Among patients diagnosed with non-small-cell lung cancer, 13% have the KRAS p.G12C mutation, for which no current cancer therapies have been approved. The mutation also can be found in between 1 and 3% of colorectal and other cancer patients.
Marwan Fakih, MD, a medical oncology at the City of Hope Comprehensive Cancer Center told MD /alert that previous studies have shown inhibiting the mutation to be “feasible, both biochemically as well as in the laboratory in animal models and in cell lines.
“So, the interest behind that particular mutation is that it’s the only one that at this point can be inhibited effectively with a chemical compound,” Fakih said. “And the reason why this particular mutation can be blocked completely is that the particular mutation, G12C, which is a switch, and only one base pair in the gene, makes that abnormal KRAS quite open to inhibition by a small molecule that binds to the existing part of KRAS12 G12C, which is the abnormal amino acids order. The wrong amino acids in place. That results in a total blockade of the KSG12C and prevents it from turning on.”
A recent phase 1 trial published in the New England Journal of Medicine studied sotorasib as a treatment for patients with advanced solid tumors with the rare mutation. The 129 patients enrolled in the trial received the drug orally once daily. Safety served as the primary endpoint.
In the NSCLC subgroup, 19 patients had a confirmed objective response, while 52 had disease control.
The median progression-free survival was 6.3 months in the subgroup, ranging from 0.0 months to 14.9 months.
In the subgroup with colorectal cancer, three patients had a confirmed response, and 31 had disease control.
The median progression-free survival was four months, ranging from 0 months to 11.1 months. The researchers noted that “responses were also observed in endometrial, and appendiceal cancers and melanoma.”
“So, while we found benefit in both groups, with non-small-cell lung cancer and colorectal cancer, clearly there is more activity in non-small-cell lung cancer,” Fakih told MD /alert. “This data leads us to believe that targeting KSG12C is quite effective, but there may be biological differences between different tumor types that also play into the sensitivity of the drug or play into the acquired resistance to the therapy.”
A total of 73 patients reported treatment-related adverse events, with 15 reporting grade 3 or 4 events.
Fakih said the safety profile is “really minor” compared to chemotherapy, with patients experiencing mild anemia and mild gastrointestinal toxicity. He added that the researchers were encouraged that none of the patients experienced dose-limiting toxicities.
“In cancer, and especially in advanced cancer, one of our biggest problems is resistance to treatment. People tend to respond to therapy but then acquire resistance. So, I feel that we’ve kind of reached the first milestone here in showing that we can drug KRAS, which was really kind of termed the undruggable target. So we’ve shown that it’s targetable. We’ve shown that you can inhibit it. We’ve shown that the inhibition results in inactivity, and I think the subsequent milestones are to better understand who are the patients who are going to benefit more from this within the group of patients with KRAS p.G12C, and more importantly, why are patients becoming resistant to this therapy. And, at last, how can we overcome that resistance,” Fakih concluded.