Title of Research Proposal: Clinical implications of body mass index and weight in metastatic breast cancer patients receiving abemaciclib. A combined individual patient level data sub-analysis of MONARCH 2 and MONARCH 3 trials
Potential Conflicts of Interest: None.
In the metastatic setting the prognostic relationship between body max index (BMI) and prognosis is still debatable, as results are contradictory. Recent findings in metastatic breast cancer differ with data from studies in early-stage BC, as they show that, paradoxically, obesity may be a potential protective factor in the metastatic setting. This favourable aspect of obesity appeared also in patients with metastatic solid tumours treated with immunotherapy. Additional research is needed to clarify the complex relationship between BMI in metastatic BC to tailor weight management strategies after cancer diagnosis and hopefully improve overall clinical outcome.
There is strong pre-clinical data suggesting that cell cycle regulators (ex: cyclin-dependent kinase 4 and 6 [CDK 4/6]) also have an impact on cell metabolism and metabolic functions (adipose tissue, glucose regulation, and muscular tissue). Recent studies pointed CDK-4 and CDK-6 as potentials preclinical targets for diet-induced obesity, suggesting that these drugs could have more effect on body fat mass than on body muscle mass.
Given this potential relationship between obesity and CDK 4/6, this research project will assess if obesity can impact efficacy outcomes and toxicity profile in patients receiving CDK 4/6 inhibitors. We also aim to evaluate weight changes in patients under this treatment and its impact with clinical outcomes (in terms of progression free survival). The MONARCH 2 and MONARCH 3 are important prospective randomized studies evaluating the use of a CDK 4/6 inhibitor, abemaciclib, in hormonal positive metastatic BC. We intend to use data from these studies to test our hypothesis.
Statistical Analysis Plan:
The present analysis aims to determine the prognostic impact of baseline BMI and weight change in 6 months since randomization in patients under treatment with a CDK 4-6 inhibitor and hormonal therapy. Study endpoints will be Progression free survival (PFS), and response rate defined as in the original MONARCH 2 and MONARCH 3 trial.
Patient’s weight change will be calculated as a percentage (by subtracting weight since 6 months to randomization to the baseline, then dividing the result by baseline weight and finally multiplying the result by 100). According to weight change, patients will classified in three categories (weight loss defined as loss of ≥ 5.0% from baseline, weight gain defined as gain of ≥ 5.0% from baseline and stable weight defined as loss or gain that is less than 5% from baseline). The 5.0% cut-off point was chosen for consistency with a prior study, and considering that this value reflects a clinically significant weight change that accounts for measurement errors or normal fluctuations.
Continuous variables will be assessed using t-test, Mann-Whitney or Kruskall-Wallis test; categorical variables will be compared using chi-square or Fisher Exact test.
The PFS endpoint will be assessed with Kaplan-Meier curves and logrank test (to assess impact of BMI and weight change at 6 month). The Cox’s proportional hazards model will be used to calculate the hazard ratio and 95% Confidence Interval. According to the question, a stratification will be done for the trial or for the treatment group. Also, multivariate analysis will be performed using Cox’s model, adjusting for age, performance status (ECOG), metastatic site, prior endocrine therapy and Progesteron receptor (PgR) positivity. As only patients survived till 6-month post randomization will have the weight change at 6 months available, we will consider a 6 months landmark when assessing the weight change as explanatory variable.
The response rate endpoint will be assessed through the estimation of individual odds ratios within each trial or within each treatment group. Individual odds ratios will be combined using a meta-analytic method. In addition, logistic regression modelling will be used to assess the impact of BMI and weight relative change. Also, a multivariate analysis will be performed using logistic regression modeling, adjusting for age, ECOG, metastatic site, prior endocrine therapy and PgR receptor positive, trial and/or treatment group.
All statistical tests will be two-sided. For the primary objective, we will consider a P-value <0.05 as statistically significant. For the secondary objective in which we will perform four comparisons, we will apply the Bonferroni method and consider only P-values <(0.05/4), i.e. <0.013 as statistically significant. In the exploratory objectives in which we will perform nine comparisons, we will apply the Bonferroni method and consider only P-values <(0.05/9), i.e. <0.006 as statistically significant.
No missing data will be imputed.
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer With No Prior Systemic Therapy in This Disease Setting
Sponsor: Eli Lilly and Company
Study ID: NCT02246621
Sponsor ID: 15417
MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK4/6 Inhibitor, for Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Study ID: NCT02107703
Sponsor ID: 15362
153P Clinical implications of body mass index (BMI) and weight in metastatic breast cancer (BC) patients treated with abemaciclib and endocrine therapy: A pooled individual patient level data analysis of MONARCH 2 and MONARCH 3 trials. Franzoi, M.A. et al. Annals of Oncology, Volume 31, S71.
Maria Alice Franzoi, MD, Daniel Eiger, MD, Lieveke Ameye, MSc, Noam Ponde, MD, Rafael Caparica, MD, Claudia De Angelis, MD, Mariana Brandão, MD, Christine Desmedt, PhD, Serena Di Cosimo, MD, Nuria Kotecki, MD, Matteo Lambertini, MD PhD, Ahmad Awada, MD PhD, Martine Piccart, MD PhD, Evandro de Azambuja, MD PhD, Clinical implications of body mass index in metastatic breast cancer patients treated with abemaciclib and endocrine therapy, JNCI: Journal of the National Cancer Institute, djaa116, https://doi.org/10.1093/jnci/djaa116