A new drug is showing promise in lung and pancreatic cancers — two of the most aggressive forms of cancer — by targeting one of the most common cancer-driving mutations.
Setidegrasib, formerly known as ASP3082, tags and destroys the cancer-causing protein produced by the KRAS G12D mutation. This new method for targeting a long-known mutation is called a KRAS degrader.
KRAS mutations are present in about 1 in 5 cancers. The G12D subtype drives about 40% of pancreatic cancers and 5% of non-small cell lung cancers.
“Setidegrasib is the first drug in this KRAS degrader class targeting KRAS G12D in solid tumors,” says gastrointestinal medical oncologist Wungki Park, MD, at Memorial Sloan Kettering Cancer Center (MSK) who led the global phase 1 clinical trial, which is the first study of the drug in humans. “Rather than blocking the signal, setidegrasib removes the KRAS protein itself.”
Results from the trial were published in the New England Journal of Medicine, in March 2026. The study demonstrated benefit and safety in both lung and pancreatic cancers that had gotten worse on prior treatments.
- About a third of the patients with metastatic lung cancer responded to setidegrasib with encouraging durability, which means the length of time the drug stays effective.
- About 60% of the lung cancer patients were alive after one year.
- Among the patients with pancreatic cancer, about 25% responded to the drug, and the median overall survival was 10 months. Two out of three patients in the trial with pancreatic cancer had stopped responding to 2 other lines of treatment before joining the trial.
“This drug’s potential is exciting,” says Dr. Park, “because the trial results suggest that setidegrasib can not only extend life for some patients with these aggressive cancers, it also has a very good safety profile, meaning the drug was well-tolerated with side effects that can be managed quite easily.”
Dr. Park says that can mean a better quality of life for patients. And it also offers hope that the drug can be combined with other therapies, offering new ways to treat people who have limited options.
How KRAS Mutations Drive Many Pancreatic and Lung Cancers
Researchers have known for decades that mutations in the RAS gene can drive cancer. This happens because KRAS mutations send a continuous signal to cells, directing them to divide and multiply uncontrollably.
Scientists long feared that KRAS mutations were “undruggable” because their structure makes it difficult for drugs to attach and block their cancer-causing effect. But scientists have recently been able to design drugs that overcome this challenge.
Lung cancer is responsible for the majority of cancer deaths in the United States, according to the American Cancer Society. Pancreatic cancer is projected to become the second leading cause of cancer deaths by 2030.
Setidegrasib Phase 1 Clinical Trial Results
As a novel, first-in-human, first-in-class clinical trial, the main goals were to ensure that the drug is safe and would benefit participants in the trial. The trial found the recommended dose of the drug — which is given intravenously once a week — is 600 milligrams. Based on the success of this early trial, a global phase 3 randomized study has launched and is enrolling patients.
Setidegrasib Results in Lung Cancer
In the trial, 45 patients with non-small cell lung cancer were treated with a dose of 600 milligrams.
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The median age was 68, with patients ranging from 36 to 76 years old.
- All patients had metastatic cancer, meaning cancer that had spread.
- All patients had been given at least one other treatment before joining the trial.
- The response rate was 36%.
- The median progression free survival — the amount of time patients lived without the cancer getting worse — was 8.3 months.
- The estimated overall survival at 12 months was 59%.
Dr. Park stresses that the results will need to be borne out in future larger trials. But he calls them “an exciting sign that the drug may improve outcomes for lung cancer patients with this mutation.”
Setidegrasib Results in Pancreatic Cancer
In the trial, 21 patients with pancreatic ductal adenocarcinoma — which accounts for 90% of cases — were treated with 600 milligrams.
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The median age was 65, with patients ranging from 36 to 79 years old.
- All patients had metastatic cancer.
- All patients had received at least one form of treatment that no longer worked, and two-thirds had been treated with two lines of treatment prior to setidegrasib.
- The response rate was 24%.
- The median progression free survival was three months.
- The median overall survival was 10.3 months.
Dr. Park says the results “are better than what we expect with the standard of care chemotherapy. Particularly because most participants had already undergone two previous treatments that no longer worked. Chemotherapy is typically ineffective in that setting.”
Setidegrasib Phase 1 Clinical Trial Safety
Dr. Park is also encouraged by the results because setidegrasib has fewer side effects than standard chemotherapy for both lung cancer and pancreatic cancer patients.
“Most side effects were related not to the drug itself but reactions to the intravenous administration of setidegrasib,” Dr. Park says. The teams caring for patients used antihistamine drugs — like Benadryl — to clear up these reactions for most people.
“No patient had to leave the trial because of adverse events related to the drug,” he says. “The drug was well tolerated by patients, with one of the best safety profiles I’ve seen in an investigational drug.”
He points out that less toxicity can mean a better quality of life for patients. “That’s a big win for people who have been through a lot,” Dr. Park says.
How Setidegrasib and Related KRAS Drugs Work
Dr. Park compares KRAS mutations to a broken light switch that stays stuck in the “on” and can’t be turned off. The result is a protein that constantly signals cells to grow.
After decades of frustration, scientists recently figured out how to fight back.
One approach is called a KRAS inhibitor, which blocks the signal sent by the mutation, slowing or shutting down the chain reaction that leads to uncontrolled cell growth.
Dr. Park leads MSK’s efforts with this approach, together with gastrointestinal medical oncologist Eileen O’Reilly, MD, focused on promising RAS and KRAS inhibitors that have resulted in global phase 3 clinical trials.
Setidegrasib is slightly different from a KRAS inhibitor. As a KRAS degrader, setidegrasib “essentially tells the body that it doesn’t need the protein created by the KRAS mutation, so it’s disposed of,” Dr. Park says.
The difference, he explains, “is that the KRAS inhibitor turns off the lamp. The KRAS degrader unscrews the light bulb and throws it in the garbage.”
Other Advances in KRAS Therapies at MSK
MSK is also advancing a range of KRAS-targeted therapies across multiple cancer types, including next-generation inhibitors and other emerging therapies. This comprehensive approach is reflected in the leadership of the setidegrasib trial — Dr. Park, Dr. O’Reilly, and MSK thoracic oncologist Kathryn C. Arbour, MD.
Another example is the work of MSK gastrointestinal oncologist and early drug development specialist Rona Yaeger, MD. She led clinical trials involving the drug adagrasilb that led to the first FDA approval of a KRAS drug for colorectal cancer.
“MSK is at the forefront of this amazing translational science and I’m very glad to be part of this big team,” says Dr. Park. “This is truly helping patients with some of the most aggressive cancers.”
Key Takeaways
- A new drug called setidegrasib targets a gene mutation called KRAS G12D, which causes cancer cells to grow out of control. This mutation is responsible for about 40% of pancreatic cancers and 5% of lung cancers, making it an important target for treatment.
- In clinical trials, the drug showed encouraging results for both lung and pancreatic cancer patients who had already tried other treatments that stopped working. About 36% of patients with lung cancer responded to the drug, and about 24% of patients with pancreatic cancer responded — both settings in which standard chemotherapy is typically ineffective.
- One advantage of setidegrasib is that it had very manageable side effects. Most reactions were caused by the IV delivery method and could be treated with antihistamine drugs like Benadryl. No patients had to leave the trial due to drug-related side effects.
Additional Authors, Funding and Disclosures
Additional authors, funding, disclosures, and acknowledgements can be found in the paper at the New England Journal of Medicine.