CALIBRATION: Can early changes in circulating tumour DNA (ctDNA) predict durable tumour responses in patients with advanced Oesophageal Adenocarcinoma receiving anti PD-L1 antibody durvalumab?


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Constanza Linossi, Gabriel Funingana Ionnut, Michelle Petruzzelli, Bruno Rala De Paula, Maria O'Donovan, Andrea Machin, Sarah Hewitt, Alexandra L Williams, Nicola Grehan, Aisling Redmond, Elizabeth Smyth, Richard Baird, Edmund M. Godfrey, Massimiliano Di Pietro, Iris Faull, Simon Dovedi, Rebecca C. Fitzgerald, Simon Pacey

Abstract

Background

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

Method

Prospective, open-label, pilot trial of durvalumab (1500mg/4week) for advanced OAC. Intensive blood sampling (PBMCs, plasma) & tumor biopsies are taken at pre-defined time-points (screening/week12/disease progression). Tumour-derived variant allele fractions (VAF) & copy-number alterations (CN) are analysed using Guardant360 assay. The primary objective is to determine if early changes (at week 4/7) in ctDNA (VAF, CN) correlates with long-term radiological responses (week26). Enrolment of 19 evaluable pts is planned. Translational studies will analyse the effect of durvalumab on the immuno-genomic landscape of OAC. We report the interim data.

Results

7 pts were recruited (all male, median age: 71.7 yr, 1 patient HER2+), 6 received durvalumab. Prior chemotherapy: perioperative only in 2/6 pts, 4/6 had ≥1 prior treatment lines. Three pts received ≥ 3 doses of durvalumab. 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 treatment withdrawal, respectively. Both resolved. Primary endpoint: changes in “total-ctDNA fraction" and RECIST1.1 response were evaluable in 4/6 pts:

 

Relative change in total ctDNA fraction (scr to wk 7)

Response 

1

1.85

PD

2

2

PD

3

0.31

Partial response (PR)

4

1.07

Stable disease 

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).


Conclusion

Durvalumab was well tolerated with potential activity in OAC. 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 will be presented

Impact statement


Characterisation of multiple biomarkers throughout a patient's treatment, in the tumour bed and the periphery, will hep understand response to ICBs from a multidimensional perspective and can be used for treatment allocation.