Abstract OT1-03-04: INTERACT- INTegrated Evaluation of Resistance and Actionability using Circulating Tumor DNA in hormone receptor (HR) positive metastatic breast cancers (MBC)
Authors: Damodaran S , Meric-Bernstam F , Hess KR , Litton JK , Raymond V , Lanman R , Ueno NT , Hamilton S , Wistuba II , Valero V , Moulder SL , Tripathy D 
Published: May 2019

Background

Mutations in the ligand-binding domain of ESR1 have been demonstrated to mediate resistance to aromatase inhibitors (AI) and are associated with poor survival. Analyses of circulating tumor DNA (ctDNA) offer a minimally invasive and real-time approach to characterize genomic landscape, clonal evolution, and treatment response. Early detection and intervention with alternate therapy to overcome resistance at minimal disease burden progression could have a larger impact than treating higher burden disease at clinical progression. However, whether treatment decisions made based on the emergence of secondary resistance mutations or mutant allele fraction (MAF) changes in ctDNA can improve clinical outcomes is unknown. Currently, the most effective therapy for patients harboring ESR1 mutations is unclear; although, pre-clinical and retrospective clinical trial analyses have suggested that some of these mutations may exhibit greater sensitivity to fulvestrant, a selective estrogen receptor down-regulator, compared to AI. This study hypothesizes that real-time monitoring of ctDNA for secondary ESR1 alterations can identify subclinical progression and early intervention with a targeted-agent that has greater efficacy against ESR1 mutations can improve disease-free survival.

Trial Design

This is a randomized, open-label, Phase-2 study for HR-positive MBC patients who are on AI and CDK 4/6 inhibitor as first line therapy. Patients on treatment for at least 12 months without evidence of clinical progression would be screened for ESR1 mutations using Guardant360 ctDNA assay. Patients with positive ESR1 mutations would be randomized to change of endocrine therapy to fulvestrant vs. continuing AI.

Eligibility criteria

-Histologically confirmed HR-positive (ER and/or PR &gt;10%) and HER2-negative MBC

-On AI with CDK4/6 inhibitor as first line therapy for 12 months without evidence of clinical progression

-Activating ESR1 mutation identified on ctDNA

-ECOG performance status ≤1

-Normal organ and marrow function

Specific aims

- To assess progression-free survival (PFS) with transition to fulvestrant compared with continuing AI therapy in patients with emergence of ESR1 mutations in plasma

-To assess ctDNA ESR1 mutant allele fraction and kinetics with transition to fulvestrant compared with AI

-To assess the prevalence of ESR1 mutations in patients with exposure to endocrine therapy

-To assess overall survival with fulvestrant transition compared with continuing AI therapy in patients with emergence of ESR1 mutations

Statistical methods

To detect a change in median PFS from 5 months (for AI arm) to 9 months (with fulvestrant arm) would require about 124 patients (5% two-sided alpha, 80% power, log rank testing). Interim analysis will be performed when 42 PFS events are observed. Using O'Brien-Fleming stopping boundaries, we will stop for futility if the log rank test p-value &gt; 0.72 and stop for success if it is &lt; 0.004.

Citation Format: Damodaran S, Meric-Bernstam F, Hess KR, Litton JK, Raymond V, Lanman R, Ueno NT, Hamilton S, Wistuba II, Valero V, Moulder SL, Tripathy D. INTERACT- INTegrated Evaluation of Resistance and Actionability using Circulating Tumor DNA in hormone receptor (HR) positive metastatic breast cancers (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-03-04.