FDA Approves Palbociclib for Metastatic Breast Cancer

Richard Pazdur, MD

The FDA has granted an accelerated approval to palbociclib (Ibrance) 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 the novel CDK 4/6-inhibitor 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).

Palbociclib 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.

“The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in a statement. “The FDA is committed to expediting marketing approval of cancer drugs through our accelerated approval regulations.”

The 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.

At the final analysis from the trial that was presented at the 2014 AACR Annual Meeting in April 2014, 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.

In Part 1 of the study, the median PFS was 26.7 months with palbociclib versus 5.7 months for letrozole alone (HR = 0.299; 95% CI, 0.156-0.572; P = .0001). In the larger Part 2, the median PFS was 18.1 versus 11.1 months, for palbociclib combination and letrozole, respectively (HR = 0.508; 95% CI, 0.303-0.853; P = .0046). The combination resulted in a response rate of 45% compared with 31% for the monotherapy and the overall clinical benefit rate was 70% versus 44%. 

"Palbociclib is the first drug in its class to be approved by the FDA," lead investigator Richard Finn, MD, from the Jonsson Comprehensive Cancer Center at UCLA, said in a statement. "What is really remarkable is that we doubled the median progression-free survival. That type of result is not often seen in cancer medicine."

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.

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%).

"With the FDA approval, this study represents a potential practice-changing result," the study’s coauthor Dennis Slamon, MD, PhD, professor of medicine and director of the Revlon/UCLA Women’s Cancer Research Program, said in a statement. "I believe palbociclib will now become a standard treatment approach for postmenopausal women with ER+/HER2- metastatic breast cancer."

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).