1. Fuerst, Mark L.

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BOSTON-An investigational KRAS inhibitor induced clinical responses in patients with non-small cell lung cancer (NSCLC) and colorectal cancer harboring KRAS mutations, according to the results of a new study. Data demonstrating the efficacy of KRAS inhibitor MRTX849 in preclinical studies and in two patients with solid tumors were published simultaneously in Cancer Discovery (2019; doi: 10.1158/2159-8290.CD-19-1167).

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"Preclinical data show MRTX849 is a highly selective KRAS inhibitor that leads to the shutdown of kinase signaling. There are currently no effective targeted therapies for patients with KRAS-mutant cancers," said Pasi A. Janne, MD, PhD, Director of the 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."


Janne presented the results of the phase I clinical trial at a press briefing before the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.


Study Details

Information in the published paper shows that MRTX849 is a potent, selective, and covalent small molecule inhibitor specifically of KRAS G12C. The inhibitor 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 IV 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.


Currently, Janne and colleagues have enrolled 17 patients with solid tumors bearing KRAS G12C mutations in the phase I trial. All the patients had metastatic disease, had no available treatment options, and had 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, he noted.


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. I think this finding is remarkable and opens the avenue for a targeted therapy for certain KRAS-mutant cancers," said Janne.


Adverse events included mostly grade 1 toxicities, the most common being diarrhea and nausea. 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," Janne said. The only grade 3 or 4 treatment-related adverse event was one patient with amylase/lipase increase with isolated enzyme elevation without pancreatitis. The only dose-limiting toxicity observed was one patient who could not tolerate the 1,200 mg daily capsule.


"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, also noting that one limitation of the study was its small sample size.


"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 U.S. 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," Janne said.


Mark L. Fuerst is a contributing writer.