Onvansertib Regimen Shows Early Promise in KRAS-Mutant mCRC

Heinz-Josef Lenz, MD, FACP, discusses the next steps for the trial examining the onvansertib combination and sheds light on the possibility of this regimen eventually being used in the frontline setting.

Heinz-Josef Lenz, MD, FACP

The regimen of onvansertib, FOLFIRI (5-fluorouracil, leucovorin, irinotecan), and bevacizumab (Avastin) showed early activity without any notable safety signals in patients with KRAS-mutated metastatic colorectal cancer (mCRC), according to Heinz-Josef Lenz, MD, FACP.1

"As we all know, [patients with] KRAS mutations represent a significant [subgroup] in metastatic colon cancer. Up to 50% of patients have some sort of mutation, such as KRAS or NRAS, and currently we don’t have any targeted treatment options," said Lenz, the associate director for Clinical Research and co-leader of the Gastrointestinal Cancers Program at the University of Southern California (USC) Norris Comprehensive Cancer Center. "We are very excited about these early and preliminary data indicating that this might be an effective option for patients with KRAS-mutant [disease] in the future."

In a phase 1b/2 trial, investigators examined PLK1 inhibition as a potential target in patients with KRAS-mutated mCRC by pairing the PLK1 inhibitor onvansertib with FOLFIRI and bevacizumab. To be eligible for enrollment, patients had to have histologically confirmed metastatic and unresectable KRAS-mutated disease; aged ≥18 years; have an ECOG performance status of 0 or 1; and either relapsed on or are intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab.2

For the phase 1b segment of the trial, investigators are using a standard 3+3 dose-escalation design to identify the maximum-tolerated dose (MTD) 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, Lenz, who is also a professor of medicine and preventive medicine; section head of GI Oncology in the Division of Medical Oncology; and co-director of the Colorectal Center at the USC Keck School of Medicine, discussed the next steps for the trial examining the onvansertib combination and shed light on the possibility of this regimen eventually being used in the frontline setting.

OncLive: What was the rationale to conduct this type of trial?

Lenz: Many efforts have been made in the past couple of years to develop RAS targeted treatments, including vaccines and small molecules. Some of these approaches seem to work for lung cancer, but not as well as in CRC. Early ongoing clinical trials are examining a SOS1 inhibitor, which is one of the key proteins radiating the signaling from the membrane of the KRAS into the nucleus. Although there seems to be some promising results, it is still very early.

In this particular project, the focus is PLK1. 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.

In addition to the single-agent activity, there have been a lot of data generated [from research dedicated to examining] whether combinations with chemotherapy or targeted agents would be synergistic or additive. Some data show significant synergism when the PLK1 inhibitor is combined with irinotecan; there also appears to be an additive effect with bevacizumab. The preclinical data, including animal model data, show significant activity when the PLK1 inhibitor onvansertib [was combined] with irinotecan and bevacizumab. That [research] led to an investigator-initiated clinical trial, which is out of USC Norris Comprehensive Cancer Center in collaboration with Cardiff Oncology.

What was the design of this trial?

This is a phase 1b/2 study focusing only on patients with metastatic colon cancer who have a documented KRAS mutation. The trial is designed for the second-line setting, enrolling patients in whom FOLFOX and bevacizumab treatment failed in order to establish the MTD of onvansertib, as well as the preliminary efficacy. After the MTD is reached, [we want to explore this approach] into an expansion cohort to better confirm the efficacy of this regimen.

What was the activity that was seen with the regimen?

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.

What are the next steps following this study?

Right now, we are excited that we don't see any safety issues. We do see an efficacy signal so we will be expanding to a phase 2 trial to determine the efficacy. The next steps, if we see promising results, would be [to conduct] a randomized phase 2 clinical trial. What will be very helpful is [to learn more about] the correlative signs incorporated into the clinical trial. We will look for KRAS-mutant circulating DNA and see whether these patients have a significant decrease in allele frequency of KRAS mutations [because this] seems to go along with the efficacy. In 5 out of 7 patients where we detected it, [we saw] a decrease of KRAS-mutant allele frequencies. We are happy that we may have an additional biomarker to monitor in these patients for efficacy because it seems that we can predict the efficacy prior to the imaging results.

This is an early study, but do you foresee this agent potentially being used in the frontline setting?

That could be, yes. Many opportunities exist. We still do not have any available treatment options for [patients with] KRAS-mutant mCRC and I believe this [research] will open up an opportunity for us because, right now, our default [option] is [to use] a bevacizumab-based chemotherapy regimen with either FOLFOX or FOLFIRI [in these patients].

The reason the second line was chosen is because we wanted to combine the regimen with FOLFIRI in light of the preclinical synergism [we saw]. There is no reason not to move [this agent with] FOLFIRI and bevacizumab into the first-line [setting] and that may be something that would be very helpful. In the United States, it is just FOLFOX and bevacizumab [that is used] as the default. Most clinical trials are designed to use FOLFOX as a backbone and FOLFIRI in second-line treatment, but many have data questioning that there may be a more effective treatment in the first line. As such, I believe this standard will hopefully change.


  1. 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.
  2. 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 04, 2020