Abstract P1-19-04: Results from plasmaMATCH trial treatment cohort A: A phase II trial of extended-dose fulvestrant in patients with an ESR1 mutation identified via ctDNA screening (CRUK/15/010)

Abstract

Abstract Background: Ligand binding domain ESR1 mutations are acquired in ER positive cancers during prior aromatase inhibitor therapy for advanced ER positive breast cancer (BC). ESR1 mutant cancer models are sensitive to fulvestrant at high concentrations, however standard dose fulvestrant may not achieve the concentration required to fully inhibit mutant ESR1 in the clinic. The plasmaMATCH trial Cohort A assessed the efficacy of extended-dose fulvestrant (double the current standard dose achieved by doubling the frequency of administration) in patients with an ESR1 mutation identified via ctDNA testing. Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC. Patients with an ESR1 mutation identified in ctDNA testing were potentially eligible to enter Cohort A. Patients were treated with fulvestrant 500mg intramuscularly on Cycle 1 Days 1, 8 and 15 of a 28 day cycle, and from Cycle 2 onwards every 15 days. Pharmacokinetics samples were collected pre-dose on Day 1 of Cycles 2, 3 and 4. The primary endpoint for Cohort A was confirmed objective response rate as defined by RECIST v1.1. The original planned sample size was 40 patients, to detect a 25% response rate, assuming predominantly clonally dominant mutations. As the trial progressed it became apparent that ctDNA screening may also detect sub clonal ESR1 mutations, which were expected to have a lower response rate. Using a single-stage A’Hern design with a target response rate of 20%, unacceptable response rate of 10%, alpha=5%, power=80, the sample size was increased to 78 evaluable patients with 13 or more responses required to infer efficacy. Results: Following ctDNA testing, 84 patients enrolled in Cohort A (38% of patients with ESR1 mutations identified in ctDNA testing). All were ER positive, seven were HER2 amplified, 78 (93%) had visceral metastases. The most common ESR1 mutations detected in baseline plasma were D538G (52.4%), Y537S (35.7%), E380Q (33.3%). In the 74 evaluable patients, confirmed response rate was 8.1% (95%CI 3.0-16.8%, 6/74). One additional patient had an unconfirmed partial response. Median progression free survival was 2.2 months (IQR 1.7-5.3 months) and median duration of response was 7.0 months (IQR 3.7-8.3 months) with 4 patients continuing on treatment. In exploratory analysis, 39 patients had clonally dominant ESR1 mutations in baseline ctDNA analysis whilst 25 patients had subclonal mutations and 10 had unknown clonality. The response rate in those with clonally dominant ESR1 mutations was 10% (95%CI: 2.9-24.2%, 4/39) with no confirmed responses in those with subclonal mutations. The most common clinically significant grade 3 or 4 adverse event was hypertension (13%). Pharmacokinetic analysis was consistent with elevated fulvestrant exposure compared to approved 500mg PopPk model (pre-dose Cycle 3, 71% increase, and pre-dose Cycle 4 66% increase). Conclusion: In the pre-treated population studied, the response rate of extended-dose fulvestrant did not meet pre-specified criteria for efficacy in patients with ESR1 mutations identified in ctDNA testing. Extended-dose fulvestrant was well tolerated and enhanced exposure was observed. Assessment of clonal dominance of ESR1 mutations in ctDNA may identify patients who are more likely to benefit from extended-dose fulvestrant therapy. Citation Format: Iain Macpherson, Lucy Kilburn, Sarah Kernaghan, Andrew M Wardley, Richard D Baird, Rebecca Roylance, Peter Stephens, Olga Oikonomidou, Jeremy P Braybrooke, Mark Tuthill, Jacinta Abraham, Matthew C Winter, Belinda Kingston, Katie Wilkinson, Alistair Ring, Judith M Bliss, Nicholas Turner, on behalf of the plasmaMATCH Trial Management Group. Results from plasmaMATCH trial treatment cohort A: A phase II trial of extended-dose fulvestrant in patients with an ESR1 mutation identified via ctDNA screening (CRUK/15/010) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-04.