KRAS G12C in non-small cell lung cancer

KRAS is a membrane-anchored GTPase that cycles between active (GTP-bound) and inactive (GDP-bound) states. The G12C substitution introduces a reactive cysteine residue at codon 12 in the switch-II pocket. This cysteine is the molecular handle that selective KRAS G12C inhibitors (sotorasib, adagrasib) covalently bind, locking the protein in its inactive GDP-bound conformation. Other KRAS codon 12 substitutions (G12D, G12V, G12A) lack this reactive cysteine and require different inhibitor chemistry.

KRAS sits upstream of the RAF/MEK/ERK and PI3K/AKT cascades. Inhibiting KRAS G12C reduces signaling through both axes, but feedback reactivation through wild-type KRAS or through RAS-pathway bypass (HER2, MET, EGFR amplification) is common and underlies most acquired resistance.

KRAS G12C is the most common KRAS substitution in NSCLC, accounting for roughly 40% of KRAS-mutant lung adenocarcinomas. It is strongly associated with smoking history. Squamous histology and never-smoker adenocarcinoma show much lower prevalence. In colorectal cancer, KRAS G12C accounts for ~3% of all KRAS mutations and has its own approval landscape distinct from NSCLC.

KRAS G12C is not currently approved for first-line single-agent KRAS-G12C-inhibitor therapy in NSCLC. First-line in 2026 remains platinum-based chemotherapy + immune checkpoint inhibitor combinations, or ICI monotherapy when PD-L1 expression is high. Active investigation includes:

• Sotorasib + ICI combinations (CodeBreaK 100, 101, 200 series).
• Adagrasib + ICI combinations (KRYSTAL-7).
• Sotorasib or adagrasib added to chemotherapy in earlier lines.

Positioning is changing fast. Verify current label and trial readouts at decision time.

Acquired resistance to KRAS G12C inhibitors emerges in most patients within months. Mechanisms cluster into several patterns:

• STK11 (LKB1) co-mutation: negative modifier for both KRAS G12C inhibitors and ICI. Worse response and shorter PFS in retrospective and prospective series.
• KEAP1 co-mutation: similar negative-modifier signal for ICI; KEAP1 alterations also affect oxidative stress response and chemo sensitivity.
• Concurrent STK11 + KEAP1: worst response signal among these co-mutations. Strong consideration for clinical trial enrollment.
• TP53 co-mutation: common; generally does not change G12C-inhibitor selection but affects overall prognosis.

Tissue is preferred when feasible. Plasma is appropriate for monitoring and for patients without sufficient tissue for repeat NGS. Concordance is good but not perfect — interpret discordance carefully.

ClinicalTrials.gov is the source of truth. Useful filter combinations for KRAS G12C NSCLC:

• "KRAS G12C" + "Lung Cancer" + recruiting → typically 30–60 active studies at any time.
• High-volume sponsors include Amgen, Mirati/Bristol Myers Squibb, and Revolution Medicines (RAS-MAPK pipeline including pan-KRAS and pan-RAS approaches).
• Search "G12C immune checkpoint inhibitor combination" for ongoing combination readouts.
• Search "pan-RAS inhibitor lung cancer" for next-generation pan-KRAS or pan-RAS programs.

Sotorasib is metabolized primarily by CYP3A4 with secondary contribution from UGT enzymes. Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort) substantially reduce sotorasib exposure; alternative therapy or dose adjustment is required.

Adagrasib carries QT-interval prolongation risk. Concurrent QT-prolonging medications require baseline ECG, magnesium and potassium repletion, and serial monitoring. Avoid concurrent strong CYP3A4 inhibitors; concurrent strong CYP3A4 inducers reduce exposure.

• CIViC EID6184 — KRAS G12C + sotorasib.
• PubMed 33606975 — Hong et al., CodeBreaK 100, NEJM 2020.
• PubMed 35658005 — Jänne et al., KRYSTAL-1, NEJM 2022.
• AMP/ASCO/CAP 2017 — Li MM et al., J Mol Diagn 2017;19(1):4-23.
• openFDA labels for sotorasib (Lumakras), adagrasib (Krazati).

• Decision-support reference, not CAP/CLIA-validated diagnostic.
• KRAS G12C in colorectal cancer follows a different treatment landscape; adagrasib + cetuximab (KRYSTAL-1 CRC cohort) has distinct positioning. Drug-gene match depends on tumor type.
• The first-line context for KRAS G12C is changing fast as ICI combination data matures. Verify current label and trial readouts at decision time.
• Trial-recruiting status changes daily.

Is sotorasib or adagrasib first-line in KRAS G12C NSCLC?

Neither is currently approved as first-line single-agent therapy. FDA-approved indications are for previously treated locally advanced or metastatic disease (post-platinum). First-line in 2026 remains platinum-based chemotherapy + ICI, or ICI alone in PD-L1-high. Combination ICI + KRAS G12C inhibitor trials may change this.

How do STK11 and KEAP1 co-mutations affect KRAS G12C treatment?

STK11 and KEAP1 co-mutations are negative modifiers for both KRAS G12C inhibitors and ICI. Their presence shapes prognosis discussions and supports consideration of clinical trial enrollment.

What companion diagnostics are FDA-approved for KRAS G12C NSCLC?

QIAGEN therascreen KRAS RGQ PCR Kit (tissue) is the companion diagnostic for sotorasib. Agilent Resolution ctDx FIRST (plasma) is the companion diagnostic for adagrasib. Most comprehensive NGS panels also detect KRAS G12C.