Much anticipated overall survival data for palbociclib (Ibrance) plus fulvestrant (Faslodex) in advanced breast cancer were presented at the European Society for Medical Oncology (ESMO) 2018 Congress.¹ Although overall survival in PALOMA-3 was not designed to detect a statistically significant difference, the investigators suggested that a 7-month benefit is “clinically meaningful” and provides evidence of the regimen’s benefit.

Massimo Cristofanilli, MD

“This was a very clinically meaningful overall survival difference. They are the first data of this type that we have with this class of drugs,” said Massimo Cristofanilli, MD, of Northwestern University, Chicago, who presented the findings at a Presidential Symposium. The findings were simultaneously published in The New England Journal of Medicine.²

Overall survival was a secondary endpoint of PALOMA-3, and the trial design was not optimized to detect a statistically significant difference, Dr. Cristofanilli emphasized. For patients receiving the combination of palbociclib and fulvestrant, the median overall survival was 34.9 months vs 28.0 months for those treated with fulvestrant alone (stratified hazard ratio [HR] = 0.81; P = .09). The difference stretched to 10 months in endocrine-sensitive patients.

The results, according to Dr. Cristofanilli, elevate palbociclib plus fulvestrant to a new second-line standard of care for those with previously treated hormone receptor–positive advanced breast cancer.

Key Data for Oncologists

Palbociclib is the first of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors to be approved, in conjunction with endocrine therapy, for patients with advanced breast cancer progressing on prior endocrine therapy. However, as there has been no evidence of an overall survival benefit with this treatment regimen, some oncologists have not embraced it.

For patients who are sensitive to prior endocrine therapy, a 10-month difference in survival is quite significant, even though not statistically.

— Massimo Cristofanilli, MD

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“Physicians in the United States have been on the fence about the first-line treatment [with CDK4/6 inhibitors]. I would argue that for patients who are sensitive to prior endocrine therapy, most of whom received 3 prior lines in this study, a 10-month difference in survival is quite significant, even though not statistically,” said Dr. Cristofanilli. “We also show a significant delay in starting chemotherapy, so there’s an impact on quality of life.”

“There is no doubt in my mind that these data will contribute to convincing oncologists that a CDK4/6 inhibitor is definitely the best drug, at least for the second-line treatment of endocrine-insensitive disease, for which we need better control,” he said. “These data support that.”

Study Findings

PALOMA-3 randomly assigned 521 patients with hormone receptor–positive HER2-negative advanced breast cancer after disease progression on endocrine treatment 2:1 to receive fulvestrant at 500 mg plus either 125 mg/d of palbociclib every 3 weeks or placebo. The median follow-up was 44.8 months, with a 60% data maturity for overall survival.

Overall -survival improved by an absolute 6.9 months with the addition of -palbociclib to fulvestrant, vs fulvestrant alone, but the difference did not reach the prespecified threshold for statistical significance. The median survival for the combination was 34.9 months vs 28.0 months (stratified HR = 0.81; one-sided P = .0429).

When patients were analyzed based on prior endocrine sensitivity, the bulk of the benefit was seen in those with such sensitivity. For these patients, a 10-month improvement was observed, with a median survival of 39.7 months for the combination vs 29.7 months with fulvestrant alone (HR = 0.72; one-sided P = .0081). In contrast, for patients without endocrine sensitivity, the median overall survival was considerably shorter, 20.2 vs 26.2 months (HR = 1.14; P = .2969).

The combination therapy also improved survival in the postmenopausal subgroup (34.8 vs 27.1 months) but not in the smaller premenopausal subgroup (38.0 months each). In patients with visceral disease, the absolute benefit was 11.5 months. And the regimen prolonged the median time to chemotherapy, from 8.8 months with fulvestrant alone to 17.6 months with the combination therapy, and improved quality-of-life scores, he said.

In the updated progression-free survival analysis of -PALOMA-3, the combination therapy resulted in a statistically significant 6.6-month median improvement compared with placebo plus fulvestrant (11.2 vs 4.6 months; HR = 0.50: P < .000001). “This is very important for patients, as it shows that the improvement in progression-free survival observed in previous studies may have a positive impact on overall survival, which is our ultimate goal of treatment,” Dr. Cristofanilli commented.

Study Limitations

He elaborated on the lack of a statistical difference in survival. Besides the lack of power according to the study design, the benefit was skewed toward endocrine-sensitive patients. And (despite restrictions), 16% of patients crossed over from placebo to CDK4/6 inhibition after disease progression, which may have diluted the outcome, he added.

According to Dr. Cristofanilli, the findings establish the importance of palbociclib/fulvestrant but do not extend to other drugs in this class, at least not yet. “CDK4/6 inhibitors have some difference. I would not extrapolate the findings to other CDK4/6 inhibitors at this point,” he noted. ■

DISCLOSURE: Dr. Cristofanilli has received personal fees from Pfizer, Novartis, and Merus.

REFERENCES

1. Cristofanilli M, Slamon DJ, Ro J, et al: Overall survival with palbociclib plus fulvestrant in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Analyses from PALOMA-3. 2018 ESMO Congress. Abstract LBA2. Presented October 20, 2018.

2. Turner NC, Slamon DJ, Ro J, et al: Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. October 20, 2018 (early release online).