Can KRAS Positive Colorectal and Lung Cancer Finally be Targeted?
by Dr. C.H. Weaver M.D. 4/2020
The investigational KRAS G12C inhibitor drug MRTX849 yielded clinical responses in patients with non-small cell lung cancer (NSCLC) and colorectal cancer harboring KRAS G12C mutations, according the results of a from a phase I clinical trial published by Dana-Farber Cancer Institute researchers. (1)
RAS is an oncogene —a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer. There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS. Although mutations in all three can cause cancer.
KRAS mutations are the most common oncogenic alteration in all of human cancers and there are currently no effective treatments available for patients with KRAS-mutant cancers. KRAS cancer driving mutation are present in NSCLC adenocarcinomas, colorectal cancers as well as smaller percentages of several other difficult-to-treat cancers.
MRTX849 is an investigational, orally available small molecule that is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of NSCLC adenocarcinoma patients, 4% of colorectal cancer patients, and subsets of other types of cancer. Cancers characterized by KRAS G12C mutations are commonly associated with a poor prognosis and resistance to therapy, and patients with these mutations have few treatment options.
MRTX849 is being evaluated in a phase 1/2 trial treating patients with molecularly identified, KRAS G12C-positive advanced solid tumors. In an initial clinical trial two patients, one with stage 4 lung adenocarcinoma that had stopped responding to multiple lines of therapy and one with metastatic adenocarcinoma of the left colon with progressive disease after multiple lines of therapy had partial responses to treatment with MRTX849.
In the current trial researchers enrolled 17 patients with metastatic solid tumors bearing KRAS G12C mutations. The maximal tolerated dose of MTRX849 has not been attained but 12 patients have been evaluated for treatment response. Three of the NSCLC and 1 of 4 colon cancer patients have responded to treatment with MRTX849.
Over the last several years the clinical successes of genotype-directed therapy for patients with EGFR-mutated and ALK-rearranged lung cancers has been impressive. KRAS-mutant lung cancer however is much more common, and it finally appears as though researchers are zeroing in on its treatment with precision medicines. In addition to MRTX849 another medication in development, AMG510 also appears promising for targeting KRAS mutations. If the early findings with MRTX849 hold true doctors may finally have a treatment for this difficult to treat genetically driven cancer.
- by phase I clinical trial presented today at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
- Govindan et al., Annals of Oncology, Volume 30, Issue Supplement_5, October 2019. ESMO 2019