Background & Objectives: Clinical response to immunotherapies in patients with biliary tract cancer (BTC) has supported approval of these therapies1,2. However, a proportion of patients have tumors which never respond or subsequently become non-responsive. For these patients, clinically actionable data is needed to inform treatment decisions.For example, a readily measurable biological assay with results linked to a potentially successful treatment option could enable use of that option in patients with BTC after treatment with immunotherapies.

Methods and Results: We report preclinical evidence showing activity in a mouse treated with a bispecific antibody targeting both mouse DLL4 and VEGF-A in models of checkpoint inhibitor resistance. Specifically, a mouse cross-reactive surrogate of CTX-009, an anti-DLL4/VEGFA bispecific antibody currently in clinical trials, shows remarkable tumor growth inhibition in a mouse model lacking both class I MHC as well as the tumor suppressor CDKN2A – both well-documented tumor escape mechanisms from immunotherapy3–9. A cohort of patient tumors evaluated using the Tempus xT NGS assay showed evidence of genomic alterations consistent with immune checkpoint escape. Specifically, of 345 evaluable samples, approximately 50 % of the tumors showed loss of heterozygosity at the HLA locus and an additional 62% showed deletion of CDKN2A/B. 37 (~11%) tumors showed deletions in both of these loci. Interestingly, 23 (~10%) of the CDKN2A/B deleted tumors showed concurrent loss of MLLT3, suggesting co-deletion of type 1 IFN genes immediately adjacent to CDKN2A/B on chr9p217 and between CDKN2A/B and MLLT3.These observations are consistent with known immune checkpoint therapy escape mechanisms and provide a context for anticipated analyses of tumors from patients treated with CTX-009. That is, it will be important to learn whether tumor responses to CTX-009 in the clinic show the same independence with respect to these two resistance mechanisms as has been observed in mouse preclinical models.

Conclusions: In summary, these data support the testing of CTX-009 in patients with BTC whose tumors have biomarkers identifiable with standard approved genomic sequencing assays.

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