What is a KRAS G12C Mutation?
KRAS is a gene that helps regulate cell growth. It produces a protein that acts like a switch, moving between active and inactive states as cells receive and respond to growth signals.
A KRAS mutation changes how this switch is regulated. KRAS G12C is a specific mutation in which one of the protein’s building blocks, glycine, is replaced by cysteine at position 12. The mutation does not literally hold the KRAS G12C protein permanently in one position. However, it disrupts the normal switching process and favours persistent growth signalling, which can contribute to the development and progression of cancer.
KRAS mutations occur in approximately 25–30% of lung adenocarcinomas in Western populations. KRAS G12C is the most common KRAS subtype in non-small cell lung cancer (NSCLC) and is more frequently identified in people with a current or previous smoking history.
Importantly, KRAS and KRAS G12C are not interchangeable terms. There are several KRAS mutation subtypes, and the currently available KRAS G12C inhibitors are designed specifically for cancers carrying the G12C mutation.
How Do I Know Whether My Lung Cancer has a KRAS G12C Mutation?
A KRAS G12C mutation is identified through molecular testing of the cancer. Testing may be performed using:
- Tumour tissue collected through a biopsy or surgery
- A blood-based liquid biopsy that looks for tumour DNA circulating in the bloodstream
Finding a KRAS G12C mutation may identify clinical trials, support consideration of later-line targeted treatment and help clinicians assess other access options. Importantly, even if KRAS is mentioned in the report, it does not necessarily mean it is a driver mutation that dictates treatment.
Can KRAS G12C Inhibitors be Combined with Chemotherapy or Immunotherapy?
Yes, this is now one of the most active areas of KRAS G12C research. The main approaches include combining a KRAS G12C inhibitor with:
- Chemotherapy
- Immunotherapy
- Chemotherapy and immunotherapy together
Each strategy has a different rationale.
Chemotherapy attacks rapidly dividing cancer cells through mechanisms that do not depend on KRAS G12C. Immunotherapy helps the immune system recognise and attack cancer. Combining either approach with direct inhibition of KRAS G12C may improve the initial response or reduce the cancer’s ability to escape through a single route.
However, adding more treatment can also increase toxicity. Early studies combining some KRAS G12C inhibitors with immunotherapy raised concerns about liver inflammation, prompting researchers to refine doses, schedules and drug selection. The challenge is therefore not simply to identify the combination with the highest response rate. It is to determine which approach produces the best balance of cancer control, durability, safety and quality of life.
What KRAS G12C Treatment can Australian Patients Access?
Sotorasib has provisional registration from the Therapeutic Goods Administration for adults with locally advanced or metastatic KRAS G12C-positive NSCLC who have received at least one previous systemic therapy. However, sotorasib is not currently listed on the PBS for NSCLC. Its PBS listing submission was considered in 2022, and a later submission was withdrawn. The TGA registration does not automatically translate into routine subsidised access.
For an Australian patient with KRAS G12C-positive lung cancer, a clinician may therefore discuss:
- An appropriate clinical trial
- Another access pathway
- Standard chemotherapy, immunotherapy or chemoimmunotherapy
- Later treatment choices based on previous therapy, overall health and individual clinical circumstances
Availability can vary between hospitals and may change. Patients should ask their treating oncologist whether a suitable KRAS G12C clinical trial or access program is open at their treatment centre or elsewhere in Australia.
Sotorasib and adagrasib have been approved in the United States for adults with advanced or metastatic KRAS G12C-positive NSCLC who have previously received systemic treatment. These approvals established KRAS G12C inhibitors as a later-line treatment option rather than the usual first treatment given after diagnosis.
TOGA’s SHERLOCK Trial
Clinical trials are sometimes described as investments in future care. SHERLOCK is investigating first-line sotorasib combined with carboplatin, pemetrexed and bevacizumab for people with advanced KRAS G12C-positive non-squamous non-small cell lung cancer.
