First Patient Dosed AMG 510 2018: A Milestone in KRAS G12C Cancer Therapy

In August 2018, the first patient was dosed with AMG 510 (sotorasib) in a Phase 1 clinical trial. This was the first time a drug designed to target the KRAS G12C mutation reached human testing. The protein had been considered undruggable in cancer research for decades. The trial opened a new treatment path for solid tumors like non-small cell lung cancer and colorectal cancer that carry this specific genetic change.

The Challenge of Targeting KRAS Mutations

Mutations in KRAS are among the most common drivers of human cancers. The G12C variant, where glycine is replaced by cysteine at position 12, is particularly common in lung adenocarcinoma. The protein’s smooth, spherical surface made it difficult for drug molecules to bind. Earlier attempts to inhibit KRAS failed because the protein lacked deep binding pockets. Researchers at Amgen, building on discoveries from academic labs including the National Cancer Institute, developed a molecule that locked onto a specific groove that only appears when the protein is in its inactive, GDP-bound state. This approach selectively traps the mutant form of KRAS, keeping it switched off.

The Phase 1 Trial Design and Early Results

The first-in-human study of AMG 510 was registered on ClinicalTrials.gov and enrolled patients with advanced solid tumors who had the KRAS G12C mutation and had exhausted standard treatment options. The trial used a standard dose-escalation design to find the maximum tolerated dose.

Patients received AMG 510 orally once daily in 21-day cycles. Dose levels started at 180 mg and escalated up to 960 mg. The study included multiple expansion cohorts once a recommended Phase 2 dose was identified. Early data showed that AMG 510 was generally well-tolerated. Common side effects included mild nausea, diarrhea, and fatigue. More importantly, the drug produced objective responses in heavily pretreated patients. In the non-small cell lung cancer cohort, about half of patients had tumor shrinkage, and some achieved partial responses. These results were remarkable because these patients had typically progressed through multiple prior therapies.

Clinical Implications and Subsequent Development

The successful dosing of the first patient in 2018 set off a rapid development timeline. Within two years, Amgen had moved AMG 510 into larger Phase 2 trials and combination studies with other agents like immune checkpoint inhibitors.

By May 2021, the U.S. Food and Drug Administration granted accelerated approval for sotorasib (marketed as Lumakras) for adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer who had received at least one prior systemic therapy. This approval came just under three years after the first patient was dosed, an unusually fast pace for a cancer drug.

The success of AMG 510 also spurred development of other KRAS G12C inhibitors, including adagrasib from Mirati Therapeutics. Researchers continue to investigate mechanisms of resistance and ways to combine these drugs with other therapies. The Amgen pipeline now includes next-generation KRAS inhibitors and compounds targeting other RAS mutations.

What This Means for Patients and Research

For patients with KRAS G12C-mutated cancers, the availability of a targeted therapy represents a meaningful advance. Before 2018, these patients had no precision medicine option directed at their specific mutation. They relied on chemotherapy and immunotherapy, which offered limited benefit once resistance developed.

The story of AMG 510 also illustrates how basic science discoveries can translate into clinical breakthroughs. The structural biology work that revealed the switch-II binding pocket was essential. Drug developers then needed to solve the problem of creating a molecule that could reach that pocket inside cells. The first patient dosed in 2018 was the culmination of years of fundamental research.

Note: This article discusses general medical research. Individual treatment decisions should be made with a qualified healthcare professional.

Key Takeaways

• The first patient was dosed with AMG 510 in August 2018, starting the first clinical trial for a KRAS G12C-targeted therapy.
• KRAS G12C mutations were considered undruggable for decades due to the protein’s smooth surface and lack of binding pockets.
• The Phase 1 trial showed the drug was well-tolerated and produced tumor shrinkage in heavily pretreated patients.
• Sotorasib received accelerated FDA approval in 2021 for non-small cell lung cancer, less than three years after the first patient was dosed.
• The success of AMG 510 opened the field for other KRAS inhibitors and combination therapy research.