KRAS Mutations in Lung Cancer

by Matthew Cecchini, MD PhD FRCPC
March 20, 2026

KRAS is one of the most commonly mutated genes in human cancer. In the lung, mutations in the KRAS gene are found in approximately 25–30% of non-small cell lung cancers, making it the single most frequently altered driver gene in this disease, more common than EGFR mutations or ALK rearrangements. KRAS encodes a protein that functions like a molecular relay switch, passing growth signals from the cell surface inward. When KRAS is mutated, the switch becomes permanently stuck in the “on” position, continuously driving cell division without the normal regulatory checks. For decades, KRAS was considered undruggable — its smooth protein surface offered no obvious site where a drug could bind and block it. That changed in 2021 with the approval of sotorasib (Lumakras), the first drug specifically targeting a common KRAS mutation, followed by adagrasib (Krazati) in 2022. These approvals transformed KRAS from a marker of poor prognosis with limited treatment options into an actionable therapeutic target for a significant subset of patients.

What the test looks for

The KRAS protein is a GTPase — a molecular switch that cycles between an active state (when bound to GTP) and an inactive state (when bound to GDP). Growth signals from the cell surface activate KRAS, which then relays the signal downstream through pathways that stimulate cell division. Once the signal has been passed, KRAS normally inactivates itself by cleaving GTP to GDP. Mutations in KRAS impair this self-inactivation, leaving the protein permanently active and continuously driving cell proliferation.

Not all KRAS mutations are equivalent. They occur at several different positions in the gene, and the specific mutation present has increasingly important implications for treatment:

KRAS G12C. A mutation at codon 12 in which glycine is replaced by cysteine. This is the most common KRAS mutation in lung cancer, accounting for approximately 40–45% of all KRAS mutations in this setting, meaning roughly 10–13% of all non-small cell lung cancers carry this specific change. The cysteine substitution creates a unique pocket in the KRAS protein that covalent inhibitor drugs can target. Sotorasib (Lumakras) and adagrasib (Krazati) both specifically target KRAS G12C and are approved for previously treated advanced NSCLC harbouring this mutation. KRAS G12C is more common in former or current smokers than in never-smokers.
KRAS G12V. A mutation at codon 12 in which glycine is replaced by valine. The second most common KRAS mutation is in lung cancer. Unlike G12C, it does not create the targetable cysteine pocket, and specific approved inhibitors are not currently available — though clinical trials are investigating pan-KRAS inhibitors and other strategies.
KRAS G12D. Glycine is replaced by aspartate at codon 12. Common in other cancer types (particularly pancreatic cancer) but less prevalent in lung cancer than G12C or G12V. Also not currently targetable with approved drugs, though active research is ongoing.
Other codon 12 and codon 13 mutations (G12A, G12S, G12R, G13C, G13D, and others). A variety of additional mutations occur at codons 12 and 13. None of the targeted therapies in lung cancer has been approved at present.
KRAS Q61 mutations. Mutations at codon 61 are less common in lung cancer than codon 12 mutations. Their therapeutic implications in NSCLC remain poorly defined.

Why is the test done

To identify patients eligible for KRAS G12C-targeted therapy. Sotorasib and adagrasib are approved specifically for patients with KRAS G12C-mutated advanced NSCLC who have received at least one prior line of therapy (typically platinum-based chemotherapy and/or immunotherapy). Knowing the specific KRAS mutation — not just that KRAS is mutated — is necessary to determine eligibility.
To exclude other driver mutations. KRAS mutations and other major lung cancer driver mutations (such as EGFR, ALK, ROS1, and RET) are largely mutually exclusive — they rarely occur together. Finding a KRAS mutation provides important context that targeted therapies for these other drivers are unlikely to be relevant.
To guide immunotherapy decisions. KRAS-mutated lung cancers — particularly KRAS G12C — have been shown to have a meaningful rate of response to immune checkpoint inhibitors, especially when PD-L1 expression is high. Co-mutation with STK11 (also called LKB1) or KEAP1, however, is associated with reduced immunotherapy benefit, underscoring the importance of the full molecular context.
To provide prognostic information. KRAS mutations in lung cancer have historically been associated with a somewhat less favourable prognosis than EGFR or ALK driver alterations, in part because effective targeted therapies were not available for most of the period when KRAS testing became routine. The landscape is changing rapidly with new targeted drugs entering clinical practice.
To support clinical trial eligibility. The KRAS field is evolving quickly. Several clinical trials are investigating new KRAS G12C inhibitors, combinations with other agents, and drugs targeting non-G12C KRAS mutations. Knowing KRAS status — and the specific mutation — opens doors to clinical trial participation.

