FDA Grants Fast Track Designation to Onvansertib for KRAS+ mCRC Treatment

The FDA has given a fast track designation to onvansertib for the second-line treatment of patients with KRAS-mutated metastatic colorectal cancer.

The FDA has granted Fast Track designation to onvansertib (PCM-075) for the second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), according to Cardiff Oncology, Inc., the manufacturer of the oral PLK1 inhibitor.1

The designation, which will expedite the development and review of onvansertib, is specifically for use in combination with bevacizumab (Avastin) and FOLFIRI (5-fluorouracil, leucovorin, irinotecan).

"We are very pleased with the FDA's decision to grant Fast Track designation for the development of onvansertib to treat patients with KRAS-mutated mCRC," Mark Erlander, PhD, chief executive officer of Cardiff Oncology, stated in a press release. "This designation is a significant validation of not only our onvansertib clinical program, which is now eligible for priority review and accelerated approval, but it also signifies recognition of the medical need for new effective treatment options.

The efficacy of current second-line therapy in terms of response and survival prolongation remains very limited, particularly in the KRAS-mutated population, and we are confident that onvansertib, in combination with FOLFIRI/bevacizumab, represents a promising new treatment option.”

The onvansertib regimen is being evaluated in an ongoing phase 1b/2 trial (NCT03829410).2,3 To be eligible for enrollment on the trial, patients have to have histologically confirmed metastatic and unresectable KRAS-mutated disease; be aged ≥18 years; have an ECOG performance status of 0 or 1; and have either relapsed on or be intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab.

For the phase 1b segment of the trial, investigators are using a standard 3+3 dose-escalation design to identify the maximum-tolerated dose or the recommended phase 2 dose of onvansertib. As of January 24, 2020, enrollment in the second dose level has been ongoing. Efficacy will be evaluated by objective response rate per RECIST v1.1 criterion, which is the primary end point of the trial. Secondary end points include progression-free survival and reduction in KRAS allelic burden in liquid biopsies.

In an interview with OncLive during the 2020 AACR Virtual Annual Meeting I, Heinz-Josef Lenz, MD, an investigator on the phase 1b/2 trial, provided some background on the study.

“We know that the overexpression of PLK1 is associated with poor outcomes in patients with mCRC, which means high expression of PLK1 is associated with poor overall survival. In preclinical models, we know when we inhibit PLK1, we see a significant antitumor effect, particularly in RAS-mutant colon cancer models; this indicates that PLK1 inhibition seems to be sensitive to RAS-mutant colon cancers,” explained Lenz, who is head of GI Oncology in the Division of Medical Oncology and co-director of the Colorectal Center at the USC Keck School of Medicine.

Lenz also shared some preliminary insight on the safety and activity observed thus far in the trial.

“We have enrolled 12 patients so far [on the trial]. [So far], we do not see any significant safety signal; it's a lot of backbone adverse events that we would see with FOLFIRI plus bevacizumab. We have 8 evaluable patients to see whether there is any particular benefit [in terms of response]. Seven of the 8 have either stable disease or have experienced tumor shrinkage. In fact, [of] 6 patients [who] have tumor shrinkage, 1 is stable, and 1 has progression of disease. Three of those who experienced tumor shrinkage qualify for partial response.”

This article originally appeared on OncLive® as “FDA Grants Onvansertib Fast Track Designation in KRAS+ mCRC”.


  • Cardiff Oncology Announces Fast Track Designation Granted by the FDA to Onvansertib for Second-Line Treatment of KRAS-Mutated Colorectal Cancer. Published May 28, 2020. https://bit.ly/2XBAd57. Accessed May 28, 2020.
  • Barzi A, Lenz H-J, Samuëlsz E, et al. A phase 1b/2 study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC). Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT235. bit.ly/2WscpA8.
  • Onvansertib in Combination with FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients with a Kras Mutation. www. clinicaltrials.gov/ct2/show/NCT03829410. Updated June 24, 2019. Accessed May 28, 2020.