Margaret and her husband, David, were able to travel to Mexico because a clinical trial drug called zoldonrasib successfully controlled her lung cancer, which had returned after treatment.
For decades, cancers with mutations in the gene KRAS (KAY-ras) were considered “undruggable.” KRAS mutations are found in more than 20% of cancers. They are most common in lung cancer, pancreatic cancer, and colorectal cancer. Nearly four years ago, the first drug was approved to treat patients with one subtype of KRAS mutation. But there are many other subtypes, and it’s possible that targeting each one may require its own strategy.
Now, for the first time, a drug taking aim at the mutation subtype called KRAS-G12D is showing promise in a phase 1 trial for patients with non-small cell lung cancer (NSCLC) . The drug is an experimental targeted therapy called zoldonrasib (RMC-9805). The KRAS-G12D mutation is rare (appearing in about 4% of all NSCLCs) but can be found in a wide range of patients, including in younger patients who have never smoked.
Dr. Kathryn Arbour is presenting the results from the zoldonrasib clinical trial at the AACR meeting in Chicago.
The findings on zoldonrasib were presented at the 2025 American Association of Cancer Research (AACR) Annual Meeting in Chicago by thoracic medical oncologist Kathryn Arbour, MD, of Memorial Sloan Kettering Cancer Center (MSK). The trial is being led by MSK gastrointestinal medical oncologist and early drug development specialist Rona Yaeger, MD.
Analysis of the first 18 trial participants found that 11 of them (61%) had their tumors shrink substantially. Patients in the trial had previously received chemotherapy, immunotherapy, or both and had not responded.
“This trial is the first time we’ve ever seen this kind of benefit in treating non-small cell lung cancers caused by KRAS-G12D,” Dr. Arbour says. “What we saw in these patients is dramatically different than what we would expect to see with standard treatment. Usually, only about 10% of patients respond to the current treatments we use when the cancer grows despite initial treatment.”
Young Woman With Lung Cancer Treated With Zoldonrasib
One of the patients in the clinical trial moved across the country, from Portland, Oregon, to New York City to receive treatment at MSK. Margaret (who asked not to use her last name) saw her cancer return after surgery. After radiation, chemotherapy, and immunotherapy failed to control it, Margaret, now 36, enrolled in the trial. Since she began taking the investigational drug about a year ago, the size of her tumors has decreased by 87%. They continue to shrink.
Margaret said her health improved almost immediately after starting the drug, which is taken as pills at home. “I had been on oxygen, and within five days, didn’t need it anymore,” she says. “My husband also realized my constant cough had stopped.”
Within a few weeks, Margaret and her husband began taking long walks on the East River Esplanade in Manhattan. She resumed going to the gym. “I felt like I didn’t have cancer anymore, even though I obviously still did,” she says.
Delays in Diagnosing Lung Cancer in Young Never-Smokers
As is often the case with younger cancer patients, Margaret had a long journey before getting a lung cancer diagnosis. For nearly two years, she had a dry cough and felt short of breath. She was repeatedly tested for COVID-19 and treated for seasonal allergies, asthma, and acute pneumonia before finally learning she had a tumor in her left lung.
“I found out I had cancer right around my first wedding anniversary,” she says.
Even after she finally received a correct diagnosis, there were stumbling blocks to finding successful treatment. Margaret had surgery in Portland to remove the cancer, but it returned quickly and spread to her other lung, which meant it was stage 4.
Treating Lung Cancer Caused by KRAS-G12D Mutation
Because Margaret is young, female, Asian, and a never-smoker, her doctors assumed her cancer was caused by a mutation in the gene EGFR, which is more common in this population. Instead, molecular testing revealed the mutation driving her cancer was in KRAS-G12D, an entirely different gene.
“Unfortunately, KRAS-G12D tumors are much less likely to respond to standard treatments like chemotherapy and immunotherapy,” Dr. Arbour says.
Mild Side Effects From Zoldonrasib
At the AACR meeting, Dr. Arbour reported that the most common side effects of zoldonrasib were gastrointestinal upset and fatigue; most cases were mild. Margaret has experienced some nausea from zoldonrasib, which she is able to control with ginger chews. In the beginning, she had elevated blood levels of an enzyme called creatine phosphokinase, but that problem improved by lowering her dose and may have been caused when she started exercising more.
The results presented by Dr. Arbour are part of a larger trial studying zoldonrasib in a range of cancers caused by KRAS-G12D. Clinical research in all of these cancers is still ongoing.
MSK’s Expertise in Treating KRAS Cancers
Doctors and scientists at MSK are leaders in the study of the KRAS family of genes. Two drugs that block the KRAS-G12C subtype have received approvals from the U.S. Food and Drug Administration (FDA) based in large part on clinical trials and lab research done at MSK.
Clinical trials of sororasib (Lumakras®), the first drug ever approved for a KRAS gene, were led by physician-scientist Bob Li, MD, PhD, then at MSK. Another MSK expert, thoracic medical oncologist Greg Riely MD, PhD, played an important role in the approval of a second drug for KRAS-G12C lung cancer, called adagrasib (Krazati®). And gastrointestinal medical oncologist and early drug development specialist Rona Yaeger, MD, led the development of adagrasib for colorectal cancer.
Other MSK researchers, including physician-scientists Piro Lito MD, PhD, and Neal Rosen, MD, PhD, have made important laboratory studies on KRAS for many years. Dr. Arbour is a member of Dr. Lito’s lab.
Margaret’s Life With Stage 4 Lung Cancer
Under the care of MSK thoracic medical oncologist Alissa Cooper, MD, Margaret and her husband, David, have been able to resume their lives, including a trip to Mexico to visit his family. “Even walking around in the high altitude of Mexico City, I had no breathing problems,” Margaret says.
Margaret’s scans before (left) and after taking zoldonrasib. In the image on the left, the cancer appears as cloudy areas on the scan. Since beginning the drug, her tumors have shrunk by 87%.
Margaret is grateful that both she and her husband have been able to keep their jobs in Oregon and work remotely throughout her treatment in New York. (She works in marketing, and David is a research scientist). Margaret has found support from family and friends, and made new connections through the Lisa and Scott Stuart Center for Adolescent and Young Adult (AYA) Cancers at MSK.
“As unlucky as I have been with my cancer diagnosis, I have been extremely lucky in finding the care that I deserve,” Margaret says. “Moving across the country was a risk, but it was worth it to find better treatment. The MSK team always has my back.”