Onvansertib Show Early Signals of Safety and Efficacy in KRAS-Mutated mCRC

The combination of onvansertib, a third-generation adenosine triphosphate inhibitor, with FOLFIRI and bevacizumab achieved positive responses in patients with metastatic colorectal cancer in the second-line setting, according to the results of a phase Ib/II reported in a press release from Trovagene, Inc.<br /> &nbsp;

The combination of onvansertib (PCM-075), a third-generation adenosine triphosphate (ATP) inhibitor, with FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and bevacizumab (Avastin) achieved positive responses in patients with metastatic colorectal cancer (mCRC) in the second-line setting, according to the results of a phase Ib/II reported in a press release from Trovagene, Inc.1

The goal of the study was to assess the preliminary efficacy and safety of onvansertib in combination with FOLFIRI and bevacizumab in patients withKRAS-mutated mCRC, a patient population that typically has low response rates (5%) to standard-of-care therapy and for whom there are no existing targeted therapies. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in the phase Ib stage of the trial. Once the trial reached the phase II stage, patients were to be treated with the RP2D.2

Patients at University of Southern California Norris Comprehensive Cancer Center and The Mayo Clinic Arizona with mCRC who had aKRASmutation in exon 2, 3, or 4 in the primary tumor or metastasis were enrolled in the trial. Eligible patients must have failed prior treatment or shown intolerance to fluoropyrimidine and oxaliplatin with or without bevacizumab and have an ECOG performance status of 0 or 1. Patients were excluded if they had concomitantKRASandBRAFV600 mutations, and those with microsatellite instability—high/deficient mismatch repair tumors were ineligible. The study also excluded patients who were had previous chemotherapy in the metastatic setting, anti-cancer chemotherapy, or biologic therapy within 4 weeks of in-trial treatment, gastrointestinal disorders that may cause absorption of the oral agent, uncontrolled intercurrent illness, or HIV.

In the phase Ib stage used standard 3+3 dose-escalation design of the combination regimen. Onvansertib was given at 12 mg/m2, orally on days 1 through 5, every 14 days. The treatment was stopped when 6 patients had been treated at the highest dose level and 1 or more patients experienced a dose-limiting toxicity (DLT).2In phase II, the investigators looked for the overall response rate to onvansertib/FOLFIRI/bevacizumab via Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) in patients, and usedKRAScirculating tumor DNA (ctDNA) to determine which pathways were activated by the combination and contributed to the patient’s response.2

The secondary endpoints for the phase Ib/II trial were progression-free survival and reduction inKRASallelic burden, which was assessed with liquid biopsies. The 2 exploratory endpoints of the trial were the use of circulating tumors cells (CTCs) and ctDNA to evaluate relevant biomarkers and the use of archival tumor tissue to assess the genomic and transcriptomic profiles associated with patient response.

Using Guardant technology, investigators first identified mutations in copy number variation and ctDNA, then used liquid biopsy to track changes in theKRASallelic burden and CTC to record enumeration using Epic technology. These genomic tests will continue in all 8 remaining cycles of treatment during the trial.

All 4 patients who were treated in the phase Ib/II study and completed their first cycle of treatment showed decreases inKRASmutational burden as a result of the combination regimen.1One patient completed the first cycle of therapy and did not experience a DLT. This patient has moved on to phase II of the study. Another patient developed grade 4 neutropenic fever, a DLT that led to discontinuation of treatment. As a result, the cohort was expanded to 6 patients. The investigators reported that grade 2 constipation and grade 3 abdominal pain were also seen in trial patients and two additional patients are being evaluated in phase Ib for possible DLT.

In the first patient that received treatment, the frequency ofKRASG12D mutation allelic decreased by 4.6% in 7 days.

With these results, Trovegene aims to help improve outcomes for patients withKRAS-mutated mCRC, who make up 50% of patients with mCRC.2

"Although still early in the trial, we are encouraged by the decreases inKRAS, assessed following initial dosing with onvansertib in combination with FOLFIRI/ bevacizumab, in patients treated in the first cohort," Afsaneh Barzi, MD, associate professor of clinical medicine at Keck School of Medicine of USC and medical oncologist at USC Norris, stated in a press release.

According to Barzi, patients in the trial have continued treatment after the first cycle. “These initial findings suggest that onvansertib may provide clinical benefit for [patients with] mCRC who have limited therapeutic options and a poor prognosis,” he said.

KRAS is considered to be a well-established biomarker for assessing tumor mutational burden and predicting patient response to treatment. Ovansertib is also being studied in combination with abiraterone acetate (Zytiga)/prednisone in patients with metastatic castration-resistant prostate cancer (NCT03414034) and in combination with decitabine in patients with acute myeloid leukemia (NCT03303339). The study of onvansertib with FOLFIRI and bevacizumab (NCT03829410) is ongoing with an expected completion date of May 2021.


  1. Trovagene Announces Positive Response to Treatment in Phase 1b/2 Trial of Onvansertib in Patients with KRAS-Mutated Metastatic Colorectal Cancer [press release]. San Diego, CA: Trovagene, Inc; October 22, 2019. https://bit.ly/366C5X4. Accessed October 23, 2019.
  2. Lenz HJ, Ahn D, Erlander M, et al. A phase Ib/II study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer in patients with a KRAS mutation. Presented at the 2019 ESMO Congress September 27-October 2, 2019; Barcelona, Spain. Poster 667TiP.