MRTX849 Shows Clinical Activity in KRAS G12C-Mutant Cancers

News
Article

A compound called MRTX849 is showing signs of being the first effective inhibitor of the KRAS G12C-mutant subtype of non-small cell lung and colorectal cancers.

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.

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.”

REFERENCES:

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.

Recent Videos
For example, you have a belt of certain diseases or genetic disorders that you come across, such as sickle cell disease or thalassemia, that are more prevalent in these areas.
Talent shortages in the manufacturing and administration of cellular therapies are problems that must be addressed at the level of each country.
Point-of-care manufacturing, scalable manufacturing, and bringing the cost down [can help].
A novel cancer database may assist patients determine what clinical trials they are eligible to enroll on and identify the next best steps for treatment.
A consolidated database may allow providers to access information on a patient’s prior treatments and genetic abnormalities all in 1 place.
A study presented at ASTRO 2025 evaluated the feasibility of using a unified cancer database to consolidate information gathered across 14 institutions.
Co-hosts Kristie L. Kahl and Andrew Svonavec highlight what to look forward to at the 2025 ESMO Annual Congress, from hot topics and emerging trends to travel recommendations.
Physical therapists may play a key role in patient care before, during, and after treatment for cancer, according to Alison Ankiewicz, PT, DPT.
Related Content