Mace Rothenberg, MD
The Committee for Medicinal Products for Human Use (CHMP) has recommended approval of palbociclib (Ibrance) for patients with HR-positive, HER2-negative metastatic breast cancer, either in combination with an aromatase inhibitor in the frontline setting, or combined with fulvestrant after progression on endocrine therapy.
The application for the the CDK 4/6 inhibitor is based on findings from the PALOMA-1, PALOMA-2, and PALOMA-3 trials. The positive opinion has been sent to the European Commission (EC), which usually issues its final approval decision within 2 to 3 months of the CHMP recommendation.
“Today’s opinion by the CHMP to recommend marketing authorization of Ibrance in the EU is an important step toward expanding treatment options for women in Europe with HR+/HER2- metastatic breast cancer, and a step toward a potential new standard of care for this cancer,” Mace Rothenberg, MD, chief development officer, Pfizer Oncology said in a statement.
“The opinion is supported by robust data with consistent results observed across three separate randomized trials in which the addition of Ibrance to standard endocrine therapy resulted in significant prolongation of progression-free survival compared to endocrine therapy alone,” added Rothenberg.
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, 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 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 two 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 overall survival, 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.
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.
“There have been only modest improvements in the prognosis of patients with metastatic breast cancer in Europe over the past three decades, underscoring the need for new treatment advances,” Andreas Penk, MD, regional president, International Developed Markets, Pfizer Oncology, said in a statement. “We look forward to working with the EC as they conduct their review, with the goal of bringing this first-in-class medicine to appropriate patients across the EU.