MRTX849 Shows Safety, Tolerability in Treating KRAS G12C

Pasi A. Janne, MD, PhD

Pasi A. Janne, MD, PhD

In patients whose solidtumors harbor a mutation inKRASG12C, therapy with MRTX849 has produced promising responses and acceptable toxicity across 3 tumors types, according to data presented at the 2019 American Association for Cancer Research—National Cancer Institute–European Organization for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics.

“There are currently no effective targeted therapies for patients withKRAS-mutant cancers,” Pasi A. Jänne, MD, PhD, director of both the Lowe Center for Thoracic Oncology and Belfer Center for Applied Science at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, in Boston, Massachusetts, said in a press release. “KRASmutations are the most common oncogenic alteration in all of human cancers, and as such, finding a therapeutic approach for this subset of cancers would have tremendous clinical impact for patients.”

MRTX849, a highly selective mutation specificKRASG12C inhibitor, has shown broad efficacy across cell lines and patient-derived xenograft models, with about two-thirds of all tumor models and three-quarters of lung cancer models producing a response. The agent has demonstrated capability of complete targeted inhibition and stoppage of mitogen-activated protein kinase signaling.

In the phase I/II study, investigators evaluated MRTX849 in patients with unresectable or metastatic solid malignancies withKRASG12C mutations based on sponsor-approved tests. Patients could not have been eligible for any curative treatments or have active brain metastases. Primary end points included safety and pharmacokinetics. Secondary outcome measures were response by RECIST and establishing the maximum tolerated dose.

The dose-escalation phase was carried out in a single-patient accelerated titration strategy following a 21-day safety evaluation period. The first patient was started at a dose of 150 mg a day, followed by daily doses of 300 mg in 1 patient, 600 mg in 2, and 1200 mg in 1. In addition, 12 patients received 600 mg twice daily, which is the dose that will be looked at in the expansion.

Of the 17 patients enrolled, 12 were evaluable for a response at the data cutoff of October 11, 2019. Patients more commonly had non—small cell lung cancer (NSCLC; n = 6), 4 patients had colorectal cancer (CRC), and 2 had appendicle carcinoma. The trial has an accrual goal of 200 patients across both phases.

There have been 4 partial responses (PRs) observed in the entire cohort—3 in patients with NSCLC and 1 in a patient with CRC. The rates of disease control, made up of patients with PRs and stable disease (SD), were 100% in both groups. Patients with appendicle carcinoma experienced an SD rate of 100%.

The 1 CRC response was confirmed prior to the data cutoff. None of the patients with NSCLC had a confirmed response before the cutoff, but 1 had their response subsequently confirmed by a second scan. The 2 remaining responses are pending a second scan (FIGURES 1and2).

Treatment-related adverse events (TRAEs) occurring in >10% of the population included diarrhea (n = 12), nausea (n = 10), aspartate aminotransferase increase (n = 5), vomiting (n = 5), fatigue (n = 4), alanine aminotransferase increase (n = 3), creatinine increase (n = 3), and decreased appetite (n = 3). Grade 3 toxicities included fatigue, decreased appetite, and dyspnea in 1 patient each.

“The maximum-tolerated dose of MRTX849 has not been reached yet,” Jänne said during his presentation of the data. “At the 600-mg twice-daily dose, 1 dose-limiting toxicity was observed, which was in a patient that developed a grade 3 amylase increase, as well as grade 4 lipase increase. These were isolated enzyme elevations without evidence of clinical pancreatitis.”

A second toxicity was observed at the 1200-mg dose due to capsule burden intolerance that was experienced with administration of twelve 100-mg capsules.

“This emphasizes the excitement...for what is happening the cancer field in general and specifically in the RAS pathway,” Jänne concluded.

Reference:

Jänne PA. A phase 1 clinical trial evaluating the pharmacokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRASG12C inhibitor, in advanced solid tumors. Presented at: 2019 American Association for Cancer Research