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

Author(s): Daniel H. Ahn, DO¹, Maya Ridinger, PhD², Timothy L. Cannon, MD³, Lawrence Mendelsohn, MD⁴, Jason S. Starr, DO⁵, Joleen M. Hubbard, MD⁶, Anup Kasi, MD⁷, Afsaneh Barzi, MD, PhD⁸, Errin Samuëlsz, BA², Anju Karki, PhD², Ramanand A. Subramanian, PhD², Divora Yemane, BA², Roy Kim, BA², Chu-Chiao Wu, PhD², Peter J.P. Croucher, DPhil², Tod Smeal, PhD², Fairooz F. Kabbinavar, MD², Heinz-Josef Lenz, MD⁹

Source: https://doi.org/10.1200/JCO-24-01266

Dr. Anjan Patel's Thoughts

This PLK1-inhibitor seems extremely promising. This phase II trial studied pre-treated KRAS-mut patients with FOLFIRI + bev + study drug and the response rates and PFS were quite remarkable. Given the compelling results, they went from this study to a phase III 1L study.

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. Pre 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).

Author 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

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