Sotorasib, marketed as Lumakras, has shown promising results in treating non-small cell lung cancer (NSCLC) driven by a specific KRAS G12C mutation. The global phase 2 clinical trial results, presented at the American Society of Clinical Oncology (ASCO) annual meeting and published in The New England Journal of Medicine, led to FDA approval on May 28 for patients who have undergone at least one prior therapy.
Targeting KRAS G12C Mutation
The KRAS G12C mutation, found in approximately 13% of lung adenocarcinoma cases, results in a constantly active KRAS protein that drives tumor growth. Sotorasib is designed to inhibit this activity by trapping the KRAS protein in its inactive state. The trial involved 126 patients with NSCLC harboring this mutation, most of whom had previously been treated with chemotherapy and PD-1 inhibitors.
Clinical Efficacy and Outcomes
The study revealed that sotorasib induced tumor shrinkage in 82% of patients. Specifically, 34% of patients experienced a partial response, indicating substantial tumor reduction and controlled growth, while 3% achieved a complete response with no evidence of disease. The average tumor size reduction was approximately 60% among responders.
The effects of sotorasib lasted an average of 11 months, with a progression-free survival of nearly seven months. This compares favorably to the two to four months of progression-free survival typically seen with standard therapy in this patient population. The average overall survival for all patients in the trial was 12.5 months.
Safety and Tolerability
While almost 70% of patients experienced some side effects, only 7% discontinued treatment due to severe adverse events. No life-threatening side effects or treatment-related deaths were reported. The most common side effects included diarrhea, fatigue, nausea, and elevated liver enzyme levels, with 22% of patients requiring a dose reduction due to adverse events.
Addressing an Unmet Need
"This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies," said Dr. Ramaswamy Govindan, co-senior author of the study from Washington University School of Medicine. "The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after."
Future Directions
Researchers are currently conducting a phase 3 clinical trial comparing sotorasib to docetaxel in 345 patients with KRAS G12C-mutated NSCLC. Further investigations are also underway to explore sotorasib in combination with other experimental drugs to enhance treatment responses and survival rates. "Moving forward, our team will seek to inform the development of combination therapies featuring sotorasib and other emerging drugs, and to determine which best fit the mix of mutations in each patient’s cancer cells," Govindan added.
