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 4% response rate to second-line standard-of-care (SOC) FOLFIRI/Avastin® and median progression-free survival (PFS) of 5.5 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.

KRAS Mutations In Colorectal Cancer

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.

Tumor cells harboring KRAS mutations are more vulnerable to onvansertib

Colorectal cancer tumor cells harboring a KRAS mutation are more vulnerable to cell death with PLK1 inhibition (onvansertib). KRAS-mutated cells are more sensitive to onvansertib than KRAS wild-type cells.

KRAS Wild-Type

KRAS Mutant

Survival

Tumor Growth

Onvansertib is synergistic in combination with irinotecan (the “IRI” in FOLFIRI)

Onvansertib + irinotecan (the “IRI” in FOLFIRI) are synergistic in CRC cell lines. The combination has 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

Efficacy for 8 evaluable patients treated with onvansertib 12 mg/m2 and 15 mg/m2:
  • 7 of 8 (88%) patients had clinical benefit: 3 partial response (PR) and 4 stable disease (SD)
  • 1 patient proceeded to successful curative surgery
  • Responses appear durable:
    • Median PFS of 6.5 months to-date
    • 6 patients remain on treatment

Progression-Free Survival

Best Radiographic Response

KRAS Mutant Monitoring in Liquid Biopsy

Changes in Plasma KRAS Mutant are Predictive of Tumor Regression
  • 6 of the 8 patients evaluable for efficacy showed tumor regression at 8 weeks
  • Decreases in plasma KRAS mutation level has been demonstrated to be an early marker for therapeutic response
  • 7 of the 8 patients had a KRAS mutation detected by ctDNA analysis at baseline (ddPCR and NGS)
  • Changes in KRAS mutant during cycle 1 of treatment were highly predictive of tumor regression:
    • 5 patients had a decrease in KRAS mutant to non-detectable level in cycle 1 (28 days) and subsequent tumor regression at 8 weeks (cycle 3 day 1)
    • 2 patients had detectable KRAS mutant at end of cycle 1 and showed tumor growth at cycle 3 day 1