Directing Therapy with Circulating Tumor DNA Analysis in Advanced Breast Cancer: The PlasmaMATCH Trial

Background: Circulating tumor DNA (ctDNA) testing may provide a contemporary assessment of the genomic profile of advanced cancer, without need to repeat tumor biopsy. The plasmaMATCH trial was designed to assess the clinical utility of using ctDNA testing to select advanced breast cancer patients for targeted treatment. Methods: plasmaMATCH is an open label, multi-center, multi-cohort platform trial of ctDNA testing in ~1000 patients with advanced breast cancer, with patients recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: A:ESR1 mutation, B:HER2 mutation, C:AKT1 mutation (ER-positive cancer), D:AKT activation basket (AKT1 mutation ER-negative cancer or PTEN mutation). ctDNA testing was conducted with digital PCR and error-corrected targeted sequencing. Tumour sequencing from an advanced disease biopsy was conducted retrospectively, not influencing cohort entry. Each cohort had a phase II single-arm design with primary endpoint of confirmed objective response rate using RECISTv1.1 in evaluable patients. Findings: 1051 patients registered, with ctDNA testing results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 95.5%-99.4% (n=800, kappa 0.89-0.93). ctDNA testing had 93-98% sensitivity for mutations identified in tissue sequencing. In patients with HER2 mutations, response rate with neratinib, plus fulvestrant in ER-positive cancer, was 25.0% (5/20, 95%CI 8.7-49.1%). In patients with AKT1 mutations and ER-positive cancer, response rate with capivasertib plus fulvestrant was 22.2% (4/18, 95%CI 6.4-47.6%). In patients with AKT1 mutations and ER-negative cancer, 33.3% (2/6, 95%CI,4.3-77.7) responded to capivasertib, although 0/13 patients with PTEN mutation responded. Response rate of ESR1 mutations with extended-dose fulvestrant was 8.1% (6/74, 95%CI 3.0-16.8%). Adverse events were consistent with prior reports. Interpretation: ctDNA testing offers accurate, rapid genotyping that enables the selection of patients for mutation-directed therapies. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations. Trial Registration: ISRCTN16945804 ClinicalTrials.gov Identifier: NCT03182634 Funding: Cancer Research UK (CRUK/15/010,C30746/A19505), AstraZeneca, and Puma Biotechnology. Declaration of Interests: NCT, AR, JMB, LSK, CS, LM, SK, KW, SM, HB, MH, BK and RC report grants from Cancer Research UK, grants and non-financial support in the form of study drug provision from AstraZeneca and Puma Biotechnology and non-financial support in the form of ctDNA sequencing from Guardant Health and provision of reagents from BioRad during the conduct of the study. NCT also reports grants and personal fees from AstraZeneca, Pfizer, and Roche/Genentech, personal fees from Bristol-Myers Squibb, Lilly, MSD, Novartis, Bicycle Theraputics, Taiiho, Zeno Pharmaceuticals and Repare Therapeutics and grants from BioRad, Clovis, Merck Sharpe and Dohme, and Guardant Health outside the submitted work. BK also reports personal fees from Guardant Health outside the submitted work. AMW reports personal fees from Roche, personal fees and other support from Novartis, Pfizer, Lilly, Daiichi-Sankyo, MSD, AstraZeneca, Athenex and other support from Seattle Genetics, Andrew Wardley Ltd, Manchester Cancer Academy and Outreach Research and Innovation Group Limited outside the submitted work. IRM reports personal fees and non-financial support from Roche Products UK Ltd, Eli Lilly and Eisai and personal fees from Novartis, Pfizer, Daichi Sankyo, Genomic Health, Pierre Fabre and MSD outside the submitted work. RDB reports grants from AstraZeneca and Roche/Genentech outside the submitted work. RR reports personal fees from Novartis, Eli-Lilly and Pfizer, personal fees and non-financial support from Daiichi Sankyo and G1Therapeutics and non-financial support from Roche and AstraZeneca outside the submitted work. PS reports personal fees from Novartis, Eisai and Daiichi Sankyo outside the submitted work.OO reports grants and personal fees from Pfizer and Eisai, personal fees from Roche/GNE and Tesaro, non-financial support from AstraZeneca, personal fees and non-financial support from Eli Lilly, grants from Novartis outside the submitted work. MT reports personal fees from Pfizer, Novartis, Roche, Vaccitech, Oxford Vacmedix, Lilly, Astellas, Genomic Health and Esai, personal fees and non-financial support from Janssen, BMS, Ipsen and non-financial support from EUSA Pharma outside the submitted work. JA reports grant and personal fees from Eisai and personal fees from Merck outside the submitted work. MCW reports personal fees and non-financial support from Easai, Lilly and Roche and personal fees from Pfizer, Genomic Health and Novartis outside the submitted work. HB also reports personal fees from AstraZeneca outside of the submitted work. MH also reports personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Roche Diagnostics and Eli Lilly during the conduct of the study. AS reports grants from Ventana Roche and Genomic Heath, personal fees from Daiichi Sankyo, Hologic, Genomic Health and Ventana Roche outside the submitted work. JMB also reports grants and non-financial support from AstraZeneca, Novartis, Janssen-Cilag, Merck Sharpe & Dohme, Pfizer, Roche, and Clovis Oncology and grants from Medivation outside the submitted work. AR also reports personal fees from Roche Products Limited, Pfizer, Novartis, Lilly and MSD outside the submitted work. JPB, HG, DR, DC and KR have nothing to disclose. Ethics Approval Statement: The study was co-sponsored by The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust and approved by a Research Ethics Committee (16/SC/0271). All participants gave written informed consent prior to registration for ctDNA testing, and again prior to treatment cohort entry. Safety and efficacy data were reviewed regularly by an Independent Data Monitoring Committee (IDMC). Trial oversight was provided by an independent Trial Steering Committee.