The benefit of OS confirmed with the Palbociclib combo in HR + / HER2 breast cancer pre-treated

Massimo Cristofanilli, MD

The association palbociclib (Ibrance) and fulvestrant (Faslodex) resulted in a clinically significant benefit in terms of overall survival (OS) in patients with advanced HER2-negative breast cancer presenting with treatment progression or relapse, before prior endocrine treatment. , according to an analysis of the PALOMA-3 Phase III study presented at the ESMO 2018 congress.¹ The regimen showed a statistically significant improvement in OS of 10.0 months in patients with previous endocrine sensitivity.

After a median follow-up of 44.8 months in the intention-to-treat population, the combination of palbociclib / fulvestrant showed a median OS improvement of 6.9 months compared with fulvestrant plus placebo (stratified CT, 0, 81; 95% (0.64-1.03) 1; side P = .043), explained the lead author of the study, Massimo Cristofanilli, during a press briefing during the meeting. The median IL associated with palbociclib / fulvestrant was 34.9 months (95% CI, 28.8 to 40.0) compared with 28.0 months (95% CI, 23.6 to 34.6) with fulvestrant / placebo. The results were reported simultaneously in the New England Journal of Medicine.^1.2

"These results confirm that the use of palbociclib plus fulvestrant is a standard of treatment in patients already treated with advanced breast cancer, HR-positive and HER2-negative," said Cristofanilli, professor of medicine (hematology and Oncology), H. Lurie Center for Cancer Control, at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois. "The combination palbociclib / fulvestrant has shown a clinically significant improvement in SG."

The double-blind PALOMA-3 study randomized 521 patients with advanced breast cancer whose disease was endocrine-treated or endocrine-treated at a ratio of 2: 1 to the standard dose of 500 mg. fulvestrant plus 125 mg of oral palbociclib per day weeks or placebo (n = 174). Women were eligible for registration regardless of their menopausal status.

In previous conclusions published in Oncology Lancet,³ 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 baseline data were the basis of FDA approval in February 2016 of palbociclib in combination with fulvestrant for the treatment of women with advanced or metastatic breast cancer with positive HR, HER2 negative, evolving after endocrine therapy.

However, in June 2018, Pfizer, the manufacturer of palbociclib, reported that PALOMA-3 did not allow to improve SG compared to fulvestrant / placebo in patients with metastatic breast cancer. positive, HER2-negative, previously treated with endocrine. SE was a secondary evaluation criterion of the study.

"The first [OS] analysis that was reported, in fact, statistically speaking, did not reach statistical significance, "said Cristofanilli in an interview with OncLive. "But once we started looking at the different stratification factors, we probably identified one of the main reasons. The study was never designed to show overall survival. On top of that, we had this stratification, so the patients were not equal – they had different sensitivities to endocrine therapy. Not only that, but even if the study did not allow crossover, [15% of patients] were treated with a CDK4 / 6 inhibitor. Although we had some control of the postprogression treatment, we did not have complete control when we used CDK4 / 6. [inhibitors] once the patients have progressed. "

In the analysis of the ESMO congress of 2018, the updated median PFS was 11.2 months for palbociclib and 4.6 months for placebo (HR, 0.50, 95% CI, 0, 40-.62; P <0.000001). In addition to HR stratification for SG, Cristofanilli also reported unstratified HR for OS of 0.79 (95% CI, 0.63 to 1.00; P = 0.246).^1.2

The results were also stratified by patients with sensitivity to previous endocrine therapy. In patients with sensitivity, the median value of OS was 39.7 months (95% CI, 34.8-45.7) for those treated with palbociclib / fulvestrant (n = 274) and 29.7 months (95% CI, 23.8 to 37.9) for placebo / fulvestrant (n = 136, HR, 0.72, 95% CI, 0.55 to 0.94, one side P = 0.0081).

In patients not sensitive to previous endocrine therapy, the median value of OS was 20.2 months (95% CI, 17.2 to 26.4) for the palbociclib / fulvestrant arm (n = 73) and 26.2 months (95% CI, 17.5 to 31.8) for treated patients. with placebo / fulvestrant (n = 38, HR, 1.14, 95% CI, 0.71 to 1.84, 1 side P = 0.2969).

"There is an absolute difference of 6.9 months, similar to the 6.6-month PFS difference, [along with] a significant 10-month improvement in SG in patients who already had sensitivity to endocrine therapy, "said Cristofanilli.