Abstract P5-02-19: ctDNA as dynamic marker of response to fulvestrant and everolimus in CDK4/6 inhibitor-pretreated ER+ HER2- metastatic breast cancer patients: a prospective study

Abstract ctDNA as dynamic marker of response to fulvestrant and everolimus in CDK4/6 inhibitor-pretreated ER+ HER2- metastatic breast cancer patients: a prospective study. Background The combination of fulvestrant with everolimus is recognized by NCCN and ESMO guidelines as a valid second line treatment option for ER+ HER2- metastatic breast cancer (mBC), upon progression on CDK4/6 inhibitor. The underlying evidence consists in a single randomized phase 2 trial (PrE0102, JCO 2018), in which N=66 patients allocated to fulvestrant and everolimus achieved a median PFS of 10.3 months (95%CI [7.6-13.8]). However, none of PrE0102 patients were pre-treated with CDK4/6 inhibitors. We set up a prospective study to document the PFS achieved by fulvestrant and everolimus in the pre-treated patients and investigated the clinical validity of ctDNA early changes as pharmacodynamic marker. Methods Eligible patients had ER+ HER2- mBC and had to be pre-treated by CDK4/6 inhibitor. Upon the signature of informed consent, patients were enrolled in the prospective observational ALCINA study (NCT02866149) and had their blood drawn at baseline (prior to treatment start), after 1 month on treatment, at first radiological assessment (3-4 months) and at disease progression. DNA from archived tumor tissue sample (or, when missing, from plasma obtained at baseline) was subjected to a large panel next generation sequencing. ctDNA levels were then assessed on the matched serial plasma samples by targeting the identified somatic mutation(s) with droplet digital PCR (ddPCR). Associations between clinicopathological characteristics, ctDNA levels and prospectively registered patient outcomes (PFS and OS) were then analyzed. Results Fifty-seven patients have been included, with a median age of 56.8 years. N=30 (52.6%) patients had ≥3 metastatic sites and N=34 (59.6%) had visceral metastases. Most patients (N=48, 84.2%) had only one prior line of treatment in the metastatic setting. After a median follow-up of 17.7 months, the median PFS was 6.9 months (95%CI[5.3-10.7]) and the median OS was 38.3 months (95%CI[26.9-NA]). The ORR was 33.3% (N=19 PR, no CR) whereas N=22 (38.6%) patients had a stable disease at best response. In the subgroup of N=22 (38.6%) patients with somatic PIK3CA mutations, median PFS was 3.1 months (95%CI[2.87-10.9]), while median OS was not reached. In multivariate analysis, somatic PIK3CA mutation was associated with a trend toward a shorter PFS (HR=1.84, 95%CI[0.97-3.99], p=0.06) and OS (HR=2.23, 95%CI[0.88-5.69], p=0.09). Duration of CDK4/6 inhibitor treatment had no overt impact on PFS (HR=0.68, 95%CI[0.38-1.22], p=0.2). Ten (19.6%) patients discontinued everolimus due to toxicity and 17 (29.9%) had at least one dose reduction due to an adverse event. The most grade 3 adverse event were mucositis (10.5%) and hypertriglyceridemia (3.5%), only 1 patient had a grade 3 pneumopathy. At least one mutation trackable by ddPCR was found in N=48 patients. As of July 2022, ctDNA levels have been analyzed in 34 patients (PIK3CAmut: N=19; ESR1mut: N=6; TP53mut: N=4; AKTmut: N=2; CUX1mut: N=1; GATA3mut: N=1; PTENmut: N=1). At baseline, N= 26/34 patients (76.5%) of patients had detectable ctDNA levels. Baseline ctDNA positivity had no prognostic impact on PFS (HR=0.93, 95%CI[0.4-2.13], p=0.86). ctDNA monitoring in the whole cohort will be available for the congress. Conclusion To our knowledge, this is the first prospective study to evaluate the efficacy of fulvestrant-everolimus after progression on CDK4/6 inhibitor. Efficacy data on 57 patients shows that fulvestrant-everolimus is an active regimen in this population. The PFS observed under fulvestrant-everolimus in patients with PIK3CA-mutant mBC appears shorter than previouly reported with alpelisib in the BYLIEVE study. Results of ctDNA to monitor the individual response to therapy will be presented at the congress. Citation Format: Antoine Vasseur, Caroline Hego, Wissam Taka, Olfa Trabelsi-Grati, Florence Lerebours, Jean-Yves Pierga, Delphine Loirat, Etienne Brain, Paul COTTU, Marie-Paule Sablin, Luc Cabel, Benjamin Renouf, Shufang Renault, Francois-Clement Bidard. ctDNA as dynamic marker of response to fulvestrant and everolimus in CDK4/6 inhibitor-pretreated ER+ HER2- metastatic breast cancer patients: a prospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-19.