Glecirasib is a medication designed as a targeted therapy. This oral inhibitor is currently undergoing clinical development, showing promise in addressing certain cancers driven by specific genetic alterations. Its development marks a step forward in precision medicine.
Understanding the Target: KRAS G12C Mutation
The KRAS gene plays a role in normal cell growth and division, acting like a molecular switch. It cycles between an inactive state and an active state to regulate pathways that control cell proliferation and survival. When mutations occur in the KRAS gene, particularly at codon 12, this balance is disrupted.
The G12C mutation is a change where glycine at position 12 is replaced by cysteine. This alteration locks the KRAS protein in its active, “on” conformation, leading to continuous activation of downstream signaling pathways. This uncontrolled signaling drives persistent cell division and tumor growth. The KRAS G12C mutation is found in approximately 13% of non-small cell lung cancers (NSCLC), 3% to 5% of colorectal cancers, and 1% to 2% of pancreatic cancers.
How Glecirasib Works
Glecirasib operates through a specific mechanism, targeting the KRAS G12C mutation. This small molecule inhibitor is designed to selectively and irreversibly bind to the mutated cysteine residue at position 12 of the KRAS G12C protein. This binding occurs when the KRAS protein is in its inactive, GDP-bound state.
By covalently modifying the mutant protein, glecirasib locks KRAS G12C in this inactive conformation. This prevents the protein from becoming active and transmitting signals that promote cancer cell proliferation and survival. Glecirasib “turns off” the hyperactive KRAS G12C, inhibiting tumor cell growth and inducing cancer cell death. This selective inhibition of the mutant KRAS protein, while sparing the normal protein, is a hallmark of precision medicine.
Clinical Use and Effectiveness
Glecirasib is being investigated for cancers with the KRAS G12C mutation, focusing on non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). A pivotal Chinese phase II study of glecirasib monotherapy in previously treated patients with KRAS G12C-mutated advanced NSCLC showed an objective response rate (ORR) of 47.9%, meaning nearly half of the patients experienced a reduction in tumor size. The disease control rate (DCR), which includes patients with complete response, partial response, and stable disease, was 86.3%.
In this NSCLC trial, the median progression-free survival (PFS) was 8.2 months, indicating the average time patients lived without their cancer worsening. The median overall survival (OS) was 13.6 months. The median duration of response had not been reached, with responses ongoing in 73.6% of patients at 6 months and 56.6% at 12 months.
For colorectal cancer, glecirasib showed activity. In a monotherapy study, the ORR was 33.3%, and the DCR was 90.9%. Median PFS was 6.9 months. When glecirasib was combined with cetuximab for advanced KRAS G12C-mutated CRC, the ORR increased to 62.8%, and the DCR was 93%. The median PFS for the combination therapy had not been reached, but median overall survival was 16.0 months for monotherapy and 19.3 months for combination therapy.
Patient Considerations and Side Effects
Patients considered for glecirasib treatment must undergo testing to confirm the presence of the KRAS G12C mutation in their tumor. Glecirasib is administered orally once daily, typically at a dose of 800 mg.
Common side effects include anemia, increased blood bilirubin, and elevated liver enzymes (alanine aminotransferase and aspartate aminotransferase). Hypertriglyceridemia, an increase in blood fats, was also reported. While most adverse events were mild to moderate, approximately 38.7% of patients experienced at least one grade 3 or 4 treatment-related adverse event, primarily related to liver toxicity and hypertriglyceridemia. Few patients (around 5%) discontinued treatment due to side effects, and no fatal treatment-related adverse events were reported. Glecirasib has shown low rates of nausea (5.9% to 6.7%), vomiting (7.6%), and diarrhea (3.4%), which are lower compared to other KRAS G12C inhibitors.
Glecirasib Compared to Other Treatments
Glecirasib joins a growing class of targeted therapies for KRAS G12C-mutated cancers, including sotorasib and adagrasib. Sotorasib received accelerated approval in May 2021, followed by adagrasib in December 2022. All three drugs are covalent KRAS G12C inhibitors, meaning they bind to and inactivate the mutated protein to prevent cancer cell growth.
Sotorasib and adagrasib have shown median PFS ranging from 5.7 to 6.5 months and OS around 11.4 to 12.6 months in NSCLC. Glecirasib has demonstrated a median PFS of 8.2 months and OS of 13.6 months in NSCLC. Differences exist in their side effect profiles. Glecirasib has lower rates of gastrointestinal toxicities like nausea, vomiting, and diarrhea compared to sotorasib and adagrasib. However, glecirasib may have higher rates of anemia and liver toxicity. Adagrasib has also shown efficacy in treating brain metastases, a factor still being evaluated for other inhibitors.