Early results reported a confirmed objective response rate of 64%, with responses observed in 30 of 47 evaluable participants. These early findings are encouraging, but longer follow-up is needed to understand how durable the responses are and how the treatment affects survival and quality of life. SHERLOCK is important not only because it evaluates a new combination. It also gave eligible Australian patients access to KRAS G12C targeted therapy while contributing evidence that may shape future treatment internationally.
While SHERLOCK has now closed to recruitment, many other clinical trials providing access to a KRAS G12C inihibitor are available. Patients should ask their treating clinician about possibilities.
Lynda’s experience of the SHERLOCK trial
Lynda was diagnosed with stage IV lung cancer in 2023 and was initially told she might have six to twelve months to live. Genomic testing of her tumour identified a KRAS G12C mutation, and she was offered participation in SHERLOCK. Currently, she remains on the trial and continues to receive the full study treatment. She has experienced side effects, but says her overall experience has been positive.
Since her diagnosis, four grandchildren have been born into her family. Lynda believes trial participation has allowed her to meet them and to continue living as herself, rather than allowing lung cancer to define her identity. She describes the research nurse, oncologist and trial team as “supportive, attentive and genuinely interested in how I’m feeling”.
“I’ve got nothing to lose and a lot to gain. Even if it doesn’t work for me, hopefully something positive will come out of it for others and my family in the future.”
The patient-centred approach has made the burdens of treatment and her diagnosis easier to tolerate. Lynda was referred early to palliative care. She found this practical and empowering. It helped her prepare an advance care plan, organise important matters for her family and learn ways to manage symptoms such as pain and breathlessness.
Her experience reflects the value of combining active cancer treatment with early supportive and palliative care, rather than treating them as competing approaches.
Frequently Asked Questions
No. KRAS is the name of the gene. KRAS G12C is one specific mutation in that gene.
Other KRAS mutations include G12D, G12V, G13D and Q61H. A drug designed for KRAS G12C will not necessarily work against another KRAS subtype.
In most people with lung cancer, the KRAS G12C mutation is a somatic mutation. This means it developed in the tumour and is not present in every cell of the body.
It is generally not an inherited mutation passed from parent to child. Patients concerned about their personal or family cancer history should discuss whether genetic counselling is appropriate.
KRAS G12C is more frequently found in people with a current or previous smoking history, but it can also occur in people who have never smoked.
Smoking history alone cannot determine whether the mutation is present. Molecular testing is required.
Yes. KRAS G12C inhibitors have demonstrated activity in advanced non-small cell lung cancer and are approved for previously treated disease in some countries.
Access in Australia is more limited because these therapies are not currently PBS subsidised for lung cancer. A clinical trial or another access pathway may be considered.
Not all KRAS G12C mutations present are responsible for driving tumour growth, so its presence alone does not always mean a KRAS G12C inhibitor is the best treatment option.
No, KRAS G12C inhibitor is currently PBS listed for the treatment of lung cancer.
Sotorasib is provisionally registered by the TGA for previously treated advanced KRAS G12C-positive non-small cell lung cancer, but TGA registration and PBS reimbursement are separate processes.
Not necessarily. A trial must be clinically appropriate, accessible and consistent with the patient’s goals.
However, because routine access to KRAS G12C targeted therapy remains limited in Australia, asking about clinical trials is particularly relevant.
People whose test results show a KRAS G12C mutation may wish to ask:
- Has my cancer had comprehensive molecular testing?
- Are there other mutations that may affect treatment decisions?
- What is the recommended standard first-line treatment for me?
- Is there a KRAS G12C clinical trial for which I may be eligible?
- Are trials available at another Australian cancer centre?
- Is sotorasib or another KRAS G12C inhibitor accessible through a special-access pathway?
- What is known about the benefits and side effects of the proposed treatment?
- How would participation in a clinical trial affect my usual care?
- Who would I contact if I experienced side effects during the trial?
Eligibility for a clinical trial depends on detailed criteria. Having a KRAS G12C mutation does not automatically mean that a particular study will be suitable, but it provides an important reason to ask.
