Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis
Menée à partir des données de 3 essais randomisés incluant 1 960 patientes atteintes d'un cancer du sein HR+ HER2- de stade avancé ou métastatique, cette étude évalue l'efficacité, du point de vue de la survie globale, des inhibiteurs de kinases CDK 4/6 en combinaison avec le fulvestrant
Background : Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved foruse in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breastcancer. We previously reported the pooled analyses of progression-free survival inpatients in specific clinicopathological subgroups, all of whom received consistentbenefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. Methods : In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients withbreast cancer submitted to the US Food and Drug Administration and approved beforeAug 1, 2020, in support of marketing applications. All analysed patients were agedat least 18 years, had an Eastern Cooperative Oncology Group performance status of0–1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer,and received at least one dose of CDKI or placebo in combination with fulvestrant.The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios(HRs) with corresponding 95% CIs were estimated using Cox regression models. Patientswere analysed collectively, by number of previous lines of systemic endocrine therapyin any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest.The estimated median overall survival was not reported by group when the pooled populationincluded patients treated across lines of therapy because of potential patient heterogeneity.All results presented are considered exploratory and hypothesis generating. Findings : Across the three pooled trials, 1960 patients were randomly assigned between Oct 7,2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients wererandomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948),the estimated HR for overall survival was 0·77 (95% CI 0·68–0·88), with a median follow-upof 43·7 months (IQR 37·8–47·7) and deaths in 935 (48%) of the 1948 patients. The differencein estimated median overall survival was 7·1 months, favouring CDKIs. In patientswho received CDKIs or placebo in combination with fulvestrant as first-line systemicendocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74(95% CI 0·52–1·07), with a median follow-up of 39·4 months (IQR 37·0–42·2). 123 (31%)of these patients died. The difference in estimated median overall survival couldnot be calculated because median overall survival was not estimable (95% CI 50·9–notestimable) in the CDKI group and was 45·7 months (95% CI 41·7–not estimable) in theplacebo group. In patients who received CDKIs or placebo in combination with fulvestrantas second-line or later systemic endocrine therapy (three trials; n=1552), the estimatedHR for overall survival was 0·77 (95% CI 0·67–0·89), with a median follow-up of 45·1months (95% CI 39·2–48·5). 812 (52%) of these patients died. The difference in estimatedmedian overall survival was 7·0 months, favouring CDKIs. Interpretation : The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefitin all pooled patients and within most clinicopathological subgroups of interest.These findings support the existing standard of care of CDKIs plus fulvestrant forthe treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer.
The Lancet Oncology 2021