123P - Combination potential of EO-3021, a CLDN18.2 vc-MMAE ADC, with VEGFR2 or PD1 inhibition in preclinical models of CLDN18.2-expressing cancers

Background

EO-3021 (SYSA1801) is a CLDN18.2 ADC featuring a glutamine 295-conjugated vc-MMAE payload with a DAR of 2. EO-3021 has shown promising anti-tumor activity in patients with gastric/gastroesophageal junction (GEJ) cancer that express CLDN18.2 (NCT05980416). The current treatment landscape of gastric/GEJ cancer includes the combination of a fluoropyrimidine and platinum-based chemotherapy with an anti-PD1 inhibitor in the first line and paclitaxel with the VEGFR2 inhibitor ramucirumab in second line metastatic setting. MMAE is a potent cytotoxic payload that inhibits tubulin polymerization and can elicit immunogenic cell death, which may amplify the innate and adaptive immune response within an immunosuppressive tumor microenvironment. We conducted preclinical studies to evaluate the anti-tumor activity of EO-3021 with an anti-PD1 or VEGFR2 inhibitor.

Methods

Mice bearing NUGC4-hCLDN18.2 gastric tumors (CrownBio) were treated with a ramucirumab surrogate, DC101 (BioXCell; 20 mg/kg twice-weekly), EO-3021 (2 mg/kg once-weekly), or the combination. Mice bearing syngeneic MC38-B-hCLDN18.2 tumors (Biocytogen) were treated with an anti-PD1 (BioXCell; 4 mg/kg twice-weekly), EO-3021 (7.5 mg/kg once-weekly), or the combination. An additional study was conducted to assess frequency and durability of complete responses (CRs) of EO-3021 + anti-PD1.

Results

EO-3021 + DC101 exhibited superior tumor growth inhibition (TGI: 88.2%) over EO-3021 (TGI: 20.1%; p < 0.0002) or DC101 (TGI: 59.2%; p < 0.0001). EO-3021 + anti-PD1 (TGI: 79.9%) displayed synergistic anti-tumor activity vs. EO-3021 (TGI: 33.8%; p < 0.0008) or anti-PD1 (TGI: 25.0%; p < 0.0001). CRs were observed with EO-3021 (6/12 mice, 50%), anti-PD1 (2/12 mice, 17%) and the combination (11/12 mice, 92%). An update on durability of CRs, details on the immune infiltrate in mice from the EO-3021 + anti-PD1 study, and comparisons to the ADCC/CDC-inducing CLDN18.2 mAb, zolbetuximab, will be presented.

Conclusions

Each of the combinations provided a more robust anti-tumor response compared to the single agents. Results from preclinical studies support the planned clinical evaluation of EO-3021 in combination with ramucirumab or a PD1 inhibitor.

Legal entity responsible for the study

Elevation Oncology.

Funding

Elevation Oncology.

Disclosure

T. O'Hare, J. Cleveland, V.M. Jansen, D. Dornan: Financial Interests, Institutional, Full or part-time Employment: Elevation Oncology; Financial Interests, Institutional, Stocks/Shares: Elevation Oncology.