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Palbociclib plus letrozole doubled PFS in advanced HER-2-negative breast cancer
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The addition of palbociclib to letrozole as first-line treatment nearly doubled PFS in patients with advanced ER-positive, HER-2–negative breast cancer, according to results of a phase 2 trial.
“We’re essentially putting the brakes on cell proliferation and causing these tumor cells to stop growing,” researcher Richard S. Finn, MD, associate professor of medicine at University of California, Los Angeles, said in a press release. “With the addition of palbociclib, PFS effectively doubled. That type of result is not often seen in cancer medicine.”
Finn and colleagues evaluated data from 165 postmenopausal women who had not received previous systemic treatment for their advanced disease.
Researchers enrolled patients in two cohorts. The 66 patients in the first cohort were enrolled on the basis of their ER-positive, HER-2–negative disease alone. The 99 patients in the second cohort exhibited these features as well as the overexpression of cyclin D1 (CCND1), loss of p16 (also known as INK4A or CDKN2A) or both.
About half of the patients in both cohorts were randomly assigned to 28-day cycles of 2.5 mg daily letrozole alone (n=81). The remaining 84 patients received letrozole plus 125 mg palbociclib (PD-0332991, Pfizer) — a cyclin-dependent kinase (CDK) 4/6 inhibitor — once daily for 3 weeks followed by 1 week off.
Median follow-up for the current, final PFS analysis was 29.6 months for the letrozole plus palbociclib arm and 27.9 months for the letrozole-only arm. By this time, 59 PFS events had occurred in the letrozole arm compared with 41 events in the combination arm.
Overall, median PFS was 20.2 months in the palbociclib arm (95% CI, 13.8-27.5) vs. 10.2 months (95% CI, 5.7-12.6) in the letrozole arm (HR=0.48; 95% CI, 0.31-0.74).
In the first cohort, median PFS was 26.1 months (95% CI, 11.2-not estimable) in the palbociclib arm and 5.7 months (95% CI, 2.6-10.5) in the letrozole arm. Median PFS also was higher in the palbociclib arm (18.1 months; 95% CI, 13.1-27.5) than the letrozole arm (11.1 months; 95% CI, 7.1-16.4) in the second cohort.
Palbociclib was associated with a significant reduction in the risk for a PFS event in the first (HR=0.29; 95% CI, 0.15-0.57) and second cohorts (HR=0.5; 05% CI, 0.3-0.85).
More patients who received palbociclib experienced grade 3 to grade 4 neutropenia (54% vs. 1%), leucopenia (19% vs. 0%) and fatigue (4% vs. 1%). Serious adverse events associated with palbociclib included pulmonary embolism (4%), back pain (2%) and diarrhea (2%). Treatment discontinuation due to adverse events also occurred more frequently in the palbociclib arm (13% vs. 2%).
The researchers observed no cases of febrile neutropenia or neutropenia-related infections.
“These data clearly warrant further investigation of the efficacy and safety of palbociclib in combination with hormonal blockade, both in patients with this subtype of breast cancer and in other cancer settings,” Finn and colleagues concluded. “A phase 3, double-blind, placebo-controlled studying in a similar patient population with the aim of confirming the present phase 2 findings is now fully enrolled and ongoing.”
These results demonstrate the promise of CDK4/6 inhibitors in this setting, Michael Gnant, MD; Guenther G. Steger, MD; and Rupert Bartsch, MD, all of the Breast Health Center of the Comprehensive Cancer Center at the Medical University of Vienna, wrote in an accompanying editorial.
“Doubling PFS matters to our patients and is something that physicians have been long waiting to see,” Gnant, Steger and Bartsch wrote. “In a population that usually presents with few or no disease-related symptoms, the clinical relevance of prolonged PFS can only be claimed when toxic effects are acceptable. Here, this seems to be the case. Therefore, and with all due caution, based on sound preclinical evidence and these new clinical results, we believe that CDK4/6 inhibitors are here to stay.”
For more information:
Finn RS. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)71159-3.
Gnant M. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)71188-X.
Disclosure: The study was funded in part by Pfizer. One researcher reports research funding for CDK4/6 inhibition from the US Department of Defense Breast Cancer Innovator Award, the Revlon/UCLA Women’s Cancer Research Program and the Peter and Denise Wittich Breast Cancer Program. Gnant, Steger and Bartsch report no relevant