Roswell Park Comprehensive Cancer Center is now offering clinical trials of two new KRAS-targeting agents, providing new hope for patients with advanced cancers harboring KRAS mutations. These agents employ different mechanisms of action compared to the first FDA-approved KRAS inhibitor, sotorasib, offering potential benefits for patients who do not respond or develop resistance to existing therapies.
Overcoming KRAS Resistance: A New Approach
KRAS mutations, found in up to 30% of all cancers, including colorectal, lung, pancreatic, and leukemia, have historically been difficult to target. While sotorasib targets the G12C mutation, other KRAS mutations remain a challenge. Christos Fountzilas, MD, FACP, Associate Professor of Oncology and Associate Director for Solid Tumors, Early Phase Clinical Trials Program at Roswell Park, notes, "There remains a need for additional KRAS-targeting drugs to provide other treatment options for patients who do not respond — or who develop resistance — to the drug."
'Cutting the Wire': A Novel KRAS Degradation Strategy
One of the clinical trials at Roswell Park, led by Dr. Fountzilas, is investigating an agent that directly binds to the KRAS molecule and breaks it down. This approach, described as "cutting the wire," effectively shuts off the signal that tells the cell to grow and multiply. The Phase 1 trial is specifically for patients with advanced pancreatic, colorectal, and lung cancers that have the KRAS G12D mutation.
Dual-Targeting Strategy for Bile Duct Cancer
Another clinical trial, led by medical oncologist Kannan Thanikachalam, MD, focuses on patients with advanced bile duct cancer and any KRAS mutation. This trial combines a new agent, ezurpimtrostat, with trametinib. Ezurpimtrostat aims to interfere with the housekeeping process that cancer cells use to survive, while trametinib blocks an abnormal protein from signaling cancer cells to multiply. The combination aims to fully block the growth of cancer cells. "If this trial shows that this combination is safe and effective, it would be a significant step in improving outcomes for patients," says Dr. Thanikachalam.
Implications for KRAS-Mutated Cancers
The development of these new KRAS-targeting agents represents a significant advancement in the treatment of KRAS-mutated cancers. As Dr. Fountzilas explains, "We screen every patient with pancreatic, lung, or colon cancer for KRAS mutations. We used to test people for KRAS because having the mutation meant certain other drugs would not work for you... Now we can say that because you have a specific KRAS mutation, we have options that specifically target the very factor that is making your cancer grow."
