Targeted therapies aim to block the activity of genes that cause cancer, providing a direct attack on tumors while sparing healthy cells. Identifying genes that trigger tumor growth is only the first hurdle to developing targeted drugs — just because investigators know a gene may cause cancer doesn’t mean they can prevent it from wreaking havoc.
The cancer gene KRAS (pronounced “kay-rass”) is a case in point. It’s been studied for about 40 years and is known to be responsible for many of the most common cancers. This includes about one-quarter of lung cancers and between one-third and one-half of colon and rectal cancers. Until recently, however, the KRAS protein was considered an “undruggable” target.
On September 20, 2020, in the New England Journal of Medicine (NEJM), investigators reported results from CodeBreak 100, the first-ever clinical study of a drug that directly targets KRAS. In this international phase 1 trial, researchers found that a drug called sotorasib (AMG 510) slowed or stopped cancer growth in many people with advanced cancer that had a KRAS mutation. The investigators say much more research is needed to determine how to best use this drug, but this trial is a significant first step.
“Sotorasib is not a cure, but this study is the first to crack KRAS in a clinically meaningful way,” says Memorial Sloan Kettering medical oncologist Bob Li, a senior investigator and corresponding author of the study. “It’s an important step forward, but it’s not yet a home run.”
Shutting Down Cancer Growth
The challenge in targeting the KRAS gene comes from the uncommon shape of the KRAS protein. Most proteins have a lumpy, irregular shape, with many clefts and pockets where a drug can wedge in. When this happens, a drug can act as a key, locking up a protein and shutting down its activity. “By contrast, the KRAS protein is quite round and smooth,” Dr. Li explains. “There’s no lock-and-key approach.”
In 2013, researchers at the University of California, San Francisco, reported there may be a way in: They found a small pocket in a version of the mutant KRAS protein, called KRAS-G12C, and designed a drug to fit into this pocket when it was open.
In 2016, MSK physician-scientists Piro Lito and Neal Rosen published a study that built on this work. They described the trapping mechanism that enables the new class of drugs to shut down the growth of cancer cells driven by the KRAS-G12C mutation.
“When one of these drugs goes in the protein’s pocket, it traps KRAS-G12C in its ‘off’ state,” says Dr. Lito, who is also a senior author on the new NEJM paper. “The protein can’t wake up, and the tumor cell cannot grow.”
Sotorasib, which was developed by investigators at the biopharmaceutical company Amgen, is an improved and more potent KRAS-G12C inhibitor. Combining their respective strengths in phase 1 clinical trial development and translational science, Drs. Li and Lito partnered with Amgen to bring the first-in-class KRAS-G12C inhibitor sotorasib to patients.
Promising Findings from an International Trial
In the trial for sotorasib, 129 people whose tumors had KRAS-G12C received the drug, which is taken as a pill. Fifty-nine of them had non-small cell lung cancer, 42 had colorectal cancer, and 28 had other types of tumors. All of the study participants had disease that spread to other parts of the body; they already had received an average of three previous treatments. The trial included people treated at more than two dozen hospitals around the world.
Among those 59 people with lung cancer, seven patients did not respond and 52 experienced disease control (which means that their tumors either stopped growing or shrank). In that group of 52, 19 patients had their tumors shrink substantially. The average time until the disease got worse was about six months. “That level of response is significant for this population of patients because most of them have exhausted other treatment options.” Dr. Li explains.
A little more than half of the people in the trial (73 patients) had some side effects, but only 15 of them had significant side effects. All but one patient were able to safely continue the drug when the side effects resolved, and no one died from side effects. “Because the drug is selective for this specific KRAS mutation, it was well tolerated by patients,” Dr. Lito says. “It only binds to and inhibits the mutated form of the protein in cancer cells. This is important because it enables high doses of the drug to be safely administered.”
Next Steps for Research
Responses for other types of cancer — including colorectal cancer, as well as pancreatic, endometrial (uterine), and appendiceal cancers and melanoma — were not as good as they were for lung cancer. But some patients with those other cancers did benefit with substantial tumor shrinkage. The investigators plan to study why sotorasib appears to work better in some types of cancer than it does in others, even when the cancers have the same mutated protein. Additional trials are already underway to continue studying sotorasib, both alone and in combination with other drugs.
Research on how to block KRAS is continuing in the laboratory as well. In January 2020, Dr. Lito’s lab published a study that looked at new approaches for combining KRAS inhibitors with other drugs. “We’re taking what we’ve learned in patients back to the bench to continue developing new treatments,” Dr. Lito says. “We’re already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.”
The results from this clinical trial are also being presented at the European Society for Medical Oncology 2020 Virtual Congress.