Acting two months ahead of its deadline, the FDA granted an accelerated approval to palbociclib (Ibrance) as a first-line treatment for patients with ER-positive metastatic breast cancer.
Richard S. Finn, MD
Acting two months ahead of schedule, the FDA has granted an accelerated approval to palbociclib (Ibrance) as a first-line treatment for patients with ER-positive metastatic breast cancer.
The approval was based on the open-label phase II PALOMA-1 trial, which showed that the novel CDK 4/6-inhibitor in combination with 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 with 10.2 months for letrozole alone (HR = 0.488;P= .0004).
"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."
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%.
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.
"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).