Abstract 5310: KK2269, an epithelial cell adhesion molecule-targeted CD40 agonist, demonstrates antitumor effects in combination with standard therapies for NSCLC

Abstract CD40 is a key molecule expressed on antigen presenting cells (APCs), whose signaling activates APCs and generates antitumor immune responses. Although CD40 agonists have been investigated in clinical trials, systemic toxicities have limited their full potential in providing adequate antitumor effects. To overcome this limitation, we developed KK2269, a bispecific antibody, using REGULGENT™ technology. KK2269 binds to CD40 and tumor-expressed epithelial cell adhesion molecule (EpCAM) to allow activation of CD40+ APCs only at EpCAM+ tumor sites, thus avoiding systemic toxicity. EpCAM is overexpressed in many types of epithelial cancers, including non-small cell lung cancer (NSCLC). KK2269 exerts synergistic antitumor activity and tumor-specific immune responses in combination with docetaxel, a common chemotherapy for NSCLC, in an EpCAM-expressing tumor mouse model. Hence, we aimed to evaluate KK2269 for the treatment of NSCLC. Docetaxel is used as a combination therapy with ramucirumab, an anti-VEGF receptor 2 (VEGFR2) antibody, for previously treated advanced NSCLC. In addition, many clinical studies are evaluating the add-on effects of PD-1/PD-L1 blockade combined with standard chemotherapies (including docetaxel) in NSCLC, which may become the standard of care for advanced NSCLC in the future. Therefore, we investigated the antitumor effect of KK2269 in combination with docetaxel + anti-mouse VEGFR2 (study 1) and with docetaxel + anti-mouse PD-1 (study 2) using a mouse EpCAM-expressing B16F10 tumor-bearing human CD40 transgenic mouse model. The prolongation of TTP5X (the day on which the tumor volume is observed to be ≥5-fold of that observed on day 0) was evaluated. In study 1, the median TTP5X (95% confidence interval CI) with the control, docetaxel + anti-VEGFR2, and triple combination (KK2269, docetaxel, anti-VEGFR2) was 10. 0 days (7. 0, 10. 0), 26. 0 days (17. 0, 28. 0), and 52. 0 days (42. 0, not calculable), respectively. The TTP5X was significantly prolonged with the triple combination compared with the control (p=0. 000007, log-rank test) and docetaxel + anti-VEGFR2 (p=0. 000004, log-rank test). In study 2, the median TTP5X (95% CI) was 7. 0 days (not calculable), 9. 0 days (6. 0, 11. 0), 16. 0 days (7. 0, 18. 0), and 26. 5 days (7. 0, 32. 0) with the control, KK2269, docetaxel + anti-PD-1, and triple combination (KK2269, docetaxel, anti-PD-1), respectively. TTP5X was significantly prolonged with the triple combination compared with the control, KK2269, and docetaxel + anti-PD-1 (p0. 0001, p=0. 0003, and p=0. 0023, respectively, log-rank test). Thus, a significant antitumor effect was demonstrated when KK2269 was added to the standard treatment of NSCLC (docetaxel + anti-VEGFR2 antibody) and to docetaxel + anti-PD-1 antibody. Our findings strongly suggest that KK2269 provides improved treatment options for patients with NSCLC. Citation Format: Yuta Tezuka, Kyoko Kawasaki, Yoshiki Sumitomo, Masato Saito, Akari Yao, Munetoshi Ando. KK2269, an epithelial cell adhesion molecule-targeted CD40 agonist, demonstrates antitumor effects in combination with standard therapies for NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5310.