In a highly unusual move, the US FDA today approved Pfizer’s new breast cancer drug Ibrance (palbociclib) far before it’s expected April decision, and without the benefit of a pivotal Phase III clinical trial. Ibrance could become the new standard of care for advanced, metastatic breast cancer patients. The drug is now approved for breast cancer patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) tumors, which represent approximately 60% of the patient population.

The initial data from Ibrance’s Phase II study PALOMA-1 that the FDA was encouraged to approve this first-in-class drug. Ibrance is an oral cyclin-dependent kinase inhibitor which blocks the enzymes CDK4 and CDK6, both of which are commonly dysregulated in cancer and help spur uncontrolled growth of cancer cells.

PFS for palbociclib plus letrozole vs letrozole alone in Pfizer's PALOMA-1 Phase II study

PFS for palbociclib plus letrozole vs letrozole alone in Pfizer’s PALOMA-1 Phase II study

Pfizer’s PALOMA-1 Phase II study measured the current standard of care in this patient group, letrozole, with letrozole plus palbociclib. Pfizer recruited 2 sets of patients, 66 in Part 1 and 99 in Part 2, for a total of 165. The median progression-free survival (PFS) for the Part 1 group was 26.1 months with letrozole plus palbociclib compared with 5.7 months for letrozole alone. Those numbers were released with understandably great fanfare in 2012 at the 2012 San Antonio Breast Cancer Symposium. When the numbers were combined for Part 1 and 2 and reported at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego, the total median PFS for the letrozole plus palbociclib group dropped to 20.2 months, compared to 10.2 months for letrozole alone. Overall, this still almost doubled PFS over the current standard of care.

The most frequently reported adverse event for palbociclib plus letrozole in PALOMA-1 was neutropenia. Adverse events associated more frequently with the combination than with letrozole alone included neutropenia (grade 3, 48%, grade 4, 6%), leukopenia (grade 3, 19%), fatigue, and anemia.

Pfizer’s Senior Vice President of Clinical Development and Medical Affairs, Mace Rothenberg, said, “This approval represents the first treatment advance for this group of women in more than 10 years.” Their Phase III trial, PALOMA-2, is fully enrolled and will continue.

One note of concern with Ibrance is the sometimes elusive data point of overall survival (OS). It’s widely believed that progression-free survival is an easier gauge than overall survival, and in this case, a dramatic improvement in PFS did not translate well to an improvement in OS. While PFS was dramatically improved in patients treated with the combination of palbociclib and letrozole, the difference in overall survival compared to the letrozole group alone (37.5 vs. 33.3 months, respectively) was not statistically significant. Pfizer has not updated the overall survival data from the trial since April 6, 2014.

Ibrance continues to be tested in a wide variety of cancers, including brainstem gliomas, lymphomas, multiple myeloma, non-small cell lung cancer, and GI stromal tumors. Studies of the effects of proton pump inhibitors and H2-receptor antagonists (antacids) on the absorption of palbociclib are ongoing.