MAINTAIN is the first randomised, placebo-controlled study to show the benefit of switching endocrine treatment and subsequent cyclin-dependent kinase 4/6 (CDK4/6) inhibitor after CDK4/6 inhibitor progression among patients with hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). There was a 43% risk reduction in the hazard of progression or death with ribociclib in the modified intention-to-treat (ITT) population, and a higher progression-free survival (PFS) rate at 6 and 12 months favouring those randomly assigned to ribociclib.
Like phase III studies with ribociclib, ribociclib and endocrine treatment demonstrated a manageable safety profile, with primarily haematologic events, in particular neutropenia, and low-grade non-haematologic side effects. Findings are published by Dr. Kevin Kalinsky of the Winship Cancer Institute, Emory University in Atlanta, GA, US, and colleagues on 19 May 2023 in the JCO.
The authors wrote in the background that CDK4/6 inhibition with endocrine treatment is standard of care in patients with HR-positive, HER2-negative MBC. In 3 randomised, placebo-controlled studies, combining ribociclib with endocrine treatment among patients without previous CDK4/6 inhibitor has resulted in improvement in PFS and overall survival (OS) versus endocrine treatment alone.
Although preclinical and clinical data demonstrate a benefit in changing endocrine treatment and continuing a CDK4/6 inhibitor at progression, no randomised prospective studies have evaluated this approach. The MAINTAIN investigators conducted a phase II, randomised, double-blind placebo-controlled study comparing switching endocrine treatment plus ribociclib versus switching endocrine treatment plus placebo in patients whose tumours progressed on any CDK4/6 inhibitor and endocrine treatment.
In this investigator-initiated study, patients switched endocrine treatment (fulvestrant or exemestane) from endocrine treatment used pre-random assignment and randomly assigned 1:1 to the CDK4/6 inhibitor ribociclib versus placebo. PFS was the primary endpoint, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, 80% power was needed to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%.
Of the 119 randomly assigned patients, 103 (86.5%) previously received palbociclib and 14 patients received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched endocrine treatment plus ribociclib with median 5.29 months (95% confidence interval [CI] 3.02 to 8.12 months) versus switched endocrine treatment plus placebo with median 2.76 months (95% CI 2.66 to 3.25 months); HR was 0.57 (95% CI 0.39 to 0.85; p = 0.006). At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib compared with 23.9% and 7.4% with placebo.
The authors concluded that MAINTAIN study informs treatment decisions for patients progressing on initial endocrine treatment with palbociclib. Additional studies are needed to compare this approach with other second-line endocrine treatment options such as phosphatidylinositol 3-kinase- and mammalian target of rapamycin-inhibitor based treatments.
With the limited benefit of fulvestrant as a single agent post-CDK4/6 inhibitor, these findings highlight the ongoing need to clarify and optimise sequencing of combined endocrine and targeted treatments, with the utilisation of biomarkers to guide this approach. Given the PFS improvement with currently available targeted treatments in HR-positive, HER2-negative MBC, ongoing studies will hopefully identify the ideal sequencing of endocrine treatment-based strategies to improve clinical outcomes while balancing side effects and quality-of-life.
The study was previously presented at the ASCO 2022 Annual Meeting (Chicago, IL, US, 3-7 June 2022).
This was investigator-initiated study with study and drug supply support from Novartis Pharmaceuticals, Breast Cancer Research Foundation.
Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer: MAINTAIN Trial. JCO; Published online 19 May 2023. DOI: 10.1200/JCO.22.02392