Survey of CTX-009 Patient Selection Hypotheses Using Real World Biliary Tract Cancer Data

Authors Minori Rosales, Thomas Schuetz, Anna Gifford, Nicole Gampp, Alberto Visintin, Rachael Duffy, Diana Albu, Patricia Gonzalez, Kelly Ocasio, Karin Herrera, Kris F. Sachsenmeier

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.