to letrozole resulted in a median progression-free survival of 24.8 months compared with 14.5 months for letrozole alone (hazard ratio, 0.58; 95% CI, 0.46-0.72; P < .0010).
“The median progression-free survival of 24.8 months in PALOMA-2 is longer than that seen in other phase III studies involving women with advanced breast cancer,” the researchers wrote. “Whether this progression-free survival will result in longer overall survival is uncertain until further follow-up is completed.”
Patients assigned to the drug combination had a high incidence of hematologic adverse events, but the researchers wrote that they were consistent with those observed in other trials of palbociclib. Adverse events included grade 3 or 4 neutropenia (66.4% vs 1.4%), leukopenia (24.8% vs 0%), anemia (5.4% vs 1.8%), and fatigue (1.8% vs 0.5%). Forty-three patients (9.7%) assigned to the combination discontinued therapy because of adverse events compared with only 5.9% of patients in the letrozole alone arm. Serious adverse events from any cause occurred in 19.6% of patients assigned palbociclib/letrozole and 12.6% of patients assigned letrozole alone.
In an editorial that accompanied the study, Antonio C. Wolff, MD, wrote that the data from the PALOMA-2 trial are striking because at least one-half of patients also received prior adjuvant endocrine therapy.
“The findings of PALOMA-2 affirm the decision by the Food and Drug Administration (FDA) to grant accelerated approval for palbociclib, which was based on the results of PALOMA-1, and the findings of PALOMA-3 led to the recent approval of palbociclib in combination with fulvestrant for the treatment of patients who had disease progression during endocrine therapy,” Wolff wrote. “CDK4 and CDK6 inhibition in combination with antiestrogens is clearly a new standard for the treatment of advanced ER-positive breast cancer.”
However, he noted also that palbociclib “is costly and has some toxic effects.”
“Some patients derive strong clinical benefit with antiestrogens alone as first-line therapy, and we must learn to identify those patients so that we can apply CDK4 and CDK6 inhibition in those who will benefit the most,” he wrote.