KRAS inhibitor sotorasib appears safe, achieves durable clinical benefit in early trial

Phase I study encouraging for patients with advanced cancers and KRAS G12C mutations

MD Anderson News Release September 20, 2020

ABSTRACT: 1257O

In a Phase I clinical trial for patients with advanced solid cancers marked by KRAS G12C mutations, the KRAS^G12C inhibitor sotorasib (AMG 510) resulted in manageable toxicities and durable clinical benefits. Results from the trial were published today in the New England Journal of Medicine and data from the lung cancer cohort also were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 by lead author David S. Hong, M.D., professor of Investigational Cancer Therapeutics.

For patients with KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC), this targeted therapy resulted in a confirmed response rate (tumor shrinkage) of 32.2% and disease control rate (tumor shrinkage or stable disease) of 88.1% across all dose levels. In patients with KRAS G12C-mutant colorectal cancer (CRC), response rate was 7.1% and 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 non-small cell lung cancer,” said 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.”

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 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 and 3-5% of CRC. Sotorasib is a small-molecule inhibitor that specifically and irreversibly binds the mutant KRAS^G12C protein to lock it in an inactive state.

The multi-center Phase I, first-in-human CodeBreak 100 trial was designed as a dose-escalation study to evaluate sotorasib in heavily pre-treated patients with advanced solid cancers 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 CRC and 28 with other cancer types. Trial participants were 76% Caucasian, 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. Seventy-three  patients (56.6%) experienced treatment-related adverse events of any grade, the most common of which were diarrhea, fatigue, and nausea, and adverse events of grade 3 or higher were reported in 15 patients (11.6%).

For patients with NSCLC, median duration of response was 10.9 months, and median progression-free survival (PFS) was 6.3 months. In CRC, median duration of response was 6.9 months and median PFS 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 960mg resulted in a 35.3% response rate and 91.2% disease control rate. For CRC patients, the highest dose achieved a response and control rate of 12% and 80%, respectively.

Among patients with other cancer types, four (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 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.”

The trial was supported by Amgen, Inc. The work was also supported in part by the Cancer Prevention and Research Institute of Texas (RP150535), the National Institutes of Health (P30 CA016672, P30 CA006927, P30 CA008748, 1R01CA23074501, 1R01CA23026701A1), the Pew Charitable Trusts and the Damon Runyon Cancer Research Foundation. A full list of collaborating authors and their disclosures can be found with the paper here.