Abstract 366P
Background
Despite advances in the treatment of mCRC, chemotherapy resistance is present or develops in most pts and overcoming this constitutes a highly unmet medical need. Onvansertib (Onv), is a highly specific PLK1 inhibitor, that demonstrated preliminary safety and efficacy in combination with FOLFIRI/bev in 2L treatment of mKRAS mCRC pts with no prior irinotecan treatment (Lenz et al, JCO 2022). Here we tested the potential of Onv to overcome resistance to irinotecan-based therapies in CRC.
Methods
The anti-tumor activity of Onv (60 mpk, QDx21, PO) in combination with irinotecan (40 mpk, QWx3, IP) was tested preclinically in mRAS and irinotecan-resistant mCRC patient-derived xenografts (PDXs). Additionally, an expanded access program (EAP) was open in which mKRAS mCRC pts who had failed or progressed on standard-of-care (SoC), including irinotecan, were treated with Onv +FOLFIRI/bev. Progression-free survival (PFS) of Onv +FOLFIRI/bev and changes in KRAS mutant allele frequency (MAF) after 1 treatment cycle were analyzed in pts with prior irinotecan treatment.
Results
In mRAS irinotecan resistant PDX models, Onv+irinotecan induced significantly higher tumor growth inhibition (up to 100%) than vehicle or single agents, demonstrating that Onv can re-sensitize tumors to irinotecan. In the EAP, 43 mKRAS mCRC pts with prior irinotecan treatment received Onv+FOLFIRI/bev. As of 10-Mar-2022, median PFS was 4 mos (range 0.4-17.4), with 14 (33%) of pts benefiting for >6 months. Five pts remained on treatment at data cutoff for 9.3 to 17.4 mo. Of the 32 pts evaluable for KRAS MAF changes, pts with a decrease in KRAS MAF of ≥90% (n=11) had a significantly longer PFS of 11.1 mo (CI 5.5-NR) versus 3.2 mo (CI 2.5-6.6) for pts with <90% decrease in KRAS MAF (p=0.0022).
Conclusions
Preclinical and clinical data support that Onv can overcome irinotecan-resistance in mRAS CRC. Early changes in KRAS MAF were associated with increased benefit to Onv+FOLFIRI/bev. Additional studies are warranted to ascertain the clinical benefit of Onv+FOLFIRI/bev for mKRAS mCRC pts progressing on SoC and the use of KRAS MAF as a response biomarker.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Cardiff Oncology.
Disclosure
S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GlaxoSmithKline, Jazz, Xilis, AbbVie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis. M. Ridinger: Financial Interests, Personal, Full or part-time Employment: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Cardiff Oncology; Financial Interests, Personal, Proprietary Information: Cardiff Oncology. A. Sorokin: Financial Interests, Personal, Licensing Fees: Boehringer Ingelheim Pharmaceuticals. E. Samuelsz: Financial Interests, Personal, Full or part-time Employment: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Cardiff Oncology; Financial Interests, Personal, Proprietary Information: Cardiff Oncology. T. Smeal: Financial Interests, Personal, Full or part-time Employment: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Cardiff Oncology, Hexagon Bio, Pfizer, Eli Lilly. J.S. Starr: Financial Interests, Personal, Advisory Role: Advanced Accelerated Applications, Tersera, Ipsen, Taiho, Helsinn Therapeutics, Tempus, Natera, Pfizer. M.R. Sharma: Financial Interests, Personal, Stocks/Shares: AbbVie, Amgen, AstraZeneca, BMS, Incyte, J&J, Eli Lilly, Merck, Moderna, Pfizer, Regeneron, Vertex. All other authors have declared no conflicts of interest.