The FDA has assigned a priority review designation to palbociclib in combination with letrozole as a frontline treatment for postmenopausal patients with ER-positive, HER2-negative advanced breast cancer, according to Pfizer, Inc., the company developing the drug. Under this program, the agency plans to take action on the drug's application within 6 months, placing a decision date on April 13, 2015.
The application for the CDK 4/6 inhibitor was based on data from the phase II open-label PALOMA-1 trial that compared palbociclib plus letrozole with letrozole alone in untreated patients with ER-positive, HER2-negative advanced breast cancer. A final analysis from this study revealed a 51% reduction in the risk of progression and a 29% decrease in the risk of death with the addition of palbociclib to letrozole compared with letrozole alone. The priority review follows a breakthrough therapy designation in April 2013.
“If approved as a first-line therapy in combination with letrozole, palbociclib will be an important new option for the thousands of women in the U.S. who are living with metastatic breast cancer,” Garry Nicholson, president, Pfizer Oncology, said in a statement. “We look forward to continuing to work closely with the FDA through the review process.”
The PALOMA-1 study randomized 165 postmenopausal patients with ER-positive, HER2-negative metastatic 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 progression-free survival (PFS) by investigator assessment.
According to an analysis presented at the 2014 AACR Annual Meeting in April 2014, the median PFS was 20.2 months with palbociclib compared with 10.2 months for letrozole alone (HR = 0.488; P
= .0004). The median overall survival (OS) was 37.5 months with palbociclib compared with 33.3 months with letrozole alone (HR = 0.813; 95% CI, 0.492-1.345; P
= .2105). This first analysis of OS contained data from only 61 patients (37%) and was not deemed statistically significant.
The most common adverse events in the palbociclib arm were neutropenia, leukopenia, anemia, and fatigue. Palbociclib-induced neutropenia was short lasting and reversible with conservative management. No cases of febrile neutropenia were reported.
Neutropenia is thought to be an on-target side effect of palbociclib that is related to the inhibition of CDK4 and its effect on bone marrow. Palbociclib inhibits both CDK4 and 6, which prevents DNA replication by prohibiting progression from G1 to S phase during cell division. Blocking this mechanism prevents tumor cell proliferation through control of the cell cycle.
Several phase III trials exploring palbociclib as a treatment for patients with advanced breast cancer are currently ongoing. The PALOMA-2 trial is comparing the combination of palbociclib and letrozole with letrozole plus placebo as frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427). The PALOMA-3 trial is comparing palbociclib plus fulvestrant with fulvestrant plus placebo in women with HR-positive, HER2-negative metastatic breast cancer following progression on prior endocrine therapy (NCT01942135).
Both phase III studies have reached their recruitment goals. As a result, in August Pfizer initiated an expanded access program. Through this program, the FDA allows access to investigational therapies for select patients who do not otherwise qualify for participation in a clinical trial. Patients with HER2-negative, ER-positive breast cancer enrolling in the phase III expanded access program will receive palbociclib in combination with letrozole (NCT02142868).
"With recruitment of new patients to our phase III PALOMA-2 and PALOMA-3 trials now complete, Pfizer is initiating the Palbociclib Expanded Access Program," Mace Rothenberg, MD, the senior vice president, Clinical Development and Medical Affairs, and chief medical officer, Pfizer Oncology, said in a statement. "This program will provide a mechanism by which eligible women who may benefit from treatment with palbociclib can gain access to this investigational therapy at this time.”
A number of investigator-led phase III trials have been established to explore palbociclib across a number of settings. The open-label phase III PEARL trial will compare exemestane plus palbociclib with capecitabine in HR-positive patients with metastatic breast cancer who are resistant to treatment with non-steroidal aromatase inhibitors (NCT02028507). Additionally, the phase III PENELOPE-B trial will examine post-neoadjuvant treatment with palbociclib plus endocrine therapy in HR-positive patients with residual disease following chemotherapy and surgery (NCT01864746).