A heralded drug that experts hope will open a new era in treating pancreatic cancer is also showing early but strong signs it could be effective against lung cancer.
Tumors shrank and health improved for 30% of lung cancer patients who took the targeted therapy daraxonrasib in a phase 1/2 clinical trial led by thoracic medical oncologist Kathryn Arbour, MD, at Memorial Sloan Kettering Cancer Center (MSK). She is also the lead author of the trial results published in September 2026 in the New England Journal of Medicine.
Daraxonrasib, formerly known as RMC 6236, works by taking direct aim at mutations affecting the RAS gene. RAS mutations fuel cancer by signaling cells to grow out of control in the lungs and other organs, particularly the family of mutations known as KRAS (pronounced KAY-rass).
For decades, researchers feared RAS mutations were “undruggable” because every effort to target them resulted in failure — until quite recently.
“Daraxonrasib is the first time we’ve had a therapy that can target all the different KRAS mutations we find in lung cancer,” says Dr. Arbour.
Because RAS mutations drive about 30% of lung cancer cases, daraxonrasib “could really expand our treatment options for people with lung cancer, especially those who do not respond well to chemotherapy and immunotherapy,” Dr. Arbour says.
“It was always heartbreaking to meet patients and say, ‘I know the specific mutations that are causing your cancer to grow, but we have no way to shut them off with a targeted therapy,’ ” Dr. Arbour says. “So to be able to offer that to so many patients for the first time is incredibly exciting.”
Clinical trial results testing daraxonrasib for lung cancer
More than 30% of patients on the phase 1/2 trial responded to daraxonrasib, meaning their tumors shrank and their condition improved. The clinical trial involved:
- 136 patients with metastatic lung cancer (meaning cancer that has spread).
- All patients had been previously treated, usually with a combination of chemotherapy and immunotherapy.
- Lung cancer that was driven by KRAS mutation variants G12V, G12A, G12D, G13D, Q61, and others.
Because this was an early-phase trial, the primary goals were to make sure the drug is safe, that it shows activity against tumors, and to establish the optimal dose for the next phase of testing.
Ultimately, trial investigators decided that 200mg was the ideal dose. “We were really focused on a dose that’s tolerable for the long run and not just in the short term,” Dr. Arbour says, “so people can live fuller, more productive lives on the medication.”
Dr. Arbour says two other important goals of the trial also showed encouraging results. Progression-free survival measures the amount of time on a therapy before cancer starts to gets worse. In the clinical trial, median progression-free survival was 8.3 months. “We found that the response to daraxonrasib was quite durable, meaning that the amount of time it helps people is longer than the standard of care chemotherapy.”
Dr. Arbour says median overall survival on the drug looks promising as well, at 16.0 months. Many people had been through extensive treatment with other treatments before joining the trial, which can leave them weakened. Nonetheless, overall survival looks to be better than chemotherapy.
Testing daraxonrasib in more patients
Dr. Arbour is investigating daraxonrasib head-to-head against chemotherapy in a Phase 3 trial that is now open and enrolling patients at MSK.
“This is just the beginning of our attempt to help people facing lung cancer with daraxonrasib, but the early signals are very hopeful,” Dr. Arbour says.
“One woman in her 80s who came to us was so short of breath that it was hard for her to walk even a few yards. But this medicine helped her get well enough to go back to the golf course. Daraxonrasib can work quickly and profoundly for some patients, shrinking their tumors and improving their symptoms so they can get back to a more active life.”
Some side effects but better quality of life
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Overall, 54% of patient suffered significant (grade 3/4) side effects, including:
- Rash
- Diarrhea
- Nausea and vomiting
- Irritation of the mouth
A few patients had to drop out of the trial because of side effects.
However, Dr. Arbour says side effects of daraxonrasib were generally better tolerated by patients than with chemotherapy. And MSK has developed special expertise in helping relieve side effects associated with daraxonrasib and other RAS inhibitors.
“We’re really fortunate at MSK to have a team of dermatologists who are experts at managing side effects, including complex rashes that are sometimes caused by daraxonrasib.”
Dr. Arbour also says many patients report a higher quality of life with daraxonrasib because it is a pill taken orally once a day rather than chemotherapy given through infusion.
“Chemo is given every three weeks and sometimes even every week,” Dr. Arbour explains. “But with daraxonrasib, people can just take the pill with them if they want to travel. There is so much more freedom and flexibility.”
Patients also found the side effects easier to cope with. “Chemo side effects can last for days after the infusion,” Dr. Arbour says. “But with daraxonrasib, there are patients who worked full-time on the medication, which is very difficult to do with chemo. We want people to live life as they want to — and to live well.”
How daraxonrasib works
Dr. Arbour compares RAS mutations in lung cancer cells to a light switch that’s flipped on. “We want to use any possible approach to flip that light switch off,” she says.
RAS mutations — particularly KRAS — create proteins that send abnormal signals to cells. These signals tell cancer cells to divide and grow out of control, and this runaway growth is cancer.
