KRAS-Mutated mCRC Clinical Program

Turning the Tide

on KRAS-Mutated Metastatic Colorectal Cancer (mCRC)

Onvansertib in Combination with Second-Line Standard-of-Care is Reducing Tumor Growth and Increasing Progression-Free Survival

Improving response to second-line treatment and increasing progression-free survival

There is currently only a 5-13% response rate to second-line standard-of-care (SOC) FOLFIRI/Avastin® and median progression-free survival (mPFS) of 4.5 – 5.7 months.

Onvansertib in combination with standard-of-care is a promising new second-line therapy to improve response to treatment and increase progression-free survival.

  • 50% of patients with mCRC have a KRAS mutation
  • Prognosis is poor with a five-year survival rate of 10%
  • Other drugs currently in development do not address the most prevalent KRAS mutations in mCRC
Onvansertib targets the major KRAS mutations associated with mCRC

Onvansertib is the only PLK1 inhibitor and targeted therapy in clinical development that has demonstrated activity against aggressive and difficult-to-drug KRAS mutations in metastatic colorectal cancer.

Cells with KRAS Mutations are Hypersensitive to Inhibition of PLK1

RAS activates PLK1 through a MEK/ERK-independent mechanism.

Downstream target CRAF interacts with PLK1 and promotes PLK1 activation, leading to mitosis and tumor progression.

Synergy in Combination with Irinotecan

Synergy in Combination with 5-FU

Onvansertib is Synergistic in Combination with Irinotecan and 5-FU

The combinations have demonstrated significantly greater tumor growth inhibition than either drug alone.

Why onvansertib is a promising new treatment option for KRAS-mutated mCRC: Targeting the once ‘undruggable’ KRAS mutations

Approximately 50% of mCRC is associated with the difficult-to-treat KRAS mutation which is believed to drive aggressive tumor growth and resistance to currently available treatment.

Despite decades of attempts, until recently there had not been any therapeutic options that specifically and effectively target KRAS mutations.

Patient Jorge Rivera’s Journey

Onvansertib in Combination with FOLFIRI/Avastin® is Demonstrating Safety and Efficacy in KRAS-Mutated Metastatic Colorectal Cancer

Phase 1b/2 multi-center, open-label clinical trial NCT03829410

“So far everything we hoped for has happened - no toxicity and signs of efficacy. We are very optimistic because we are seeing the anti-tumor effects and opening the opportunity for a new treatment designed to attack KRAS-mutant tumors that acts synergistically with standard-of-care chemotherapy”

Dr. Heinz-Josef Lenz,
Principal Investigator,
USC Norris Comprehensive Cancer Center

Assessment of Preliminary Efficacy and Duration of Response

  • 39% (7/18 evaluable patients) ORR
  • 7 PRs observed across 5 different KRAS mutations
  • Median PFS to-date is 9.4 months, which is ~2-fold greater than current SOC mPFS of 4.5 – 5.7 months

Significant Decreases in KRAS Mutational Burden in Cycle 1 are Predictive of Subsequent Tumor Shrinkage on Radiographic Scan

  • Clinical responses were observed across different KRAS mutations, including the 3 most common in CRC (G12D, G12V, G13D)
  • The greatest decreases in KRAS MAF after 1 cycle of treatment were observed in patients achieving a PR
    • All 7 patients with a PR had >75% decrease
    • 5 of the 7 patients with SD had reductions >75%
    • the 2 patients who progressed showed a more modest decrease in KRAS MAF (-55% and -26%)

Our Clinical Programs

KRAS-Mutated Metastatic Colorectal Cancer (mCRC)

Combining onvansertib with FOLFIRI/Avastin® to improve efficacy by increasing duration of response and overall survival.

Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)

Leveraging the synergy of onvansertib to increase duration and response of overall survival.

Zytiga-Resistant Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Adding onvansertib to daily Zytiga® to overcome resistance, extend treatment response and overall survival.