Palbociclib Approval Will Improve Quality of Life for Late-Stage Breast Cancer Patients

The big difference in progression-free survival seen in pivotal trial data propelled palbociclib to its accelerated FDA approval for the treatment of metastatic breast cancer, bringing with it the potential for the drug to quickly become adapted as the new standard of care, Brian Wojciechowski, MD, said.

The phase II PALOMA-1 trial, comparing palbociclib plus letrozole to letrozole alone, found that the combination reduced the risk of disease progression by 51%. The median progression-free survival (PFS) with palbociclib was 20.2 versus 10.2 months for letrozole alone (HR = 0.488; P = .0004).

“It’s not common to see such a drastic difference like this,” he said. “This drug, having been approved, will make a very big difference in women with stage IV breast cancer that’s hormone receptor positive.”

Palbociclib, a novel CDK 4/6 inhibitor, was approved under the FDA's breakthrough therapy designation and priority review program, which provides an expedited approval process for treatments that provide a substantial benefit over current options. The FDA was not scheduled to make a decision on the drug's application until April 2015.

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.

Palbociclib is the first drug in this class to be approved.

Wojciechowski, a medical advisor with Breastcancer.org and a private-practice oncologist, said that when treating stage IV breast cancer patients, physicians are only trying to extend the patient’s life as long as possible while maintaining a good functional status so that patients can “live their life the way they want to live it and not be limited by the side effects from therapy.”

While the side effects of palbociclib are manageable and better tolerated than chemotherapy, there are some things that physicians and nurses will have to be aware of.

The study found that 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.

Oncology nurses need to keep an eye on leucopenia, Wojciechowski said.

“Because of the potential of a decreased blood count, nurses should be aware of the potential threat for fevers and infections on this drug,” he said. “Fever plus a low white blood cell count is an emergency.”

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%).

A number of 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, many of 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).

Additionally, the open-label phase III PEARL trial will compare exemestane plus palbociclib with capecitabine in a 1:1 ratio for patients with HR-positive 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).

However, Wojciechowski says palbociclib may have some utility in the adjuvant setting as well to increase the chance of breast cancer cure. And since the agent targets the cell cycle and not a specific target, it also may prove to be a promising treatment for other solid tumors.