2. Academic Validation
  3. Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial

Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial

  • J Clin Oncol. 2024 Oct 30:JCO2401266. doi: 10.1200/JCO-24-01266.
Daniel H Ahn 1,  Maya Ridinger 2,  Timothy L Cannon 3,  Lawrence Mendelsohn 4,  Jason S Starr 5,  Joleen M Hubbard 6,  Anup Kasi 7,  Afsaneh Barzi 8,  Errin Samuëlsz 2,  Anju Karki 2,  Ramanand A Subramanian 2,  Divora Yemane 2,  Roy Kim 2,  Chu-Chiao Wu 2,  Peter J P Croucher 2,  Tod Smeal 2,  Fairooz F Kabbinavar 2,  Heinz-Josef Lenz 9
Affiliations

Affiliations

  • 1 Division of Medical Oncology, Mayo Clinic, Phoenix, AZ.
  • 2 Cardiff Oncology Inc, San Diego, CA.
  • 3 Inova Schar Cancer Institute, Fairfax, VA.
  • 4 Carti Cancer Center, Little Rock, AR.
  • 5 Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL.
  • 6 Division of Oncology, Department of Medicine, Mayo Clinic, Rochester, MN.
  • 7 Division of Medical Oncology, University of Kansas Medical Center, Kansas City, KS.
  • 8 Division of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA.
  • 9 Division of Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA.
PMID: 39475591 DOI: 10.1200/JCO-24-01266
Abstract

Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal Cancer (mCRC).

Patients and methods: This multicenter, open-label, single-arm study enrolled patients with KRAS-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC.

Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.

Conclusion: Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).

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