In the phase III PALOMA-2 trial reported in The New England Journal of Medicine, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues 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.¹

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.

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 letrozole alone, although the rates of myelotoxic effects were higher with palbociclib/letrozole.

— Richard S. Finn, MD, and colleagues

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For the combination and letrozole groups: median age was 62 and 61 years; 78% in both were white and 15% and 14% were Asian; 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%; the disease-free interval was > 12 months in 40% and 42%, ≤ 12 months in 22% in both, with newly metastatic disease in 38% and 37%; the disease site was visceral in 48% and 50% and nonvisceral in 52% and 50%, with bone-only disease in 23% and 22%; the 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%). One death in the letrozole group alone was 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 letrozole alone, although the rates of myelotoxic effects were higher with palbociclib/letrozole.” ■

Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.