KRAS mutations are the most common oncogene with no targeted treatment options, according to the scientific literature. Yet an estimated 14,000 non-small-cell lung cancers (NSCLC; 14% of all cases), 5,000 colorectal cancers (4% of all cases), and 1,000 pancreatic cancers (2% of all cases) test positive for the mutation in the United States annually.
Now a compound called MRTX849 is showing signs of being the first effective inhibitor of the KRAS G12C-mutant subtype, according to a phase I clinical trial presented at the AACR-NCI-EORTC conference, held October 26 to 30 in Boson, and published simultaneously in Cancer Discovery.1
“The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRAS G12Cin patients,” the researchers wrote. “The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provides new insight toward KRAS dependence and the rational development of this class of agents.”
The paper touts therapeutic-caused tumor shrinkage in 65% of KRAS G12C-positive cell line-derived, and patient-derived xenograft models of multiple tumor types.2
Two patients were singled out: 1 with stage IV adenocarcinoma of the lung, and another with metastatic adenocarcinoma of the left colon. The first stopped responding to multiple lines of therapy, and the second had progressive disease after multiple strategic options had been exhausted.
Both showed partial responses to treatment with MRTX849.
The data presented included 17 patients with solid tumors, all of which showed KRAS G12Cmutations. Patients had no available treatment options left, but none had brain metastases. The phase I results were intended to determine a maximum tolerated dose, which has not been yet established—but researchers are currently evaluating a twice daily dose of 600 mg.
Twelve patients were evaluable, 6 of which had metastatic NSCLC and 4 with colorectal cancer. Three patients with NSCLC and 1 with colorectal cancer experienced partial responses.
Two patients had grade 3 or greater toxicities including fatigue and reduced appetite. The majority of other events were grade 1, like diarrhea and nausea, according to study investigator Pasi A. Janne, MD, PHD, of the Dana-Farber Cancer Institute.
Successful targeting of the KRAS mutations could make a huge difference in some tumor types, said Janne.
“KRAS-mutant lung cancer accounts for more patients in the United States than those with EGFRmutations and ALK rearrangements combined,” he added. “If the early findings with MRTX849 continue to hold true in larger patient populations, it will impact a significant fraction of lung cancer patients.”
1. Janne, P, et al. MRTX849 Shows Clinical Activity in Patients with KRAS G12C-mutant Solid Cancer. Abstract Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Boston; October 26-30, 2019.
2. Hallin J, Engstrom L, Hargis L, et al. The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Disc. doi:10.1158/2159-8290.CD-19-1167.