The combination of palbociclib plus fulvestrant led to a clinically meaningful benefit in overall survival in patients with hormone receptor–positive, HER2-negative advanced breast cancer who had progressed or relapsed on prior endocrine therapy.
Massimo Cristofanilli, MD
The combination of palbociclib (Ibrance) plus fulvestrant (Faslodex) led to a clinically meaningful benefit in overall survival (OS) in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer who had progressed or relapsed on prior endocrine therapy, according to an analysis of the phase III PALOMA-3 study that was presented at the 2018 ESMO Congress.1 The regimen demonstrated a statistically significant 10.0-month OS improvement in patients who were sensitive to previous endocrine therapy.
At a median follow-up of 44.8 months in the intent-to-treat population, the palbociclib/fulvestrant combination demonstrated a median OS improvement of 6.9 months over fulvestrant plus placebo (stratified HR, 0.81; 95% (0.64-1.03); 1-sided P = .043), explained lead study author Massimo Cristofanilli, MD, during a press briefing at the meeting. The median OS with palbociclib/fulvestrant was 34.9 months (95% CI, 28.8-40.0) versus 28.0 months (95% CI, 23.6-34.6) with fulvestrant/placebo. Findings were simultaneously reported in the New England Journal of Medicine.1,2
“These findings confirm that the use of palbociclib plus fulvestrant is a standard of care now in previously treated patients with HR-positive, HER2-negative advanced breast cancer,” said Cristofanilli, who is a professor of medicine (hematology and oncology), Robert H. Lurie Comprehensive Cancer Center, at Feinberg School of Medicine at Northwestern University in Chicago, Illinois. “The combination of palbociclib/fulvestrant showed a clinically meaningful improvement in OS.”
The double-blind PALOMA-3 study randomized 521 patients with advanced breast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio to standard 500 mg of fulvestrant plus either 125 mg of daily oral palbociclib (n = 347) every 3 weeks or placebo (n = 174). Women were eligible for enrollment regardless of menopausal status.
In earlier findings published in Lancet Oncology,3 the median progression-free survival (PFS) was 9.5 months with palbociclib/fulvestrant compared with 4.6 months for fulvestrant alone (HR, 0.46; 95% CI, 0.36-0.59; P <.0001). These initial data were the basis for the FDA’s February 2016 approval for palbociclib in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
However, in June 2018, Pfizer, the manufacturer of palbociclib, reported that the combination failed to improve OS versus fulvestrant/placebo in PALOMA-3 for patients with HR-positive, HER2-negative metastatic breast cancer who received prior endocrine therapy. OS was a secondary endpoint of the study.
“The first [OS] analysis that was reported, in fact, statistically speaking, did not achieve statistical significance,” Cristofanilli said in an interview with OncLive. “But once we started to look at the different stratification factors, we probably identified one of the main reasons. The study was never designed of power to show overall survival. On top of that, we had this stratification, so patients were not equal—they had different sensitivities to endocrine therapy. Not only that, but even though the study did not allow crossover, [15% of patients] later on were treated with a CDK4/6 inhibitor. While we had some control of postprogression therapy, we did not have full control when we got to the use of CDK4/6 [inhibitors] once patients had progressed.”
In the 2018 ESMO Congress analysis, the updated median PFS was 11.2 months for palbociclib and 4.6 months for placebo (HR, 0.50; 95% CI, 0.40—0.62; P <.000001). In addition to the stratified HR for OS, Cristofanilli also reported an unstratified HR for OS of 0.79 (95% CI, 0.63-1.00; 1-sided P = 0.246).1,2
Results also were stratified by patients who had sensitivity to prior endocrine therapy. In patients with sensitivity, the median OS was 39.7 months (95% CI, 34.8-45.7) for those who were treated with palbociclib/fulvestrant (n = 274) and 29.7 months (95% CI, 23.8-37.9) for those who received placebo/fulvestrant (n = 136; HR, 0.72; 95% CI, 0.55-0.94; 1-sided P = .0081).
In patients without sensitivity to prior endocrine therapy, the median OS was 20.2 months (95% CI, 17.2-26.4) on the palbociclib/fulvestrant arm (n = 73) and 26.2 months (95% CI, 17.5-31.8) for those treated with placebo/fulvestrant (n = 38; HR, 1.14; 95% CI, 0.71-1.84; 1-sided P = .2969).
“There is an absolute difference of 6.9 months, similar to the PFS difference of 6.6 months, [along with] a significant 10-month improvement in OS in patients who had prior sensitivity to endocrine therapy,” Cristofanilli said.
Moreover, median OS improved significantly by 11.5 months in patients without visceral disease; it was 46.9 months (95% CI, 39.3-not estimable [NE]) with palbociclib/fulvestrant and 35.4 months (95% CI, 24.6-NE) with fulvestrant/placebo (HR, 0.69; 95% CI, 0.46-1.04).
Treatment with palbociclib also did not interfere with the type or efficacy of standard treatment following disease progression, Cristofanilli concluded. Also, no new safety signals were observed with the additional follow-up.
Nadia Harbeck, MD, PhD, head of the Breast Center and Oncology Day Clinic, Women's Hospital of the University of Munich, Germany, who is a co-author of the PALOMA-3 update, discussed the significance of the findings.
“We’ve seen the CDK4/6 inhibitors; there are 3 compounds from 3 different companies. They all prolong PFS, but there is still a lot of uncertainty about them in the community—whether to give these drugs, where to give these drugs, and also from the payer’s perspective, but there is no OS,” she explained. “Now this is going to change. A 10-month OS benefit in a CDK4/6 inhibitor study in the second-line setting is unprecedented and will change people’s hearts. We can now confidently say to our patients, ‘This is the drug to take—in my personal opinion also—in the first-line setting.’”
The FDA initially granted palbociclib an accelerated approval in February 2015 in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor—positive, HER2-negative metastatic breast cancer. A full approval for that indication was granted by the agency in March 2017.