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Targeted Inhibitor of Mutant KRAS Gene Shows Activity in Early Trial


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Adagrasib (MRTX849), a novel agent that targets a mutated form of the KRAS gene—the most commonly altered oncogene in human cancers, and one long considered “undruggable”—caused tumor shrinkage in most patients in a clinical trial, with manageable side effects, researchers reported at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

Adagrasib targets the KRAS G12C mutation specifically; this particular mutation is associated with a poor prognosis and lack of response to standard treatments. The mutation occurs in approximately 14% of lung adenocarcinomas, 3% to 4% of colorectal cancers, and 2% of pancreatic cancers.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its ability to send cell-growth signals and leading to cancer cell death. Until recently, no KRAS inhibitor had moved beyond preclinical testing, but in 2018, adagrasib was among several KRAS inhibitors approved by the U.S. Food and Drug Administration (FDA) for study in clinical trials beginning in January 2019.

KRYSTAL-1

The phase I/II KRYSTAL-1 trial (Abstract LBA-03) tested the efficacy of adagrasib in patients with non–small lung cancer (NSCLC), colorectal cancer, and other solid tumors such as pancreatic, endometrial, and ovarian cancers. All patients in the trial had advanced cancer and had previously received standard treatment for their disease, including chemotherapy and immunotherapy.

Pasi A. Jänne, MD, PhD

Pasi A. Jänne, MD, PhD

At the symposium, Pasi A. Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, reported that of 51 patients with NSCLC participating in the trial, 45% had an objective response. The disease control rate was 96%—meaning that 49 of the patients had a partial or complete response or stable disease.

Among the 14 patients in the phase I/Ib cohort who had been followed for a longer period of time (median = 9.6 months), an objective response was seen in 6 (43%). Five of these six patients were still on adagrasib therapy as of the cutoff date; four of the six have been receiving the drug for more than 11 months.

Researchers also analyzed the treatment-related adverse side effects in all 110 patients who participated in the phase I/Ib and II parts of the trial, including those with colorectal cancer and other solid tumors, as well as those with NSCLC. Side effects included nausea, diarrhea, vomiting, fatigue, and increased alanine aminotransferase. The only serious adverse side effect to occur in more than one patient was low sodium in the blood, which occurred in two patients.

“[Patients with a] KRAS G12C [mutation] are a population for which there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, treatment options are limited,” said Dr. Jänne. “The fact that we are seeing responses in 45% of patients with adagrasib is incredibly meaningful, as it opens up the possibility of a new treatment option for this subset of [patients with] lung cancer.”

Results for 31 trial participants with colorectal cancer or other solid tumors were presented by Melissa L. Johnson, MD, Associate Director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology (Abstract LBA-04).

Melissa L. Johnson, MD

Melissa L. Johnson, MD

Of 18 patients with colorectal cancer who could be evaluated, 3 (17%) had a confirmed objective response and 2 continue to receive treatment. Disease control was seen in 17 of the patients (94%), and 12 of these patients continue to be treated, including 10 of 18 patients on treatment for more than 4 months.

Among the six patients with other solid tumors who could be evaluated, a partial response was confirmed in one patient each with endometrial cancer, pancreatic cancer, ovarian cancer, and cholangiocarcinoma. Two patients with appendiceal cancer who were treated achieved stable disease. All six patients remain on the treatment.

In the future, researchers are also looking at combining adagrasib with other targeted therapies, such as pembrolizumab for NSCLC; cetuximab for colon cancer; the investigational SHP-2 inhibitor TNO-155 for either NSCLC or colon cancer; and afatinib for NSCLC.

Disclosure: This study was sponsored by Mirati Therapeutics, Inc. For full disclosures of the study authors, visit cm.eortc.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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