Background

Response of EAC to immune-checkpoint blockade (ICB) is modest and clinicians lack biomarkers for pt selection. EAC's mutational signature profile suggest 'mutagenic' & 'DDR' subtypes might respond to ICB. Furthermore, ctDNA can detect treatment & genomic variations before other tests.

Methods

Prospective, open-label, pilot trial of D (1500mg/4wk) for advanced EAC. Intensive blood sampling (PBMCs, plasma) & tumor biopsies are taken at pre-defined time-points (screening/wk12/disease progression). Tumour-derived variant allele fractions (VAF) & copy-number alterations (CN) are analyzed using Guardant360 assay. Primary objective: determine if early changes (wk4/7) in ctDNA (VAF, CN) correlates with long-term radiological responses (wk26). Enrolment of 19 evaluable pts is planned. Translational studies will analyze D on the immuno-genomic landscape of EAC. We report the interim data.

Results

7 pts were recruited (all male, median age: 71.7 yr, 1 patient HER2+), 6 received D. Prior chemotherapy: perioperative only in 2/6, ≥ 1 line in 4/6. Three pts received ≥ 3 doses of D. Adverse events (AE) : 68% Grade 1-2, 32% (8/25) Grade 3 (none drug-related). Two drug-related AE (hyperamylasemia, hypothyroidism) led to dose delay and withdrawal, respectively. Both resolved. Primary endpoint : 'changes in “total-ctDNA fraction" and RECIST1.1 response' were evaluable in 4/6 pts: Table: 1940P

Also, individual gene changes reflect RECIST responses: -Pt3 had PR & ≥10% relative reduction in VAFs (PI3KCA, TP53, APC, ERBB2) & CNs (CDK4, FGFR2, CCNE1). -Pt2 had PD & ≥10% relative increase of VAFs (TP53, BRCA1, ATM) & CN (KRAS, EGRF).

Conclusions

D was well tolerated with potential activity in EAC. Data suggest a relationship between changes in ctDNA & RECIST response. Mature data is required. Recruitment & translational studies are ongoing, mutational signature profile (WGS data) of 4pts will be presented.

Clinical trial identification

NCT03653052.

Legal entity responsible for the study

Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.

Funding

AstraZeneca.

Disclosure

M. Di Pietro: Advisory/Consultancy, Travel/Accommodation/Expenses: Medtronic. I. Faull: Honoraria (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Guardant Health. S. Dovedi: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. R.C. Fitzgerald: Honoraria (self), Advisory/Consultancy: Medtronic; Honoraria (institution): Roche; Honoraria (institution): AstraZeneca; Licensing/Royalties: Cytosponge, TFF3. S. Pacey: Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution): Janssen; Honoraria (institution): Ferring; Honoraria (institution): Guardant Health; Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.