Sotorasib, marketed as Lumakras, is a targeted therapy medication from Amgen for specific cancers. It was developed to treat cancers with a particular genetic alteration that was long considered untreatable with targeted drugs. Sotorasib is designed to work on cancers that have this precise genetic marker, offering a focused treatment approach for patients whose tumors were historically difficult to address.
Understanding the KRAS G12C Mutation
The KRAS gene provides instructions for making a protein that is part of a signaling pathway for cell growth and division. This protein cycles between an “on” state, bound to a molecule called GTP, and an “off” state, bound to GDP. In its normal function, the KRAS protein helps regulate cell proliferation, ensuring that cells divide in a controlled manner.
A mutation known as G12C alters the protein’s function. This change occurs when the amino acid glycine is replaced by cysteine at position 12 of the protein. This results in the KRAS protein becoming stuck in its active, GTP-bound form. Consequently, the signaling pathway that controls cell growth is perpetually “on,” leading to uncontrolled cell division. This mutation is found in approximately 13-15% of non-small cell lung cancers and at lower frequencies in other solid tumors like colorectal cancer.
For decades, the KRAS protein was considered “undruggable.” Its smooth surface lacked obvious pockets where a small-molecule drug could bind and disrupt its function. This structural characteristic made it difficult for researchers to design a compound that could attach to the protein with enough specificity to inhibit its cancer-driving activity. The absence of a clear binding site created a challenge for drug developers, leaving patients with KRAS-mutated cancers with few targeted treatment options.
Sotorasib’s Mechanism of Action
Sotorasib is an inhibitor engineered to target the KRAS G12C mutated protein. It functions by forming an irreversible covalent bond with the cysteine residue present only in the mutated form of the protein. This specific interaction is possible because the drug was designed to fit into a hidden pocket on the protein surface that becomes accessible in the G12C mutant.
The binding of sotorasib acts like a key fitting into a lock that doesn’t exist on the normal KRAS protein. This specificity ensures the drug primarily affects cancer cells with the mutation while sparing healthy cells. By attaching to the cysteine, sotorasib traps the KRAS G12C protein in its inactive, GDP-bound state.
Once locked in this inactive state, the KRAS G12C protein can no longer transmit the signals that fuel tumor growth. This action turns the permanently “on” switch to “off,” halting the signaling pathways that drive uncontrolled cell proliferation. The inhibition of these signals leads to the suppression of tumor cell growth and can promote programmed cell death in cancer cells.
Clinical Applications and Efficacy
The primary approved use for sotorasib is for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that has the KRAS G12C mutation. This approval is for patients whose disease has progressed after receiving at least one prior systemic therapy. The U.S. Food and Drug Administration (FDA) granted accelerated approval for this indication, recognizing it as a first-in-class medication for this patient population.
The study supporting its approval was the CodeBreaK 100 trial for patients with KRAS G12C-mutated NSCLC. In this study, sotorasib demonstrated an objective response rate (ORR) of 37.1%, meaning this percentage of patients experienced a reduction in tumor size. The disease control rate, which includes patients whose tumors shrank or remained stable, was 81%. The responses were durable, with a median duration of 11.1 months. The median progression-free survival, the time patients lived without their cancer getting worse, was 6.8 months.
Ongoing research continues to explore sotorasib’s potential in other cancers with the same mutation. Studies are evaluating its effectiveness in patients with KRAS G12C-mutated colorectal cancer (mCRC) and other solid tumors. For mCRC, combination therapies are being investigated, such as pairing sotorasib with other targeted agents to improve response rates.
Administration and Potential Side Effects
Sotorasib is an oral tablet, offering the convenience of at-home use. The standard dosage is 960 mg taken once daily, with or without food. Patients continue the treatment until their disease progresses or they experience unacceptable toxicity. In case of adverse reactions, a healthcare provider may interrupt or reduce the dosage to manage side effects.
The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, cough, and changes in liver function tests. These reactions are manageable, and patients should communicate any symptoms to their medical team. Liver issues are detected through routine blood tests, while musculoskeletal pain can manifest as back or bone pain.
While many side effects are mild to moderate, sotorasib can cause more serious adverse reactions. Severe side effects include hepatotoxicity (liver damage), which may require treatment with corticosteroids, and interstitial lung disease or pneumonitis (lung inflammation). Patients are monitored for symptoms like worsening cough or shortness of breath. Patients should discuss the full range of potential side effects with their doctor before starting treatment.