Who should be tested

Current guidelines recommend KRAS mutation testing for:

All patients with advanced or metastatic non-small cell lung cancer undergo comprehensive molecular profiling at diagnosis.
Patients with resected early-stage lung adenocarcinoma, where molecular profiling is increasingly performed to characterise the tumour’s biology, though KRAS-specific adjuvant therapies are not yet approved.

In practice, KRAS testing is performed simultaneously with testing for all other major lung cancer biomarkers as part of a comprehensive NGS panel. Critically, the specific mutation at codon 12 (G12C versus G12V versus G12D, for example) must be reported — a result stating only “KRAS mutation detected” without specifying the amino acid change is insufficient for treatment decision-making.

How the test is performed

KRAS mutation testing is performed on tumour tissue or, in some settings, on a blood-based liquid biopsy.

Tissue-based testing

DNA is extracted from tumour tissue obtained from a biopsy or surgical specimen and analysed using molecular testing methods. Next-generation sequencing (NGS) is the preferred approach, as it simultaneously characterises KRAS and all other relevant lung cancer genes in a single test, including co-mutation status in genes such as STK11 and KEAP1 that may influence treatment decisions. PCR-based assays can also detect common KRAS mutations with high sensitivity, though they assess fewer genes simultaneously.

Liquid biopsy

Cell-free circulating tumour DNA (ctDNA) in blood can be analysed for KRAS mutations. KRAS point mutations — particularly G12C — are well suited to liquid biopsy detection because they are single-nucleotide changes that are reliably captured by sensitive ctDNA assays. Liquid biopsy is particularly useful when tissue is insufficient for NGS, when a rapid result is needed, or when monitoring disease during treatment. A negative liquid biopsy result does not rule out a KRAS mutation; tissue testing should follow if the liquid biopsy is negative and a KRAS mutation is clinically important to exclude.

How results are reported

KRAS results are reported by specifying the exact mutation using standard protein nomenclature — for example, “KRAS p.G12C (c.34G>T) detected” or “KRAS G12V mutation detected.” A result confirming no mutation is reported as “KRAS wild-type” or “No pathogenic KRAS variant detected.”

NGS reports will often include the variant allele frequency (VAF) — the proportion of tumour DNA copies carrying the mutation — which gives a sense of how prevalent the mutation is within the tumour sample. Co-mutations in other genes will also be listed and may be flagged as clinically significant where relevant.

What each result means

KRAS G12C mutation detected. The cancer carries the specific KRAS mutation for which sotorasib (Lumakras) and adagrasib (Krazati) are approved. In the second-line setting (after at least one prior therapy), either drug is an option. Your oncologist will discuss which is more appropriate based on your treatment history and overall clinical situation. Response rates in clinical trials have been approximately 35–45% for both agents, with a median progression-free survival of around six months in previously treated patients — meaningful but not as durable as responses seen with EGFR or ALK inhibitors in their respective populations. Clinical trials are investigating these drugs in earlier lines of treatment and in combination with other agents, which may further improve outcomes.
KRAS G12V, G12D, or other non-G12C mutation detected. No approved KRAS-targeted drugs are currently available for these specific mutations in lung cancer. Treatment will be guided by PD-L1 expression, co-mutation status, and overall disease characteristics — typically involving immunotherapy (with or without chemotherapy) in the first-line setting. Importantly, participation in a clinical trial investigating pan-KRAS inhibitors or mutation-specific agents targeting G12V or G12D may be an option. Your oncologist can advise on available trials.
KRAS wild-type (no KRAS mutation detected). No KRAS mutation is present in the regions tested. Testing for other driver mutations — including EGFR, ALK, ROS1, MET, RET, BRAF, NTRK, and others — should be completed (and is typically done simultaneously). The full molecular profile will guide treatment.
KRAS G12C detected with co-mutation in STK11 or KEAP1. Co-mutations in STK11 (LKB1) or KEAP1 alongside KRAS G12C have been associated with reduced benefit from both immunotherapy and, to some extent, KRAS G12C inhibitors compared with KRAS G12C alone. This does not mean treatment is ineffective, but your oncologist may weigh this information when deciding on the treatment sequence and considering clinical trial options. The prognostic and predictive significance of these co-mutations is an active area of research.

