Data Demonstrate the Clinical Benefit of Onvansertib in KRAS-Mutated mCRC

Data from a phase 1b/2 study investigating onvansertib as a treatment of Kirsten rat sarcoma (KRAS)-mutated metastatic colorectal cancer (mCRC) demonstrated that 42% of patients achieved a partial response (PR) and 67% demonstrated a durable response ranging from 6.1 months to 13.7 months, according to a presentation at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI).

Currently, the enrollment of patients in the phase 1b segment of the trial has been completed, with the researchers confirming the recommended phase 2 dose (RP2D) of onvansertib at 15 mg/m2. For the phase 2 segment, the trial is open to full enrollment with approximately 26 patients at trial sites in 6 different locations, including USC Norris Comprehensive Cancer Center, Mayo Clinic Cancer Centers (Arizona, Rochester, Jacksonville), Kansas University Medical Center, and CARTI Cancer Center.

"The phase 1b data show that a significant percentage of patients had tumor shrinkage, achieved clinical benefit and, importantly, that the response appears durable with two-thirds of the patients having been on treatment for at least six months," said Daniel H. Ahn, DO, lead investigator and medical oncologist, Mayo Clinic Cancer Center, in a press release. "This highlights the promise of onvansertib plus standard-of-care as an effective second-line treatment for patients with KRAS-mutated mCRC. We look forward to building on these promising data during the phase 2 portion of the trial."

In the findings from Cardiff Oncology's Expanded Access Program (EAP), the results were found to be similar to those of the phase 1b trial. In the EAP, 66% (6) of the first 9 patients who received onvansertib demonstrated tumor shrinkage and have continued with their treatment, with durable responses lasting 6 months on average.

Additionally, 5 different KRAS mutation subtypes were observed in the EAP, including G12A, G12C, G12V, G13D, A146T, with all patients previously receiving treatment with folfiri. The researchers observed that there were decreases in the KRAS mutational burden following the first cycle of treatment, which was found to be beneficial in predicting later tumor shrinkage.

"We are pleased with the continued advancement of our KRAS-mutated mCRC clinical study and are excited to initiate enrollment in the Phase 2 segment of this trial," said Mark Erlander, PhD, chief executive officer of Cardiff Oncology, in a press release. "Additionally, our EAP is being very well received by clinicians and patients who would otherwise not have access to onvansertib because they don't meet the strict eligibility criteria for our trial. We are encouraged by the initial observations and, in particular, the duration of response we are seeing, which is consistent with the data from our clinical trial. Of note, the key difference in the patients enrolled in our EAP is that several had received and progressed on prior FOLFIRI-based treatment and with the addition of onvansertib we are seeing tumor shrinkage and durable stable disease."

Among the 12 patients who were evaluable as of the ASCO-GI data cut-off point, 5 (42%) achieved a PR; 4 patients had a confirmed PR; 1 patient proceeded to curative surgery; and 1 patient with a non-confirmed PR left the study due to an unrelated event before a confirmatory scan was possible.

Additionally, the time to achieving a PR ranged between 2 and 6 months in patients on treatment, with 67% (8) of patients demonstrating durable responses at more than 6 months at a range between 6.1 and 13.7 months.

A KRAS variant was detected during the study by Droplet Digital PCR (ddPCR) at baseline in 10 of 12 patients, with all patients presenting with a KRAS mutation that was detectable by next-generation sequencing. Across the different KRAS variants, the researchers observed clinical responses, including among the 3 most common in CRC.

In KRAS mutant allelic frequency (MAF), the largest decreases were observed in patients achieving a PR that ranged from -78% to -100% following a single cycle of treatment, while 2 patients who progressed demonstrated a smaller reduction in KRAS MAF at -55% and -26%. However, patients in the study with PR and stable disease frequently showed a lower on-treatment KRAS MAF than patients with early progressive disease.

The researchers also found that onvansertib in combination with folfiri and bevacizumab (Avastin) was safe and well-tolerated, with adverse events (AEs) at grade 3 or 4 occurring at only 9%. The only AE reported at grade 3 or 4 was neutropenia (n=8), which occurred in ≥2 patients and was managed by dose delay, growth factor therapy, and/or the discontinuation of the 5-FU bolus. However, no patients needed to be taken off the trial because of the occurrence of neutropenia and no major or unexpected toxicities were attributed to onvansertib.

REFERENCE

Cardiff Oncology Presents Data that Continues to Demonstrate the Clinical Benefit of Onvansertib in KRAS-Mutated mCRC and Initial Findings from its Expanded Access Program. San Diego, CA: Cardiff Oncology; January 15, 2021. prnmedia.prnewswire.com/news-releases/cardiff-oncology-presents-data-that-continues-to-demonstrate-the-clinical-benefit-of-onvansertib-in-kras-mutated-mcrc-and-initial-findings-from-its-expanded-access-program-301209151.html. Accessed January 25, 2021.