For decades, scientists struggled to figure out a way to block the abnormal signals. But unlike many mutations, the physical structure of RAS mutations is smooth and difficult for medicines to penetrate or latch onto.
Then, a series of breakthroughs starting around 2013 offered new hope for inhibiting the cancer-causing signals of RAS mutations. Researchers at MSK, including Dr. Arbour, were instrumental in preclinical research and clinical trials that established the value of RAS inhibitors including sotorasib, adagrasib, and zoldonrasib.
These RAS inhibitors have proved to be lifesaving and have also helped people with few options live better for longer.
However, these “first generation” inhibitors target a specific KRAS mutation. In contrast, daraxonrasib targets many RAS mutations in lung cancer.
“Daraxonrasib is sometimes referred to as a molecular glue,” Dr. Arbour explains. “Based on its unique design, it’s able to stop protein signals for many different types of KRAS mutations, which is distinctly different than other inhibitors that may only work against a small subset of KRAS mutations.”
Targeting many RAS mutations in lung cancer
Dr. Arbour believes the ability of daraxonrasib to work so broadly is “pretty remarkable, because we see different RAS mutations in all different types of lung cancer patients — some who have smoked and some who never smoked a cigarette in their lives.”
Daraxonrasib also appears to be effective against very rare mutations, including HRAS and NRAS, as well as “mutations like KRAS-G12V and G12A, where there are no therapies currently in development,” says Dr. Arbour.
Dr. Arbour says daraxonrasib may also prove helpful when cancer cells evolve to evade treatment.
“We know that sometimes patients who have been on, let’s say, a G12C inhibitor may develop additional RAS mutations,” Dr. Arbour says. “Daraxonrasib may be helpful at addressing the bigger problem where patients can have multiple KRAS mutations, which we sometimes see in lung cancer. Other clinical trials exploring that very question are currently underway.”
MSK’s role developing treatments for RAS mutations in other cancers
Dr. Arbour says efforts across MSK have led to the advances now helping patients with RAS mutations. These include important contributions in the preclinical investigation of RAS from thoracic medical oncologist Piro Lito, MD, PhD.
MSK has also been instrumental in advancing RAS targeted therapies for colorectal cancer, through 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 approval of a KRAS drug for colorectal cancer by the U.S. Food and Drug Administration (FDA)
There is also great excitement about the use of daraxonrasib in pancreatic cancer. A phase 3 clinical trial of the therapy in patients with metastatic disease found it doubled median survival time compared with chemotherapy, which led to approval by the FDA. For pancreatic cancer, daraxonrasib will be sold under the brand name Rasonque. The drug is made by Revolution Medicine.
MSK gastrointestinal oncologists Eileen O’Reilly, MD, and Wungki Park, MD, have led the clinical trials at MSK that help demonstrate the potential of daraxonrasib in pancreatic cancer, which they believe could be a sea change in treating this challenging disease.
Dr. Arbour believes the close coordination of all these efforts at MSK has improved how daraxonrasib can help people, including patients facing lung cancer.
“Our goal with lung cancer therapy is to optimize people’s treatment so they can live full and meaningful lives,” Dr. Arbour says. “The ability to have a targeted therapy medication like daraxonrasib that’s an oral therapy gives people tremendous flexibility to go out and live their lives and do the things that they want to do.”
Key Takeaways
- A breakthrough for previously “undruggable” mutations: Daraxonrasib is the first therapy capable of targeting all the different KRAS mutations found in lung cancer, including variants like G12C, G12V, and G12D. This is significant because RAS mutations drive roughly 30% of lung cancer cases and were long considered impossible to treat with targeted therapy.
- Promising early clinical trial results: In a Phase 1/2 trial of 136 patients with metastatic lung cancer, more than 30% responded to the drug with tumor shrinkage and improved condition. Both progression-free survival and overall survival appeared better than standard chemotherapy, and researchers established 200mg as the optimal long-term dose.
- Better tolerated and more convenient than chemotherapy: While 54% of patients experienced significant side effects like rash, diarrhea, and nausea, these were generally easier to tolerate than chemotherapy side effects. Because daraxonrasib is a once-daily oral pill rather than an infusion, patients report greater freedom and quality of life, with some even able to work full-time.
- A unique “molecular glue” with broad and cross-cancer potential: Unlike first-generation inhibitors that target a single KRAS mutation, daraxonrasib works against many RAS mutations across diverse patients, including rare variants and cancers that evolve to evade other treatments. Its promise extends beyond lung cancer, as a phase 3 trial in pancreatic cancer doubled median survival compared to chemotherapy, putting it on a fast track toward FDA approval.
Dr. O’Reilly holds the Winthrop Rockefeller Chair of Medical Oncology.
Dr. Lito holds the Enid A. Haupt Chair of Therapeutic Research.
Additional authors, funding, and disclosures
Additional authors, funding, and disclosures can be found in the paper at the New England Journal of Medicine.