Abstract
Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy. PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human colorectal cancer xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3ε transgenic mice. IHC and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti-PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque. We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ε bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell-mediated in vitro activity and in vivo efficacy in multiple colorectal cancer human xenograft tumor models, including KRAS- and BRAF-mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti-PD-1/PD-L1 treatment or in combination with antiangiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile. These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.
Highlights
Gastrointestinal malignancies, including colorectal cancer, gastric cancer, and esophageal cancer, continue to be areas of high unmet medical need despite advances in targeted therapies [1, 2]
Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile. These data highlight the potential for PF07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies
Mutational status of KRAS and BRAF oncogenes was determined for cell line xenograft (CLX) and patient-derived xenograft (PDX) models used for evaluating antitumor activity of PF-07062119
Summary
Gastrointestinal malignancies, including colorectal cancer, gastric cancer, and esophageal cancer, continue to be areas of high unmet medical need despite advances in targeted therapies [1, 2]. Colorectal cancer alone is a worldwide issue affecting both men and women, and responsible for 9.2% of all cancer deaths. The lack of response to targeted therapy, such as anti-EGFR anti-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Lucas: Bristol Myers Squibb, Princeton, NJ; current address for M. Abbvie, North Chicago, IL; current address for L. Tchistiakova, Third Rock Ventures, Boston, MA; and current address for A.
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