The addition of palbociclib to the letrozole regimen prolonged progression-free survival. Grade 3 or 4 neutropenia and leukopenia were more common in the combination therapy group. In the phase II PALOMA-1/TRIO-18 trial reported in The Lancet Oncology, Finn et al. found that adding palbociclib to a letrozole regimen significantly prolonged progression-free survival in postmenopausal estrogen receptor (ER)-positive/HER2-negative patients with advanced breast cancer treated in the first line. palbociclib is an orally administered cytokine cyclein-dependent small molecule inhibitor of kinases 4 and 6. In this unblinded trial, patients were divided into 2 consecutive study cohorts, one including only estrogen receptor-positive/HER2-negative patients (cohort 1) and the other requiring the presence of amplification of cytokine D1 (CCND1), p16 (INK4A or CDKN2A) deletion or amplification of cytokine D1 (CCND1). combined with p16 deletion (cohort 2). In both cohorts, patients between December 2009 and May 2012 were randomly assigned to continuous application of letrozole 2.5 mg/day ± palbociclib 125 mg/day for 3 weeks of treatment and 1 week off for 28 days. The primary evaluation metric for intention-to-treat patients was progression-free survival. Enrollment was discontinued in cohort 2 after an unplanned interim analysis in cohort 1. The statistical analysis of the primary evaluation metric was amended to a combined analysis of cohort 1 and cohort 2, rather than cohort 2 alone. A total of 165 patients were randomly assigned to either the palbociclib/letrozole group (n = 84; 34 in cohort 1 and 50 in cohort 2) or the letrozole monotherapy group (n = 81; 32 in cohort 1 and 49 in cohort 2). Fifty-two and 46% of patients in cohort 1 and cohort 2, respectively, had no prior systemic chemotherapy, 32 and 35% had prior hormonal therapy, of whom 29 and 30%, respectively, had tamoxifen, while 10% and 14% had prior anastrozole, and 99 and 98% had stage IV disease. Progression-free survival was prolonged with a median follow-up time of 29.6 months for patients in the palbociclib/letrozole group and 27.9 months for patients in the letrozole group. median progression-free survival was 20.2 months (95% confidence interval [CI] = 13.8C27.5 months) for patients in the palbociclib/letrozole group, while patients in the letrozole group had a median progression-free survival of 20.2 months (95% confidence interval [CI] = 13.8C27.5 months). The median progression-free survival for patients in the letrozole group was 10.2 months (95% CI = 5.7C12.6 months, hazard ratio [HR] = 0.488, P = 0.0004). The median progression-free survival for patients in the palbociclib/letrozole and letrozole groups in cohort 1 was 26.1 months and 5.7 months, respectively (n = 66; HR = 0.299, P < 0.0001), and the median progression-free survival for patients in the palbociclib/letrozole and letrozole groups in cohort 2 was 18.1 months and 11.1 months (n = 99; HR = 0.508, P = 0.0046). The remission rates were 43% and 33%, respectively (complete remission rate was 1% in both groups), and the median duration of remission was 20.3 and 11.1 months, respectively. Median overall survival (assessed concurrently with median progression-free survival) was 37.5 months and 33.3 months, respectively (HR = 0.813, P = 0.42). The trial is still ongoing. The most common adverse reactions in the palbociclib/letrozole group were neutropenia, leukopenia, and fatigue. the incidence of grade 3 or 4 neutropenia was 54% and 1% in the palbociclib/letrozole and letrozole groups, respectively. the incidence of grade 3 or 4 leukopenia was 19% and 0%, respectively. the incidence of grade 3 or 4 fatigue was 4% and 1%, respectively. Other adverse reactions of any grade that were more common in the palbociclib/letrozole group included anemia and hair loss. More than one serious adverse reaction in the palbociclib/letrozole group included pulmonary embolism (4%), back pain (2%), and diarrhea (2%). There were no reports of fever with neutropenia or neutropenia-associated infections. The incidence of adverse reactions leading to interruption of dosing was 33% and 4%, respectively, and the incidence leading to treatment discontinuation was 13% and 2%, respectively. No cases of treatment-related death were observed. The investigators concluded that the addition of palbociclib to the letrozole regimen significantly prolonged survival in patients with estrogen receptor-positive and HER2-negative advanced breast cancer in this phase II trial. The phase III trial is currently underway.