NEW YORK – Revolution Medicines' zoldonrasib, a drug targeting the KRAS G12D mutation in patients with non-small cell lung cancer, shrunk tumors in around 60 percent of patients in a clinical trial.
At the American Association for Cancer Research's annual meeting on Sunday, researchers shared this data based on an analysis performed on 18 NSCLC patients in a Phase I trial in which more than 200 patients with solid tumors have received at least one other line of treatment and harbor a KRAS G12D mutation.
The US Food and Drug Administration has approved two KRAS inhibitors, Amgen's Lumakras (sotorasib) and Bristol Myers Squibb's Krazati (adagrasib), for advanced NSCLC harboring KRAS G12C mutations, but there are currently no treatments targeting KRAS G12D mutations, which show up in around 4 percent of lung cancer patients. Other therapies that target KRAS G12D are in Phase I trials, such as Alterome Therapeutics' ALTA3263 and Silexion Therapeutics' SIL204.
The latest data is just one example of the numerous efforts underway to target KRAS and its various mutations through single-agent and combination treatments. Targeting KRAS proteins was "unthinkable" just 10 to 15 years ago, said Trever Bivona, a molecular biologist at the University of California, San Francisco, who was unaffiliated with the zoldonrasib trial.
Zoldonrasib is a RAS(ON) KRAS inhibitor and is designed to target the active state of the KRAS protein. RAS proteins signal uncontrolled cell growth in cancer patients, and those with this mutation typically don't respond well to immune checkpoint inhibitors, Kathryn Arbour, assistant attending and thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, said in presenting the data from this trial at the meeting.
In addition to NSCLC patients, this study also enrolled those with pancreatic ductal adenocarcinoma and other types of tumors. Most had previously received either platinum chemotherapy or an immune checkpoint inhibitor. A majority — 54 percent — were never smokers.
In the 18 NSCLC patients, zoldonrasib treatment led to tumor reduction in 11 patients while 16 experienced disease control.
Researchers face several challenges when attempting to target RAS proteins, Bivona said. First, they are highly evolutionarily conserved, which makes them difficult to identify and target. Second, RAS proteins are involved in "almost all aspects of human physiology," Bivona said — from wound healing to neuronal differentiation. They are highly dynamic enzymes, he said, which don't simply switch on and off.
In the face of these challenges, "any clinical success that might arise really is quite a feat," Bivona said.
The efficacy seen in this early trial came with minimal or low-grade side effects. While 39 percent of patients experienced nausea, 33 percent of those individuals experienced it at a grade 1 level. Similarly, most patients who experienced diarrhea, vomiting, and rash did so at grade 1 levels. No patients in the study experienced grade 4 or 5 treatment-related adverse effects.
These low-grade side effects led the researchers to determine 1,200 mg once daily as the recommended Phase II dose.
The patient population in the study included patients as young as 36, so helping them lead normal lives was paramount, Arbour said. One younger patient in the study even began exercising regularly in the gym while receiving zoldonrasib.
"Many of these patients with KRAS G12D mutations with non-small cell lung cancer are younger, living active lives, [and] never smokers," Arbour said. "Tolerability of these drugs is of utmost concern for thinking about how they get back to an active lifestyle. And I think zoldonrasib so far really fits that in terms of treatment-related adverse events."
Because this analysis only included 18 patients and most are still on treatment, Arbour said the data are relatively immature to determine the right length of therapy and identify resistance mechanisms. Still, Arbour said she is hopeful about the potential of zoldonrasib as a single treatment and in combination with other therapies.
"The therapy certainly is promising as monotherapy, but it's also being explored in combination with the multi-RAS inhibitors daraxonrasib, as well as [with] standard-of-care regimens for non-small cell lung cancer, including chemotherapy and immunotherapy," Arbour said. "Those studies will be very informative as we think about how to translate these results into potentially even first-line regimens as we look forward in the development of this drug."