Ribociclib-Derived Resistance Mutations: ctDNA Findings from the MONALEESA-2, -3, and -7 Trials

Genetic alterations contributing to resistance may be acquired during treatment for HR-positive/HER2-negative advanced breast cancer. This analysis aimed to identify acquired resistance mutations that could impact viability of treatment options.

Plasma samples collected at cycle 1 day 1 (C1D1) and at end of treatment were utilized to sequence ctDNA using a targeted next-generation sequencing panel of approximately 550 genes. Genes with an alteration frequency of greater than 5% at end of treatment were included. Tumor mutational burden (TMB) was assessed by treatment arm with a cutoff of 10 mutations used for stratification by high or low TMB. A McNemar test was performed on paired samples and adjusted for multiple testing using the false discovery rate (FDR) to assess differences. A Bayesian mixed-effects model was used to account for ctDNA fraction and trial and to test for treatment-specific resistance by including a treatment × visit interaction term.

A total of 905 paired samples from MONALEESA-2, -3, and -7 were included in the analysis, with 441 and 464 samples from patients treated with ribociclib plus endocrine therapy (ET) and placebo plus ET, respectively. Overall, 17 genes had an alteration frequency of greater than 5% at the end of treatment, with ctDNA fraction found to be higher at end of treatment versus C1D1 in both the ribociclib (P = .037) and placebo (P = .033) arms. The frequency of alterations in RB1 (10.4% vs 2.0%), ATM (11.3% vs 8.4%), and FAT3 (5.0% vs 2.5%) was higher at end of treatment versus C1D1 in the ribociclib arm. Alterations in GATA3 were higher at end of treatment in the placebo arm (FDR-adjusted P = .11). Alterations in ESRI1 were also higher at end of treatment versus C1D1 in both the ribociclib (26.3% vs 9.1%) and placebo arms (28.9% vs 5.4%) (FDR-adjusted P <.0001). These results were consistent after adjusting for ctDNA fraction. The most common ESR1 mutations were D538G, Y537S/N/C/D, E380Q, and L536H/P/R. Treatment × visit interaction effects were observed for RB1 in the ribociclib arm. After adjusting for ctDNA fraction, a larger increase in TMB was observed for ribociclib (95% confidence interval [CI], 2.9-32.7) versus placebo (95% CI, 0.7-6.5); however, this did not provide evidence of a differential treatment effect.

This comprehensive analysis of pooled samples from MONALEESA-2, -3, and -7 identified acquired gene alterations in patients with HR-positive/HER2-negative advanced breast cancer treated with 1L or 2L ribociclib plus ET or placebo plus ET, with the frequency of several genes known to contribute to resistance (eg, ESR1, RB1, ATM, FAT3) found to be higher at end of treatment versus C1D1 in patients treated with ribociclib plus ET, while ESR1 and GATA3 alterations were higher at end of treatment versus C1D1 in patients treated with placebo plus ET. This paired data set of baseline and end-of-treatment samples from patients with HR-positive/HER2-negative advanced breast cancer treated with a CDK4/6 inhibitor and ET is the largest to date and could be used to validate and confirm acquired resistance mechanisms with low frequency of alterations.

Source:

Andre F, Solovieff N, Su F, et al. Identification of mechanisms of acquired resistance to ribociclib plus endocrine therapy using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials. San Antonio Breast Cancer Symposium 2022. Abstract P5-02-14.