Dennis J. Slamon, MD, PhD
Adding the CDK 4/6 inhibitor palbociclib (Ibrance) to letrozole reduced the risk of disease progression by 42% compared with letrozole alone in patients with ER-positive, HER2-negative advanced or metastatic breast cancer, according to results from the phase III PALOMA-2 trial presented at the 2016 ASCO Annual Meeting.1
The median progression-free survival (PFS) was improved by >10 months with the addition of palbociclib. The combination of palbociclib and letrozole was granted an accelerated approval in February 2015, based on the phase II PALOMA-1 study. These results from PALOMA-2 provide confirmation of the combination's benefits in the frontline setting.
“These data represent the longest frontline improvement in median PFS seen to date in women with advanced ER+ breast cancer,” senior study author Dennis J. Slamon, MD, PhD, chief of the Division of Hematology/Oncology in the UCLA Department of Medicine, said when presenting the findings at ASCO.
The double-blind, placebo-controlled PALOMA-2 trial randomized 666 patients in a 2:1 ratio to palbociclib plus letrozole or letrozole alone. Palbociclib was administered at 125 mg daily for 3 weeks in a 28-day cycle. Continuous letrozole was administered at 2.5 mg.
Patients were enrolled between February 2013 and July 2014 in 186 locations across 17 countries. The data cutoff was February 26, 2016. The median follow-up was 23 months for the palbociclib combination arm and 22.3 months for the letrozole alone group.
Patient characteristics were well balanced between the study arms. The majority of patients were white, had an ECOG performance status of 0 or 1, and were less than 65 years old. The median patient age in the palbociclib and control arms was 62 and 61 years, respectively. About half of the patients in each arm had visceral metastases. Fifty-six percent of patients receiving palbociclib and 57% of patients in the letrozole-alone group had prior neoadjuvant and/or adjuvant hormonal therapy.
The primary endpoint for the trial was investigator-assessed PFS, with secondary outcome measures including response, overall survival, safety, biomarkers, and patient-reported outcomes.
The investigator-assessed median PFS with the palbociclib combination was 24.8 months versus 14.5 months with letrozole alone (HR, 0.58; 95% CI, 0.46-0.72; P
<.000001. The median PFS by blinded independent central review was 30.5 months versus 19.3 months, respectively (HR, 0.65; 95% CI, 0.51-0.84; P
= .0005). The objective response rate was 42% with the combination versus 35% in the control group.
The PFS benefit with palbociclib was sustained across subgroups. “All subgroups benefited, regardless of age, ethnicity, site of disease, prior hormonal therapy, disease-free interval, performance status, visceral metastases status, prior chemotherapy, or prior hormonal therapy,” said Slamon.
In the combination arm, the median treatment duration with palbociclib and letrozole was 19.9 and 20.3 months, respectively. In the control arm, the median duration of therapy with letrozole was 13.8 months. Seventy percent and 53% of patients receiving the combination had dose interruptions with palbociclib and letrozole, respectively. Forty-five percent of patients in the control arm had a dose interruption of letrozole.
Ninety-nine percent of patients in the palbociclib arm experienced a hematologic adverse event (AE) of any grade, including neutropenia (80%), leukopenia (39%), anemia (24%), and thrombocytopenia (16%). The grade 3 rates of these AEs in the palbociclib arm were 56%, 24%, 5%, and 1%, respectively and the grade 4 rates were 10%, 1%, <1%, and <1%, respectively. Overall, 62% and 14% of patients in the palbociclib arm experienced a grade 3 and grade 4 hematologic AE, respectively.
Ninety-five percent of patients in the letrozole-alone arm experienced a hematologic AE of any grade, including neutropenia (6%), leukopenia (2%), anemia (9%), and thrombocytopenia (1%). The grade 3 rates of these AEs in the control arm were 1%, 0, 2%, and 0, respectively, and neutropenia (<1%) was the only event among the four that produced a grade 4 AE. Overall, 22% and 2% of patients in the palbociclib arm experienced a grade 3 and grade 4 hematologic AE, respectively.
In the combination arm, the most common nonhematologic all-grade AEs included fatigue (37%), nausea (35%), arthralgia, (33%) alopecia (33%), diarrhea (26%), cough (25%), back pain (22%), headache (21%), and hot flush (21%). Sixty-two percent of patients in the palbociclib arm had a grade 3 nonhematologic AE, with the most frequent being fatigue (2%) and asthenia (2%). Grade 4 nonhematologic AEs occurred in 14% of patients in the palbociclib arm.