Combining an investigational agent called PD 0332991 with letrozole(Drug information on letrozole) improved progression-free survival (PFS) over letrozole alone in women with advanced estrogen receptor (ER)-positive breast cancer, according to a study presented at the San Antonio Breast Cancer Symposium (SABCS) this week.
“This drug combination demonstrated a dramatic and clinically meaningful effect on PFS in women with ER-positive breast cancer,” said Richard S. Finn, MD, an associate professor of medicine at the University of California, Los Angeles, who led the study. “These results confirm the preclinical work.”
PD 0332991 is an oral, highly selective inhibitor of cyclin dependent kinase (CDK) 4/6. Preclinical research showed that the agent blocked CDK 4/6 and thus the growth of ER-positive and HER2-amplified cancer cells.
The new phase II study involved two distinct parts: in the first, 66 postmenopausal women with metastatic ER-positive breast cancer were randomized to either a combination of the new agent with letrozole or letrozole alone. In the second part of the trial, 99 more patients were enrolled based on genomic alterations including cylin D1 amplification and/or p16 loss. Overall, 84 patients received the combination and 81 received letrozole alone.
The median PFS was 26.1 months for the combination therapy patients and 7.5 months in the letrozole alone group, for a hazard ratio for progression of 0.37 (95% CI, 0.21-0.63; P < .001). The objective response rate was 34% in the combined group and 26% in the letrozole alone group, in an intent-to-treat analysis. These rates were 45% and 31%, respectively, in patients with measurable disease. Thirty percent of combined therapy patients had stable disease at or beyond 24 weeks, compared with 15% in the letrozole alone group.
The researchers said the combination was well tolerated in general. Among the more common adverse events were leucopenia, anemia, fatigue, alopecia, and arthralgia; neutropenia was the most common, but Finn said, “importantly, this was uncomplicated neutropenia.” There was no evidence of febrile neutropenia, he said.
“If these results are verified in a large, phase III study this could establish PD 0332991 as an important new treatment option for advanced ER-positive breast cancer in a frontline setting,” Finn said. The study’s senior author, Dennis Slamon, MD, also of UCLA, added “these results are as exciting as the initial results we saw for trastuzumab(Drug information on trastuzumab) in HER2-positive breast cancers but represent a new approach for a different and larger subset of breast cancers, ie, those that are ER-positive.”
Patients were generally well matched across the two groups. Most patients (95% of combined group, 93% of letrozole alone group) had stage IV disease, and an ECOG performance status of 0. Of the combined therapy patients, 52% had no prior systemic treatment, compared with 46% in the letrozole group; 40% and 46%, respectively had prior chemotherapy, and 31% and 35%, respectively, had prior hormonal therapy including tamoxifen(Drug information on tamoxifen), anastrozole(Drug information on anastrozole), letrozole, or exemestane(Drug information on exemestane).