The investigational KRAS G12C inhibitor MRTX849 yielded clinical responses in patients with non-small cell lung cancer (NSCLC) and colorectal cancer harboring KRAS G12C mutations, according to data from a phase I clinical trial presented today at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics by Dana-Farber Cancer Institute researchers.
Data demonstrating the efficacy of MRTX849 in preclinical studies and in two patients with solid tumors were published simultaneously in Cancer Discovery, a journal of the AACR.
“There are currently no effective targeted therapies for patients with KRAS-mutant cancers,” said Pasi A. Jänne, MD, PhD, director of Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute. “KRAS mutations are the most common oncogenic alteration in all of human cancers and as such, finding a therapeutic approach for this subset of cancer would have tremendous clinical impact for cancer patients.”
Data showed that MRTX849 is a potent, selective, and covalent small molecule inhibitor of KRAS G12C. The therapeutic caused tumor shrinkage in 65 percent of KRAS G12C-positive cell line-derived and patient-derived xenograft models of multiple tumor types. 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.
Jänne and colleagues had enrolled 17 patients with solid tumors bearing KRAS G12C mutations in this phase I trial. All the patients had metastatic disease, no available treatment options, and no active brain metastases. The initial MRTX849 dose of 150 mg once daily was escalated to doses up to 1,200 mg daily. Although a maximum tolerated dose has not been yet determined in the study, a twice daily dose of 600 mg is being evaluated in the expansion phase based on achieving preclinically defined target plasma exposure, a favorable tolerability profile, and early signs of antitumor activity.
Of the 12 evaluable patients, six had metastatic NSCLC and three had partial responses (all unconfirmed). Of the four evaluable patients with colorectal cancer, one had a confirmed partial response. All the patients with responses received the MRTX849 dose of 600 mg twice daily. These responses include the two patients described in the Cancer Discovery paper.
“Our data show that targeting KRAS G12C can lead to a clinical response in either lung or colon cancer patients. This finding is remarkable and opens the avenue for a targeted therapy for certain KRAS-mutant cancers,” noted Jänne.
Adverse events included mostly grade 1 toxicities, the most common being diarrhea and nausea, Jänne said. Two patients had grade 3 or higher toxicities, including fatigue and decreased appetite. “Overall, treatment with MRTX849 was well tolerated with a low incidence of grade 3 or 4 toxicities. One caveat for both the side effects and the efficacy is that it is still early, and we will gain more information as additional patients are enrolled on the study,” he added.
“Over the last several years we have witnessed the clinical successes of genotype-directed therapy for patients with EGFR-mutated or ALK-rearranged cancers. KRAS-mutant lung cancer accounts for more patients in the United States than those with EGFR mutations and ALK rearrangements combined. If the early findings with MRTX849 continue to hold true in larger patient populations, it will impact a significant fraction of lung cancer patients,” Jänne said.
Limitations of the study includes small sample size.
This study was sponsored by Mirati Therapeutics Inc. Jänne is a compensated scientific advisor for Mirati Therapeutics. He has received consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Merrimack Pharmaceuticals, Chugai Pharmaceutical Co., Ariad Pharmaceuticals, Eli Lilly and Company, Araxes Pharma, Ignyta, Novartis, Mirati Therapeutics, Takeda Oncology, Daiichi Sankyo, Biocartis, Voronoi, SFJ Pharmaceuticals, and LOXO Oncology; receives post-marketing royalties from Dana-Farber-owned intellectual property on EGFR mutations licensed to LabCorp; has sponsored research agreements with AstraZeneca, Daiichi Sankyo, Boehringer Ingelheim, PUMA, Eli Lilly, Astellas Pharma, and Takeda Oncology; and has stock ownership in Gatekeeper Pharmaceuticals and LOXO Oncology.