FDA Approval Sought for Palbociclib in Breast Cancer

A New Drug Application has been submitted to the FDA for palbociclib plus letrozole as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer.

Mace Rothenberg, MD

A New Drug Application has been submitted to the FDA for palbociclib plus letrozole as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer, according to Pfizer, the company that develops the drug.

The application is based on findings from the phase II PALOMA-1 trial and will be reviewed within 60 days, at which point the agency will establish a PDUFA review timeline. The fastest review under this program provides a decision within 6 months.

“Palbociclib is being evaluated as a potential new treatment for women with HR-positive, HER2-negative advanced breast cancer, who represent the largest subgroup of women with this disease,” Mace Rothenberg, MD, the senior vice president, Clinical Development and Medical Affairs, and chief medical officer, Pfizer Oncology, said in a statement. “As announced this week, we have completed the submission of a New Drug Application for palbociclib in the U.S. based on the results of our phase II, PALOMA-1 study."

Inhibition of CDK 4/6 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. The rationale for the combination of an aromatase inhibitor with palbociclib stemmed from early preclinical evidence suggesting that CDK 4/6 is more active in patients with ER-positive breast cancer, as a result of an intact retinoblastoma (Rb)-pathway.

In the open-label PALOMA-1 study, 165 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer were randomized 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.

According to an update 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). However, this first analysis of OS contained data from only 61 patients (37%) and was not deemed statistically significant.

The most commonly reported treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. Neutropenia in the study was not cumulative and febrile neutropenia was not reported.

A number of Pfizer-sponsored phase III clinical trials are exploring palbociclib as a treatment for patients with advanced breast cancer. Given the benefit demonstrated in the PALOMA-1 trial, these studies will be randomized in a 2:1 ratio favoring treatment with palbociclib

The PALOMA-2 trial 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). The PALOMA-3 trial is comparing palbociclib plus fulvestrant against fulvestrant alone in women with HR-positive, HER2-negative metastatic breast cancer following progression on prior endocrine therapy (NCT01942135).

"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," Rothenberg said in a release. "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.”

Under the expanded access 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 that enroll in the phase III expanded access program will receive palbociclib in combination with letrozole (NCT02142868).

In addition to Pfizer sponsored studies, a number of investigator-led phase III trials have been established to explore palbociclib across a number of settings. These studies randomize patients in a 1:1 ratio to palbociclib in combination with hormonal therapy or chemotherapy.

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). 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).