Phase III Trial Shows Improved PFS With Addition of Palbociclib to Letrozole in ER-Positive, HER2-Negative Breast Cancer
In the phase III PALOMA-2 trial reported in The New England Journal of Medicine, Finn et al found that the addition of palbociclib (Ibrance) to letrozole significantly improved progression-free survival in postmenopausal women with previously untreated advanced estrogen receptor–positive, HER2-negative breast cancer.
Study Details
In this double-blind study, 666 women with no prior treatment for advanced disease from 186 sites in 17 countries were randomized 2:1 between February 2013 and July 2014 to receive palbociclib plus letrozole (n = 444) or letrozole plus placebo (n = 222). Palbociclib was given at 125 mg/d with 3 weeks on and 1 week off in 4-week cycles; letrozole was given at 2.5 mg/d continuously. Randomization was stratified according to the site of disease (visceral or nonvisceral), disease-free interval from the end of adjuvant or neoadjuvant treatment to disease recurrence, and receipt or no receipt of prior adjuvant or neoadjuvant anticancer therapy. The primary endpoint was investigator-assessed progression-free survival.
For the combination and letrozole groups: median age was 62 and 61 years; 78% in both groups were white and 15% and 14% were Asian; the Eastern Cooperative Oncology Group performance status was 0 or 1 for 98% and 99%; disease stage at initial diagnosis was I, II, III, and IV in 12% and 14%, 31% in both, 16% and 18%, and 31% and 32%; recurrence was distant in 66% and 65%; disease-free interval was > 12 months in 40% and 42%, ≤ 12 months in 22% in both, with newly metastatic disease in 38% and 37%; disease site was visceral in 48% and 50% and nonvisceral in 52% and 50%, with bone only in 23% and 22%; number of disease sites was 1 in 31% and 30% and ≥ 4 in 17% and 19%; 48% and 49% had received prior adjuvant or neoadjuvant chemotherapy, and 56% and 57% had received adjuvant hormonal treatment, including tamoxifen in 47% and 44%.
Prolonged Progression-Free Survival
Median follow-up was 23 months. Median progression-free survival was 24.8 months (95% confidence interval [CI] = 22.1 to not estimable) in the palbociclib/letrozole group vs 14.5 months (95% CI = 12.9–17.1 months) in the letrozole group (hazard ratio [HR] = 0.58, P < .001). On blinded central independent review, the hazard ratio was 0.65 (P = .001). Hazard ratios significantly favored palbociclib/letrozole across all stratification factors and baseline subgroups. Confirmed objective response rates were 42.1% vs 32.7% overall and 55.3% vs 44.4% among those with measurable disease. Data on overall survival were immature at the time of the progression-free survival analysis.
Adverse Events
The most common grade 3 or 4 adverse events in the as-treated population were neutropenia (66.4% in the palbociclib/letrozole group vs 1.4% in the letrozole group), leukopenia (24.8% vs 0%), anemia (5.4% vs 1.8%), and fatigue (1.8% vs. 0.5%). The most common nonhematologic adverse events of any grade were fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), and arthralgia (33.3% vs 33.8%). The palbociclib/letrozole group had a higher incidence of grade 1 or 2 alopecia (32.9% vs 15.8%) and any-grade diarrhea (26.1% vs 19.4%), cough (25.0% vs 18.9%), and stomatitis (15.3% vs 5.9%).
Serious adverse events occurred in 19.6% vs 12.6%. Febrile neutropenia occurred in 1.8% vs 0%, and pulmonary embolism occurred in 0.9% vs 1.4%. Adverse events led to permanent discontinuation of any study treatment in 9.7% vs 5.9%. During the treatment period, 10 deaths occurred in the palbociclib/letrozole group (2.3%), and 4 deaths occurred in the letrozole group (1.8%), with 1 death in the letrozole group considered related to study treatment.
The investigators concluded: “Among patients with previously untreated [estrogen receptor]–positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib/letrozole.”
The study was funded by Pfizer.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
