(P 29) ANTI-TUMOR ACTIVITY OF MICVOTABART PELIDOTIN IS ASSOCIATED WITH ENZYME GENE EXPRESSION IN PATIENT-DERIVED XENOGRAFT SARCOMA MODELS

Objective: Sarcomas comprise a variety of heterogeneous cancer subtypes which hinders development of effective therapies. Micvotabart pelidotin (micvo, formerly PYX-201), a first-in-concept antibody drug conjugate targeting extradomain-B of fibronectin (EDB+FN) in the tumor extracellular matrix, is in clinical development and preliminary data showed favorable activity in sarcomas. Micvo has a linker that is cleaved by extracellular proteases in the tumor microenvironment and releases the cytotoxic payload to kill tumor cells. Here, a pre-clinical study was conducted to elucidate mechanisms conferring sensitivity to micvo in patient derived xenograft (PDX) models of sarcoma.

Methods: For each model, mice were randomized into two groups and treated with micvo (3mg/kg Q4D×4) or a vehicle control. Tumor growth inhibition (%TGI) was calculated at study endpoint. Tumors were collected at baseline and study endpoint (when available) for histological analyses; baseline tumors were also analyzed for gene expression profiling by Nanostring.

Results: Micvo induced strong anti-tumor activity across PDX models. Immunohistochemistry analysis demonstrated robust EDB+FN expression in baseline tumors across subtypes, but no correlation was observed between EDB+FN expression and %TGI. To identify what other factor(s) besides target expression may confer sensitivity to micvo, genes expressed in baseline tumors between PDX models with very strong response (TGI>90%) and those which did not respond (TGI < 25%) were compared and revealed an enzyme gene signature, including proteases capable of cleaving micvo’s linker, associated with response to micvo. Evaluation of on-study tumors treated with micvo is ongoing.

Conclusion: These results demonstrate anti-tumor activity of micvo across diverse PDX sarcoma subtypes and show EDB+FN is necessary but not sufficient for micvo sensitivity. Notably, an enzyme gene signature was elevated at baseline in models with very strong response to micvo, suggesting the importance of enzymes in the mechanism of action of micvo. Broad activity in PDX models supports the ongoing clinical development of micvo for patients with sarcoma in Phase 1 monotherapy (NCT05720117) and Phase 1/2 combination with pembrolizumab (NCT06795412) trials.