The PALOMA-3 trial examining a palbociclib regimen in HR+/HER2- breast cancer was halted after an independent panel determined it met the primary endpoint of improving progression-free survival (PFS).
Mace Rothenberg, MD
The PALOMA-3 trial examining a palbociclib regimen in HR+/HER2- breast cancer was halted after an independent panel determined it met the primary endpoint of improving progression-free survival (PFS), as announced by Pfizer, the company developing palbociclib. Pfizer noted that these are the first randomized phase III data reported for the CDK 4/6 inhibitor.
“We’re gratified to be able to stop the trial early and are engaging in discussions with health authorities regarding a regulatory path forward,” Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology, said in a statement.
The 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 placebo or palbociclib. Faslodex 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.
Beyond the primary PFS endpoint, secondary endpoints for the trial included overall survival, objective response, and duration of response. The adverse events reported for the palbociclib/fulvestrant combination were commensurate with those observed with previous single-agent use of the drugs. Pfizer intends to submit the full results from the study for presentation at the 2015 ASCO Annual Meeting in June.
While not approved for the use explored in PALOMA-3, palbociclib has received an FDA accelerated approval as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on findings from the phase II PALOMA-1 trial.
In the open-label phase II study, treatment with palbociclib plus letrozole reduced the risk of disease progression by 51% compared with letrozole alone. The median PFS with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR = 0.488;P= .0004).
PALOMA-1 trial randomized 165 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer in a 1:1 ratio in two 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.
The rate of grade 3/4 neutropenia was significantly higher in the palbociclib arm compared with letrozole alone (54% vs 1%). Additionally, the rate of grade 3/4 leucopenia (19% vs 0%) and fatigue (4% vs 1%) were higher with palbociclib. No cases of febrile neutropenia or neutropenia-related infections were reported in the study.
Altogether, 13% of patients discontinued treatment as a result of side effects in the palbociclib arm compared with 2% for letrozole. The most frequently reported serious adverse events with the combination were pulmonary embolism (4%) and diarrhea (2%).
At the time of approval, PALOMA-1 coauthor Dennis Slamon, MD, PhD, heralded the decision. “With the FDA approval, this study represents a potential practice-changing result. I believe palbociclib will now become a standard treatment approach for postmenopausal women with ER+/HER2- metastatic breast cancer,” Slamon, a professor of medicine and director of the Revlon/UCLA Women’s Cancer Research Program, said in a statement.
The confirmatory phase III trial for palbociclib’s accelerated approval is PALOMA-2. This study is comparing the combination of palbociclib and letrozole with letrozole alone as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427).