Abstract 2031: A phase 1b/2 clinical study of onvansertib in combination with FOLFIRI/bevacizumab revealed a new role of PLK1 in regulating the hypoxia pathway in KRAS-mutant colorectal cancer

Abstract Background: Onvansertib (Onv) is an oral, small molecule, selective PLK1 kinase inhibitor that demonstrated clinical activity at tolerated drug exposures in combination with FOLFIRI/Bevacizumab (Bev) in the 2nd-line treatment of mutated KRAS (mKRAS) metastatic colorectal cancer (mCRC) (Lenz, JCO, 2022). Here we explored biomarkers of response to the combination therapy and their associated biology. Methods: In a Phase 1b/2 study, mKRAS mCRC patients with prior exposure to oxaliplatin (with or without Bev) were treated with Onv (Days 1-5 and 15-19) in combination with FOLFIRI/Bev (Days 1 and 15) of each 28-day cycle (NCT03829410). Efficacy endpoints included objective response rate (ORR, RECIST v1. 1), progression-free survival (PFS) and duration of response (DoR). Preclinically, the combination of Onv and Bev was tested in 3 mKRAS CRC xenograft models. The role of PLK1 in hypoxia was assessed through protein and RNA analyses of mKRAS CRC cell lines exposed to low oxygen levels and treated with Onv. Results: As of 25-AUG-2023, 66 patients were evaluable for efficacy in the Phase 1b/2 and ORR of Onv + FOLFIRI/Bev was 28. 8%. Patients had a median PFS of 9. 8 months 95%CI: 7. 6, 12. 6 and median DoR of 11. 7 months 95%CI: 9. 0, NR. An analysis of baseline characteristics revealed that patients not exposed to Bev in the 1st-line setting (Bev-naïve patients, n=15) achieved superior clinical benefit compared to Bev-exposed patients (n=51). Bev-naïve patients had significantly higher ORR (73. 3% versus 15. 7%, p0. 0001) and longer median PFS (14. 9 months 95%CI: 10. 5, NR versus 7. 8 months 95%CI: 5. 6, 9. 8, p=0. 0013) than Bev-exposed patients. This data prompted us to assess the effect of Onv+Bev in mKRAS CRC xenograft models. Onv+Bev significantly reduced tumor growth in the 3 xenograft models tested. The combination resulted in a greater decrease in tumor vascularization and tumor cell proliferation, and a corresponding increase in apoptosis, compared to either monotherapy. Further, the effect of Onv on the hypoxia pathway was assessed in mKRAS CRC cell lines. Our findings indicated that under low oxygen levels, Onv inhibited the hypoxia pathway by reducing the expression of the hypoxia-inducible factor 1-alpha (HIF1α) protein, and the mRNA expression of its downstream targets. Conclusions: Onv + FOLFIRI/Bev resulted in greater clinical benefit in Bev- naïve than Bev-exposed mKRAS CRC patients. Preclinical studies revealed synergistic effect of Onv and Bev in mKRAS CRC xenografts, and a new function of PLK1 in modulating the hypoxia pathway through the regulation of HIF1α. Collectively, this data supports a crosstalk between PLK1 and angiogenesis, and further exploration of Onv + FOLFIRI/Bev therapy in Bev-naïve mCRC patients with KRAS mutation. Citation Format: Maya Ridinger, Anju Karki, Ramanand A. Subramanian, Errin Samuelsz, Divora Yemane, Roy Kim, Chu-Chiao Wu, Fairooz F. Kabbinavar, Tod Smeal, Heinz-Josef Lenz. A phase 1b/2 clinical study of onvansertib in combination with FOLFIRI/bevacizumab revealed a new role of PLK1 in regulating the hypoxia pathway in KRAS-mutant colorectal cancer 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 2031.