An Update on Drugs for KRAS Mutations

Currently, there are no KRAS inhibitors approved for pancreatic cancer, but that could soon change.

There are numerous clinical trials underway designed specifically for pancreatic cancer. And that’s a far cry from where we were not that long ago.

The cancer-promoting oncogene KRAS was first identified in 1982. When functioning normally, KRAS produces a protein regulating cell growth, division, and maturation. But when KRAS is mutated, it gets stuck in a so-called “on” position, kickstarting a relentless march of cell growth, division, and resistance to chemotherapies. 

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For decades, KRAS was called “undruggable” because its smooth surface and round shape made it tough to develop drugs that could latch onto the protein and stop it in its tracks. But in 2013, researchers at University of California San Francisco found a specific “pocket” on the surface of the mutated KRAS G12C protein. Finding this pocket led to the development of small-molecule inhibitors that target KRAS, such as sotorasib, which was approved in 2021 for non-small cell lung cancer, and adagrasib, which was approved in 2022 for non-small cell lung cancer and colorectal cancer.

“Pancreatic cancer is KRAS addicted,” explains gastrointestinal oncologist Allyson Ocean, M.D., Professor of Clinical Medicine, medical oncologist, and attending physician at Weill Cornell Medicine, New York, New York. As such, KRAS is not only the primary driver of pancreatic cancer (contributing to its development), but “once established, pancreatic tumors are dependent on KRAS for continued growth,” she says. Ocean, also chair of the Let’s Win Scientific Advisory Board, adds, “KRAS inhibitors could potentially revolutionize precision medicine in pancreatic cancer treatment. It’s early days, and we need to see more data, but everything so far is pointing in the right direction.”

Focusing on Daraxonrasib

Daraxonrasib, formerly called RMC-6236, is garnering significant attention at various cancer symposiums, and has been covered by Let’s Win. Developed by Revolution Medicines, this drug is taken orally and is a pan-RAS inhibitor. It works specifically by binding to the active “on” state of mutated RAS proteins, preventing them from sending growth signals. The drug has received multiple FDA fast-track designations for treating pancreatic cancer with RAS mutations, including Breakthrough Therapy Designation and a Commissioner’s National Priority Voucher (in October 2025). The designations were awarded based on very promising early trial results. Revolution Medicines is conducting numerous trials in pancreatic cancer. 

Below are some trials of particular interest.

Resectable Disease

RASolute 304 is a global phase III clinical trial evaluating the safety and effectiveness of daraxonrasib in pancreatic cancer patients who have had surgery and chemotherapy. The trial is active and recruiting, with a goal of enrolling approximately 500 patients. The trial will assess whether patients on daraxonrasib can improve disease-free survival compared to patients undergoing observation after treatment. The primary endpoint is disease-free survival, and secondary endpoints include overall survival, safety, and tolerability.  

Metastatic Disease

RASolute 303, which has not yet launched as of February 13, 2026, will be a global  phase III trial to evaluate daraxonrasib as a first-line treatment for patients with metastatic pancreatic cancer. The trial will have three arms:  daraxonrasib alone; the combination of daraxonrasib plus gemcitabine/nab-paclitaxel; and a control arm of gemcitabine/nab-paclitaxel.

An earlier phase III trial, RASolute 302, is evaluating daraxonrasib as a second-line treatment for metastatic disease by comparing it with standard of care treatment. The trial is active, but no longer recruiting patients.

Targeting KRAS G12D

KRAS G12D is the most prevalent mutation in pancreatic cancer, driving about 45 percent of cases, and zoldonrasib, a KRAS G12D inhibitor, is heading into phase III trials. RASolute 309 will evaluate the combination of zoldonrasib and daraxonrasib versus chemotherapy in patients with KRAS G12D-mutant metastatic pancreatic cancer. Zoldonrasib will also be tested in the RASolute 305 study, a phase III trial comparing the drug plus standard chemotherapy versus chemotherapy alone as a first-line treatment in metastatic disease. Start-up activities for both trials are ongoing.

Targeting KRAS G12V

KRAS G12V is present in about 30 percent of pancreatic cancers. RMC-5127 is an investigational KRAS inhibitor designed to selectively target and shut down the activated form of the KRAS G12V mutation. It is currently part of a phase I/Ib clinical trial for advanced solid tumors, including non-small cell lung cancer, pancreatic cancer, and colorectal cancer, that is currently recruiting. RMC-5127 will be evaluated on its own and in combination with either daraxonrasib or cetuximab in patients with KRAS G12V-mutant solid tumors.

Meeting the Challenges

Continuing research will be key to a better understanding of the impact of KRAS inhibition on patient outcomes. The Lustgarten Foundation has committed $5 million to Break Through Cancer to accelerate the translation of KRAS science into patient benefit. This initiative, called Conquering KRAS in Pancreatic Cancer, is a collaborative effort, with Dana-Farber Cancer Institute, the Sidney Kimmel Cancer Center at Johns Hopkins, MIT’s Koch Institute, MD Anderson Cancer Center, and Memorial Sloan Kettering Cancer Center all lending their expertise. This team works closely with Revolution Medicines to better understand why some patients do better on RAS(ON) inhibitors while others develop resistance.

Indeed, the development of resistance is a major challenge in KRAS inhibition as it is in other treatment efforts, says Ocean. “There are numerous reasons why resistance develops, including tumors activating parallel signaling pathways and the genetic diversity of the tumor itself,” she adds. “However, I do think science will find a way to overcome this resistance with combination strategies and other approaches.”

Although she is very hopeful about KRAS inhibitors, Ocean notes that this focus on KRAS is just one of the strategies that has the potential to change patient treatment. “There’s exciting work being done in vaccines, tumor-treating fields are showing potential, and new drug combinations are being tested. There is a lot of momentum in pancreatic cancer research right now that could be of tremendous benefit to our patients.”