Palbociclib/Letrozole Improves Progression-Free Survival in First-Line Treatment of Estrogen Receptor–Positive/HER2-Negative Advanced Breast Cancer
In the phase II PALOMA-1/TRIO-18 trial reported in The Lancet Oncology, Finn et al found that the addition of palbociclib to letrozole resulted in significant improvement in progression-free survival as first-line treatment for advanced disease in postmenopausal women with estrogen receptor–positive/HER2-negative breast cancer. Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6.
Study Details
In the open-label study, patients were enrolled in two sequential cohorts, one including patients on the basis of estrogen receptor–positive/HER2-negaitve status alone (cohort 1) and another that required presence of amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both (cohort 2). In both cohorts, patients were randomly assigned between December 2009 and May 2012 to receive continuous letrozole at 2.5 mg daily with or without palbociclib at 125 mg once daily for 3 weeks followed by 1 week off in 28-day cycles.
The primary endpoint was progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1, with the statistical analysis plan for the primary endpoint being amended to a combined analysis of cohorts 1 and 2 instead of cohort 2 alone.
In total, 165 patients were randomly assigned to palbociclib/letrozole (n = 84; 34 in cohort 1, 50 in cohort 2) or letrozole alone (n = 81; 32 in cohort 1, 49 in cohort 2). Overall, 52% and 46% of patents had received no prior systemic chemotherapy and 32% and 35% had received prior hormonal treatment, including tamoxifen in 29% and 30% and anastrozole in 10% and 14%; 99% and 98% had stage IV disease.
Increased Progression-Free Survival
Median follow-up was 29.6 months in the palbociclib/letrozole group and 27.9 months in the letrozole group. Median progression-free survival was 20.2 months (95% confidence interval [CI] =13.8–27.5 months) in the palbociclib/letrozole group vs 10.2 months (95% CI = 5.7–12.6 months) in the letrozole group (hazard ratio [HR] = 0.488, P = .0004). Median progression-free survival was 26.1 vs 5.7 months in cohort 1 (n = 66; HR = 0.299, P < .0001) and 18.1 vs 11.1 months in cohort 2 (n = 99; HR = 0.508, P = .0046).
Response rates were 43% vs 33% (including complete response in 1% of both groups), and median duration of response was 20.3 vs 11.1 months. Median overall survival, assessed at the same time as progression-free survival, was 37.5 vs 33.3 months (HR = 0.813, P = .42). The trial is ongoing.
Adverse Events
The most common adverse events in the palbociclib/letrozole group were neutropenia, leukopenia, and fatigue; grade 3 or 4 neutropenia occurred in 54% vs 1%, grade 3 or 4 leukopenia in 19% vs 0%, and grade 3 or 4 fatigue in 4% vs 1%. Other adverse events of any grade that were significantly more common with palbociclib/letrozole were anemia (35%, 6% grade 3–4, vs 6%, 1% grade 3–4) and alopecia (22% vs 3% grade 1–2).
Serious adverse events that occurred in more than one patient in the palbociclib/letrozole group were pulmonary embolism (4%), back pain (2%), and diarrhea (2%). No febrile neutropenia or neutropenia-related infections were reported. Adverse events led to dose interruptions in 33% vs 4% and to treatment discontinuation in 13% vs 2%. No treatment-related deaths were observed.
The investigators concluded: “The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway.”
Dennis J. Slamon, MD, of University of California, Los Angeles, is the corresponding author for The Lancet Oncology article.
The study was funded by Pfizer. For full disclosures of the study authors, visit www.thelancet.com.
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®.
