San Diego, CA—Palbociclib, an inhibitor of cyclin-dependent kinase (CDK) 4/6, demonstrated “striking” activity when combined with conventional hormone therapy for patients with metastatic breast cancer, according to the results of an open-label phase 2 trial presented at the 2014 American Association for Cancer Research annual meeting.
Patients who received palbociclib in addition to letrozole had a median progression-free survival (PFS) of 20.2 months compared with 10.2 months for patients who received letrozole alone as first-line therapy. The positive outcome owes to a combination of better patient selection and better therapy, said Richard S. Finn, MD, Assistant Professor of Medicine, University of California, Los Angeles, at the 2014 American Association for Cancer Research meeting.
“Two prominent reasons for this success are that we identified a subtype of breast cancer—hormone receptor-positive, HER2-negative—most likely to respond to the therapy, and we had a much-improved second-generation inhibitor of CDK 4/6,” said Dr Finn. “Palbociclib is very specific and efficient in blocking CDK 4/6, which results in less toxicity.”
The outcome of the randomized, phase 2 trial left a major question unanswered: why patients chosen on the basis of estrogen receptor (ER) positivity had better PFS with palbociclib than those selected for ER positivity and CDK 4/6 expression.
Invited discussant José Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan Kettering Cancer Center, New York, said that confirmation of the “strikingly positive” results in phase 3 studies could make palbociclib a new therapeutic standard for patients with advanced ER-positive breast cancer. Dr Baselga also cautioned that positive phase 2 results do not always translate into positive phase 3 trials, singling out the PARP (poly[ADP-ribose] polymerase) inhibitor iniparib as a prime example.
Dr Finn reported findings from a trial conducted in 2 phases involving biomarker-selected patients. Investigators in the multicenter trial first evaluated the combination of palbociclib and letrozole in patients with ER-positive breast cancer. During the second phase, patients were chosen on the basis of having ER-positive tumors that also expressed CDK 4/6.
The trial involved a total of 165 women with previously untreated metastatic breast cancer. During the first phase, 66 patients with ER-positive breast cancer were randomized to receive letrozole with or without palbociclib. During the second phase, investigators randomized 99 patients with ER-positive, CDK 4/6–positive breast cancer to the same 2 treatment regimens.
The primary end point was PFS, and the 10-month differential in favor of the palbociclib regimen resulted from combining the PFS results from the 2 phases. During the first phase, the combination led to a median PFS of 26.7 months compared with 5.8 months with letrozole alone. In the second part of the trial, patients chosen on the basis of both biomarkers had a median PFS of 18.1 months with letrozole plus the PARP inhibitor palbociclib compared with 11.1 months for letrozole alone.
The reason for the apparent disconnect between PFS benefit and biomarker status was not clear, said Dr Finn. He noted that patient selection could have focused on other potential biomarkers. Preclinical studies showed that response to palbociclib in ER-positive breast cancer was associated with overexpression of cyclin D1 and retinoblastoma protein, as well as downregulation of p16. The use of a different biomarker or biomarker profile to select patients might have led to different results.
Another possible explanation is that ER positivity is the key factor in response to the CDK 4/6 inhibitor, Dr Finn added.
Overall survival did not differ significantly between the treatment groups: 37.5 months with palbociclib and 33.3 months with letrozole alone. However, Dr Finn pointed out that survival data are immature and will continue to be analyzed.
In general, palbociclib was tolerated. The most frequently reported adverse events in patients treated with letrozole plus palbociclib were neutropenia, leukopenia, fatigue, and anemia. Adverse events were mostly grade 1/2 in severity, with the exception of grade 3/4 neutropenia, which occurred in more than 50% of patients who received palbociclib (grade 3 in 48% of patients).
Phase 3 trials of palbociclib have already begun, one of which is evaluating the CDK 4/6 inhibitor with letrozole and the other in combination with fulvestrant.