Onvansertib Added to SOC Improves Responses and Survival in KRAS-Mutant mCRC

Onvansertib has demonstrated positive efficacy and safety in patients with KRAS-mutant metastatic colorectal cancer.

In patients with KRAS-mutated metastatic colorectal cancer (mCRC), treatment with onvansertib showed improved efficacy compared with the current standard-of-care (SOC) irinotecan, fluorouracil (5-FU), and folinic acid (leucovorin; FOLFIRI) in combination with bevacizumab (Avastin), according to a press release from Cardiff Oncology.1

KRAS mutations in mCRC as well as in other diseases like pancreatic cancer and castration-resistant prostate cancer have an unmet medical need for therapies.1Onvansertib is a PLK1 inhibitor that has demonstrated the ability to regulate cell-cycle progression, causes mitotic arrest leading to cell death, and regulates tumor growth.2

"Our phase 1b/2 trial continues to generate data suggesting that the addition of onvansertib to SOC results in an objective response rate and median progression-free survival that substantially exceed those previously achieved with SOC alone," said Katherine L. Ruffner, MD, chief medical officer of Cardiff Oncology, in a press release.

The phase 1b/2 study included 44 patients with mCRC of whom 38 were evaluable for response. Patients treated at the recommended phase 2 dose (RP2D) of onvansertib of 15 mg/m2 were dosed orally on days 1 through 5 every 14 days. With the accompanying FOLFIRI regimen, patients received irinotecan 180 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil (5-FU) 400 mg/m2, and continuous intravenous infusion 5-FU at 24 mg/m2 in combination with bevacizumab 5 mg/kg.

In phase 2, the primary end point was objective response rate (ORR), and the secondary end points were the number of patients with a complete response (CR), partial response (PR), and stable disease (SD) as well as progression-free survival (PFS) and the number of patients with reduction in KRAS allelic burden on liquid biopsies.3

All patients included were 18 years of age or older with histologically confirmed metastatic and unresectable CRC with a KRAS mutation, and an ECOG performance status of 0 or 1.

PRs were achieved in 42% of the 19 patients who were treated with the RP2D of onvansertib in the study. This percentage was an improvement from the 5% to 13% ORR that was historically observed with the SOC. Looking at the outcomes of onvansertib across all dose levels (12 mg/m2, 15 mg/m2, and 18 mg/m2), the ORR was 38%, which consisted completely of PRs.1

PRs also carried over to the different KRAS mutant variants seen in the study subjects including KRAS G12D, KRAS G12V, and KRAS G13D, which are commonly observed in mCRC. Following 1 cycle of onvansertib, achievement of a PR demonstrated the highest decreases in plasma KRAS mutant allelic frequency.

“Radiographic responses have been observed across multiple KRAS mutation variants, which speaks to a key advantage of onvansertib over competing agents targeting individual mutations. These impressive results, which have remained consistent across both academic and community trial sites, highlight the potential for onvansertib to address the unmet need for new second-line therapeutic options to treat patients with KRAS-mutated mCRC. I look forward to the trial's continued advancement and future data readouts,” said Ruffner, in the press release.

In terms of survival, the median PFS across all response-evaluable patients was 9.4 months. The median PFS had not yet been reached in patients treated with the RP2D at the time of data cutoff. In comparison, the historical median PFS observed with SOC was between 4.5 month and 5.7 months.

Treatment with onvansertib and FOLFIRI in combination with bevacizumab in the study was well-tolerated. Only 10% of patients experienced grade 3 or 4 treatment-emergent adverse events (TEAEs). The majority of the TEAEs observed were manageable and reversible with supportive care.

“The strong signal of efficacy and favorable tolerability profile observed in this trial bodes well not only for our lead mCRC program, but for each of our KRAS-focused clinical programs. The meaningful improvements we are seeing in treatment response relative to historical controls demonstrate the value of combination therapy and support the synergistic effect observed preclinically when onvansertib is added to standard-of-care FOLFIRI, said Mark Erlander, PhD, chief executive officer of Cardiff Oncology, in the press release. “We are also seeing compelling biomarker results that highlight the potential utility of plasma KRAS MAF as a predictive tool that could aid in the design of subsequent trials. Looking forward, we anticipate the ongoing Phase 2 portion of the trial to provide additional data catalysts that will advance the clinical development of onvansertib, generate value for shareholders and, most importantly, provide new treatment options for patients."


1. Cardiff Oncology announces new data from phase 1b/2 Trial in KRAS-mutated metastatic colorectal cancer showing robust objective response rate and progression free survival. News release. Cardiff Oncology. September 8, 2021. Accessed September 9, 2021. https://bit.ly/3yXgduc

2. PLK1 is a proven therapeutic target that is overexpressed in most cancers​. Cardiff Oncology website. Accessed September 9, 2021.

3. Onvansertib in Combination With FOLFIRI and bevacizumab for second line treatment of metastatic colorectal cancer patients with a KRAS mutation. Clinicaltrials.gov. Accessed September 9, 2021.