Results from plasmaMATCH trial treatment cohort C: A phase II trial of capivasertib plus fulvestrant in ER positive breast cancer patients with an AKT1 mutation identified via ctDNA screening (CRUK/15/010)

Background: AKT1 mutation occurs in approximately 3% of breast cancer (BC), enriched in advanced BC. The AKT1 E17K mutation results in constitutive activation of AKT1, associated with sensitivity to AKT inhibitor capivasertib in pre-clinical models, and in a prior phase I trial with AKT1 mutations identified through tumour testing. The plasmaMATCH trial Cohort C assessed the efficacy of capivasertib and fulvestrant in ER positive BC patients with an AKT1 mutation in 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 AKT1 mutation identified via ctDNA testing were registered to Cohort C. Patients were treated with capivasertib 400mg BID 4 days on - 3 days off, plus fulvestrant 500mg intramuscularly on Cycle 1 Days 1 and 15, and Cycle 2 onwards every 28 days. The primary endpoint for Cohort C was confirmed objective response rate as defined by RECIST v1.1. Using a single stage A’Hern design with a target response rate of 25%, unacceptable response rate of 5%, alpha=5% and power=80%, at least 3 responses out of 16 evaluable patients were required to infer efficacy. Results: Following ctDNA testing, 18 patients enrolled in Cohort C (42% of patients with AKT1 mutations identified in ctDNA testing). All were ER positive, 1 (5.6%) was HER2 amplified, and 17 (94%) had visceral metastases. Mutation was AKT1 E17K in 17 patients and AKT1 L52R in 1 patient. All patients were evaluable with a confirmed response rate of 22.2% (95%CI 6.4-47.6%, 4/18) (first 16 evaluable patients: 3/16, 18.8% (95%CI 4.0-45.6)). A further 4 patients had an unconfirmed partial response. Median progression free survival was 10.2 months (IQR 3.2-18.2 months) and the median duration of response was 7.5 months (IQR 4.1-9.8 months) with 4 patients continuing on treatment. The most common clinically significant grade 3 or 4 adverse events were fatigue (22%), rash (17%), diarrhoea (11%) and hyperglycaemia (11%). Conclusions: Capivasertib plus fulvestrant was active in patients with ER positive breast cancer and AKT1 mutations identified in ctDNA testing, meeting the pre-specified threshold for efficacy Citation Format: Rebecca Roylance, Lucy Kilburn, Sarah Kernaghan, Andrew M Wardley, Iain Macpherson, Richard D Baird, 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 C: A phase II trial of capivasertib plus fulvestrant in ER positive breast cancer patients with an AKT1 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 P1-19-11.