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KRAS G12C Inhibitor Shows Activity in Solid Tumors, Lung Cancer


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In a phase I clinical trial for patients with advanced solid cancers marked by KRAS G12C mutations, the KRAS G12C inhibitor sotorasib (AMG 510) showed manageable toxicities and durable clinical benefits. Results from the trial were published in The New England Journal of Medicine, and data from the lung cancer cohort also were presented at the ESMO Virtual Congress 2020 (Abstract 1257O) by lead author David S. Hong, MD, Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

David S. Hong, MD

David S. Hong, MD

For patients with KRAS G12C–mutant advanced non–small cell lung cancer (NSCLC), treatment with sotorasib resulted in a confirmed response rate of 32.2% and a disease control rate of 88.1% across all dose levels. In patients with KRAS G12C–mutant colorectal cancer, the response rate was 7.1%, and the disease control rate was 73.8%.

“Sotorasib was well tolerated in this study, and it is the first KRAS inhibitor that has shown activity in any cancer. Although the results are early, it is promising—especially in NSCLC,” said Dr. Hong. “The fact that we have seen responses in other cancers suggests there may be benefit for more patients. More importantly, these results give us hope for the development of other KRAS inhibitors targeting additional mutations.”

KRAS G12C–Mutant Cancers and KRAS Inhibition

Patients with KRAS G12C–mutant cancers tend to have a poor prognosis, and most of the patients participating in this trial were refractory to all standard treatments, including chemotherapy and immunotherapy, explained Dr. Hong.

The KRAS protein is important in normal cellular signaling pathways regulating the growth, proliferation, and differentiation of cells. Certain mutations in KRAS result in an activated form of the protein, which can drive abnormal growth in cancer. One of the most common mutations is KRAS G12C, which occurs in approximately 13% of NSCLC cases and 3% to 5% of colorectal cancer cases. Sotorasib is a small-molecule inhibitor that specifically and irreversibly binds the mutant KRAS G12C protein to "lock it" in an inactive state.

CodeBreak 100

The multicenter phase I, first-in-human CodeBreak 100 trial was designed as a dose-escalation study to evaluate sotorasib in heavily pretreated patients with advanced solid tumors harboring KRAS G12C mutations. The primary endpoint was safety, with secondary endpoints including efficacy and pharmacokinetics.

The trial enrolled a total of 129 patients, including 59 with NSCLC, 42 with colorectal cancer, and 28 with other cancers. Trial participants were 76% White, 12.4% Asian, 4.7% Black, and 7% other. The median age was 62, with women accounting for 51.2% and men, 48.8% of participants.

There were no dose-limiting toxicities or treatment-related deaths observed in the trial. A total of 73 patients (56.6%) experienced treatment-related adverse events of any grade, the most common being diarrhea, fatigue, and nausea, and adverse events of grade ≥ 3 were reported in 15 patients (11.6%).

For patients with NSCLC, the median duration of response was 10.9 months, and the median progression-free survival was 6.3 months. In those with colorectal cancer, the median duration of response was 6.9 months, and the median progression-free survival was 4.0 months.

Responses were seen across all dose levels, with the strongest response at the highest dosage. In patients with NSCLC, the highest dose of 960 mg resulted in a 35.3% response rate and a 91.2% disease control rate. For patients with colorectal cancer, the highest dose achieved response and disease control rates of 12% and 80%, respectively.

Among patients with other cancers, 4 (14.3%) had a confirmed partial response, and 17 (60.7%) had stable disease. Partial responses were observed in patients with pancreatic cancer, endometrial cancer, appendiceal cancer, and melanoma.

“The next steps for this inhibitor are many,” said Dr. Hong. “We are working to finish the existing phase II study and transition to larger patient populations to understand the true benefit and toxicities. Understanding the best combinations of sotorasib with other therapies will also be key next steps to advancing this as an effective treatment option for patients.”

Disclosure: For full disclosures of the study authors, visit nejm.org and oncologypro.esmo.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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