The European Commission has approved the CDK4/6 inhibitor palbociclib as a treatment for adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor in the frontline setting or combined with fulvestrant after progression on endocrine therapy.
“Today’s approval of Ibrance in the European Union brings an innovative and much-needed new treatment option to tens of thousands of women with HR+/HER2- metastatic breast cancer,” Andreas Penk, MD, regional president, International Developed Markets, Pfizer Oncology, the manufacturer of palbociclib. “With strong and consistent data in 3 pivotal clinical studies and rapid adoption as a standard of care in the United States, Ibrance represents a potential new benchmark for the treatment of HR+/HER2- metastatic breast cancer in Europe.”
The approval of the CDK 4/6 inhibitor was based on findings from the PALOMA-1, PALOMA-2, and PALOMA-3 trials.
The open-label phase II PALOMA-1 trial randomized 165 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer in a 1:1 ratio in 2 parts: Part 1 contained 66 patients and Part 2 had 99 patients. Continuous daily letrozole was administered at 2.5 mg with or without palbociclib at 125 mg daily for 3 weeks followed by 1 week of rest until progression. The primary endpoint was PFS by investigator assessment.
Palbociclib plus letrozole reduced the risk of disease progression by 51% compared with letrozole alone. The median progression-free survival (PFS) with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR, 0.488;P= .0004).
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. The primary endpoint for the trial was investigator-assessed PFS, with secondary outcome measures including response, overall survival (OS), 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.
Serious adverse events (AEs) occurred in 19.6% of the palbociclib arm compared with 12.6% of the control arm. The most common serious AEs with the palbociclib combination versus letrozole alone were neutropenia (1.6% vs 0) and pulmonary embolism (0.9% vs 1.4%).
Treatment-related discontinuations occurred in 9.7% of the palbociclib arm compared with 5.9% of the placebo arm. Deaths related to AEs occurred in 2.3% and 1.8% of the 2 arms, respectively. In the control arm, there was one on-study death due to pulmonary embolism/respiratory failure that the investigator considered treatment-related.
The double-blind, multicenter PALOMA-3 study randomized 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio to fulvestrant plus either palbociclib (n = 347) or placebo (n = 174).
Fulvestrant was administered at 500 mg (IM) on days 1 and 15 of cycle 1, and then on day 1 of each cycle thereafter, and patients received oral palbociclib at 125 mg/day continuously for the first 3 weeks of each cycle, followed by 1 week off. Treatment cycles were 28 days for both arms. Goserelin was also administered to pre- and perimenopausal patients.
PFS was the primary outcome measure, with secondary objectives focusing on OS, response, and safety. Following 195 PFS events, the trial was halted in April 2015 after an independent panel determined the study had met its primary endpoint.
Median PFS was 9.5 months with the palbociclib combination versus 4.6 months in the placebo arm (HR, 0.461; 95% CI, 0.360-0.591;P<.0001). The PFS benefit was observed regardless of menopause status and remained consistent across all prespecified patient subgroups.
“Palbociclib is an exciting advance in the management of women with hormone receptorpositive breast cancer. Patients with this type of breast cancer are usually treated with hormone therapy but many will progress or relapse and as a result require chemotherapy, which often comes with life-limiting side effects,” Nicholas Turner, MD, PhD, principal investigator of the PALOMA-3 trial and team leader at The Institute of Cancer Research, London, said in a statement.
Neutropenia (66%) and leukopenia (31%) were the most common grade 3/4 AEs. The most frequently reported serious AEs in the palbociclib arm were infections, pyrexia, neutropenia, and pulmonary embolism. Dose reductions related to AEs occurred in 36% of patients, and 6% of patients discontinued treatment due to AEs.