Sotorasib, known by the brand name Lumakras, is a cancer treatment called a targeted therapy. These drugs are engineered to interfere with specific molecules involved in the growth and spread of cancer cells. Unlike traditional chemotherapy that affects all rapidly dividing cells, targeted therapies are designed for precision. This approach attacks the particular cellular changes driving a tumor’s development, aiming to disrupt cancer progression while minimizing impact on healthy tissues.
The KRAS G12C Mutation
Within our cells, the KRAS gene provides instructions for making a protein that acts as an on/off switch for cell growth and division. This protein, K-Ras, is part of a signaling pathway that relays instructions from outside the cell to the nucleus, telling it when to multiply. It is activated when bound to a molecule called GTP and deactivated when it converts GTP to another molecule, GDP. In its normal function, this switch ensures that cell growth happens in a controlled manner.
The KRAS G12C mutation is a specific error where the amino acid glycine at position 12 of the K-Ras protein is replaced with cysteine. This single change alters the protein’s structure and function, causing the on/off switch to become stuck in the “on” position. The constantly active protein continuously signals the cell to divide, leading to the uncontrolled proliferation that characterizes cancer.
For decades, the KRAS protein was considered “undruggable” by scientists. Its smooth, spherical shape lacked obvious pockets where a drug could bind, and its strong affinity for the GTP molecule made it difficult to block its activation. The discovery of the G12C mutation, however, revealed a structural vulnerability. This specific alteration created a new pocket on the protein surface, opening the door for drugs designed to fit into it.
Mechanism of Action
Sotorasib functions as a KRAS G12C inhibitor, a drug designed to exploit the structural flaw created by the mutation. The therapy works by selectively and irreversibly binding to the cysteine residue that is only present in the mutated version of the K-Ras protein. This specific targeting means the drug has little effect on the normal K-Ras protein found in healthy cells.
The drug molecule fits into a pocket on the surface of the mutated protein that is only accessible when the protein is in its inactive, GDP-bound state. By forming a permanent, covalent bond with the cysteine, sotorasib traps the KRAS G12C protein in this “off” configuration. This action prevents the protein from being reactivated and sending the continuous growth signals that drive the cancer.
By locking the protein in an inactive state, sotorasib shuts down the downstream signaling pathways that cancer cells depend on for survival and proliferation. The primary pathways affected are the MAPK and PI3K pathways, which transmit growth commands to the cell’s nucleus. Halting these signals inhibits tumor growth and can lead to the death of cancer cells that harbor the KRAS G12C mutation.
Clinical Applications and Efficacy
Sotorasib is used to treat adult patients with non-small cell lung cancer (NSCLC) that has the KRAS G12C mutation, which is found in about 13% of lung adenocarcinomas. It is approved for patients whose cancer has progressed after at least one prior systemic therapy. Sotorasib is also used for certain patients with KRAS G12C-mutated colorectal cancer. Before starting treatment, biomarker testing is required to confirm the tumor has the specific KRAS G12C mutation.
The efficacy of sotorasib was established in the CodeBreaK 100 clinical trial for patients with previously treated KRAS G12C-mutated NSCLC. The study showed a confirmed objective response rate (ORR) of 37.1%, meaning the tumors in nearly four out of ten patients shrank significantly. Some patients experienced a complete response, where all signs of the tumor disappeared.
The trial also measured the disease control rate (DCR) at 80.6%, which includes patients whose tumors shrank or remained stable. The median progression-free survival, the average time patients lived without their cancer worsening, was 6.8 months. Long-term data showed a two-year overall survival rate of 32.5%, confirming a durable benefit for a segment of this patient population.
Administration and Potential Side Effects
Sotorasib is administered as an oral medication, taken as a 960 mg dose once per day. The tablets can be taken with or without food, and patients should take their dose at approximately the same time each day. For individuals who have difficulty swallowing whole tablets, the pills can be dispersed in four ounces of non-carbonated, room-temperature water. If a dose is missed by more than six hours, the patient should skip that dose and take the next one at the regularly scheduled time.
Common side effects may occur while taking sotorasib. The most frequent adverse reactions include:
- Diarrhea
- Muscle or bone pain
- Nausea
- Fatigue
- Coughing
Changes in liver function are also frequently observed through blood tests. These side effects are generally manageable, and a healthcare provider may adjust the dosage if they become problematic.
While most side effects are mild to moderate, sotorasib can cause more serious health issues. One risk is hepatotoxicity, or liver damage, so patients will have their liver function monitored with blood tests before and during treatment. Another serious but less common side effect is interstitial lung disease or pneumonitis, which involves inflammation of the lung tissue. Patients are advised to contact their healthcare provider immediately if they experience new or worsening symptoms such as trouble breathing, cough, or fever.