KRAS mutations and immunotherapy

Unlike EGFR mutations and ALK rearrangements — where immune checkpoint inhibitors are generally less effective and sometimes potentially harmful when combined with targeted therapy — KRAS-mutated lung cancers can respond well to immunotherapy, particularly when PD-L1 expression is high. Many patients with KRAS-mutated NSCLC receive immunotherapy (alone or in combination with chemotherapy) as their first-line treatment, followed by a KRAS G12C inhibitor in the second line if the mutation is present.

The interaction between KRAS mutation status, co-mutations (particularly STK11 and KEAP1), and immunotherapy benefit is complex and continues to be studied. Your oncologist will assess all of these factors together when recommending a treatment sequence.

KRAS mutations: germline vs. somatic

KRAS mutations found in lung cancer are almost always somatic — they arise within the cancer cells and are not inherited. Germline KRAS mutations exist but are associated with a rare developmental syndrome called Noonan syndrome and are not related to lung cancer risk in the general population. Patients with a somatic KRAS mutation in their lung cancer do not need to worry that it can be passed to their children, and family members do not require KRAS screening on this basis.

The evolving KRAS treatment landscape

The approval of sotorasib in 2021 represented a landmark moment in oncology — the culmination of nearly four decades of research into what had been called an “undruggable” target. The KRAS field is now moving rapidly, with several important developments underway:

Combination strategies. Clinical trials are investigating KRAS G12C inhibitors in combination with other targeted agents, chemotherapy, or immunotherapy to improve response rates and overcome resistance. Combinations with SHP2 inhibitors, MEK inhibitors, and anti-PD-1 antibodies are among those being studied.
Non-G12C KRAS inhibitors. Drugs targeting KRAS G12D and G12V, and pan-KRAS inhibitors that block all KRAS mutations regardless of amino acid change, are in clinical development. Results from early-phase trials are emerging.
Earlier lines of treatment. Current approvals for sotorasib and adagrasib are in the second-line setting. Trials evaluating these drugs as first-line treatment — with or without chemotherapy — are ongoing.
Resistance mechanisms. Understanding how KRAS G12C-mutated cancers develop resistance to inhibitors is an active area of research, with several mechanisms identified, including secondary KRAS mutations, amplifications, and activation of bypass pathways.

Given how quickly this field is changing, asking your oncologist about current clinical trial options is particularly worthwhile if you have a KRAS-mutated lung cancer.

What happens next

If KRAS G12C is found, your oncologist will discuss the full treatment plan, which typically includes first-line immunotherapy (with or without chemotherapy), with sotorasib or adagrasib available as second-line options. Clinical trial participation at any stage may be discussed. PD-L1 testing and co-mutation status will also inform the first-line recommendation.
If a non-G12C KRAS mutation is found: No approved KRAS-targeted therapy is currently available for your specific mutation. Treatment will be guided by PD-L1 expression and overall molecular profile. Clinical trial participation is strongly worth discussing.
If KRAS is wild-type, the comprehensive molecular panel will be reviewed for other targetable alterations. The full molecular and clinical picture will guide treatment.
At progression on KRAS G12C inhibitor therapy: Repeat molecular testing — ideally with both liquid biopsy and tissue biopsy — will be recommended to identify the resistance mechanism and guide subsequent therapy.

Questions to ask your doctor

Does my tumour have a KRAS mutation? If so, which specific mutation is it —G12C, G12V, or something else?
Does my KRAS mutation make me eligible for sotorasib or adagrasib?
What is my PD-L1 expression level, and how does that affect my treatment plan?
Does my tumour have co-mutations in STK11 or KEAP1, and if so, how does that change the recommendations?
Should I receive immunotherapy, chemotherapy, or a combination of the two as my first treatment?
Are there clinical trials investigating new KRAS-targeted drugs that I might be eligible for?
If my cancer progresses on a KRAS inhibitor, will re-testing be done to find out why?
What other biomarkers have been tested in my tumour, and were any other targetable mutations found?