Abstract GS3-06: Results from the plasmaMATCH trial: A multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010)
Authors: Turner Nicholas , Kingston Belinda , Kilburn Lucy , Kernaghan Sarah , Wardley Andrew M , Macpherson Iain , Baird Richard D , Roylance Rebecca , Stephens Peter , Oikonomidou Olga , Braybrooke Jeremy P , Tuthill Mark , Abraham Jacinta , Winter Matthew C , Bye Hannah , Hubank Michael , Snowdon Claire , Rea Daniel , Cameron David , Shaaban Abeer , Randle Katrina , Wilkinson Katie , Moretti Laura , Bliss Judith M , Ring Alistair ,   on behalf of the plasmaMATCH Trial Management Group
Published: March 2020

Background: Circulating tumour DNA (ctDNA) testing may provide a more current assessment of the genetic profile of advanced breast cancer (BC) compared with analysis of the primary tumour, with repeat advanced disease biopsy conducted infrequently in routine clinical practice. The plasmaMATCH trial was designed to assess the clinical utility of using ctDNA testing to select patients for targeted therapies.

Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC, with patients recruited into four parallel treatment cohorts with therapies matched to mutations identified in ctDNA (A: ESR1 mutation - extended-dose fulvestrant 500mg every 2 weeks, B: HER2 mutation - neratinib +/- fulvestrant (standard dosing), C: AKT1 in ER positive BC -capivasertib + fulvestrant (standard dosing), D: AKT1 in ER negative BC or PTEN inactivating mutation - capivasertib). A fifth cohort (E) recruited patients with triple negative BC with no actionable mutation to receive olaparib + AZD6738, and will be reported separately. Each cohort had a specific phase II single arm design. ctDNA testing was conducted with two technologies: digital droplet PCR (ddPCR) at a central laboratory prospectively in all patients, and error corrected sequencing with Guardant360 prospectively from part-way through recruitment and retrospectively for the remaining patients. Tumour sequencing from an advanced disease biopsy was conducted retrospectively, not influencing cohort entry. The primary endpoint for Cohorts A-D is confirmed objective response rate by RECIST v1.1. Secondary endpoints include clinical benefit rate, progression-free survival, safety and frequency of mutations identified in ctDNA screening.

Results: Entry into ctDNA testing for Cohorts A-D was closed on 26/Apr/2019 with 1044 patients registered. ctDNA screening results were received for 1033 patients (99%), with 142 patients entered into Cohorts A-D (A 84, B 21, C 18, D 19). Agreement between ctDNA digital PCR and sequencing results was high (individual gene level agreement 95.5%-99.4%, kappa 0.89-0.93). Predefined efficacy criteria were met in Cohorts B (neratinib for HER2 mutations) and C (capivasertib for AKT mutations), with exploratory analysis of Cohort D identifying activity of capivasertib in AKT1 mutations (Table 1). Efficacy criteria were not met in Cohort A (extended-dose fulvestrant for ESR1 mutations). Adverse events were consistent with prior reports, with extended-dose fulvestrant well tolerated.

Table 1: Efficacy results from plasmaMATCHMutationCohortConfirmed response rate, % (95%CI; n/N)Median PFS (IQR), monthsAll patientsFirst 16 evaluable patients*ESR1A8.1% (3.0-16.8; 6/74)-2.2 (1.7-5.3)HER2B25.0% (8.7-49.1; 5/20)25.0% (7.3-52.4; 4/16)5.4 (3.4-9.1)AKT1C22.2% (6.4-47.6; 4/18)18.8% (4.0-45.6; 3/16)10.2 (3.2-18.2)AKT basketD10.5% (1.3-33.1; 2/19)12.5% (1.6-38.3; 2/16)3.4 (1.8-5.5)AKT133.3% (4.3-77.7; 2/6)--PTEN0 % (0/13)--*Predefined cohort efficacy thresholds for response were set: 13/78 (A); 3/16 (B, C, D)

Conclusion: Circulating tumour DNA testing offers accurate tumour genotyping, sufficient for routine clinical practice. This approach can be used to identify patients with rare HER2 and AKT1 mutations, who have clinically relevant response rates with matched targeted therapies.

Citation Format: Nicholas Turner, Belinda Kingston, Lucy Kilburn, Sarah Kernaghan, Andrew M Wardley, Iain Macpherson, Richard D Baird, Rebecca Roylance, Peter Stephens, Olga Oikonomidou, Jeremy P Braybrooke, Mark Tuthill, Jacinta Abraham, Matthew C Winter, Hannah Bye, Michael Hubank, Claire Snowdon, Daniel Rea, David Cameron, Abeer Shaaban, Katrina Randle, Katie Wilkinson, Laura Moretti, Judith M Bliss, Alistair Ring, on behalf of the plasmaMATCH Trial Management Group. Results from the plasmaMATCH trial: A multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (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 GS3-06.