Last updated: June 24, 2026
Krazati (adagrasib, MRTX849) is an oral KRAS G12C-selective covalent inhibitor originally developed by Mirati Therapeutics and now part of Bristol Myers Squibb (following BMS's October 2023 acquisition of Mirati). Adagrasib is FDA-approved in two indications: KRAS G12C-mutated NSCLC after at least one prior systemic therapy (December 2022 accelerated approval, KRYSTAL-1 Phase 2) and KRAS G12C-mutated metastatic colorectal cancer in combination with cetuximab (June 2024 accelerated approval, KRYSTAL-1 + KRYSTAL-10 follow-on data). A clinically meaningful differentiator vs sotorasib (Lumakras): adagrasib has documented CNS penetration and reported intracranial activity in NSCLC patients with brain metastases. Dosed 600 mg orally twice daily.
Mechanism of action:Adagrasib binds covalently to cysteine-12 (the mutant residue) on the GDP-bound inactive ('OFF') state of mutant KRAS G12C, locking the protein in the inactive state. This prevents nucleotide exchange to the GTP-bound active state and blocks downstream MAPK (RAF / MEK / ERK) and PI3K / AKT signaling that drives tumor-cell proliferation. KRAS G12C is a specific subtype of KRAS mutation — detection of G12C specifically (not just any KRAS mutation) is required for eligibility. See the KRAS Inhibitors mechanism hub for the broader class context.
Regulatory status:FDA-approved in 2 indications: KRAS G12C-mutated NSCLC 2L+ monotherapy (KRYSTAL-1, Dec 2022 accelerated approval) and KRAS G12C-mutated previously-treated metastatic colorectal cancer in combination with cetuximab (KRYSTAL-1 + KRYSTAL-10, Jun 2024 accelerated approval). Both approvals are accelerated, meaning continued approval is contingent on confirmatory Phase 3 evidence — including the registrational 1L NSCLC KRYSTAL-12 trial (NCT06875310) currently recruiting.
KRAS is a gene that makes a small switch-like protein. In normal cells, KRAS switches between an inactive 'OFF' state (bound to a small molecule called GDP) and an active 'ON' state (bound to GTP). The ON state turns on growth signals; the OFF state turns them off. In cancer, a mutation in the KRAS gene can keep the protein stuck in the ON state, driving the cell to divide without stopping.
KRAS mutations are some of the most common cancer-driving mutations: about 25-30% of non-small cell lung cancer (NSCLC) adenocarcinoma, 40-50% of colorectal cancer, and more than 90% of pancreatic cancer carry an activating KRAS mutation. But not all KRAS mutations are the same. The exact change in the protein matters — each subtype (G12C, G12D, G12V, G13D, Q61, and others) creates a slightly different shape, and different drugs only work on specific subtypes.
The KRAS G12C subtype — where the amino acid at position 12 is changed from glycine to cysteine — is found in approximately 13% of NSCLC and 3% of colorectal cancer, with smaller percentages in pancreatic, endometrial, and other tumor types. The cysteine at position 12 has a reactive sulfur atom that creates a small chemical handle on the protein. KRAS G12C inhibitors like Krazati are designed to covalently bind to that cysteine handle and lock the protein in the OFF state. Because they target the cysteine specifically, they only work on KRAS G12C — not on G12D, G12V, G13D, or Q61.
This is why knowing your exact KRAS mutation matters. A pathology report that says "KRAS mutated" is not enough to determine adagrasib eligibility — you need the exact codon and amino acid change (e.g., "KRAS p.G12C" or "KRAS c.34G>T"). Standard tumor next-generation sequencing (NGS) and many ctDNA panels report this directly. If your report does not show the exact mutation, ask your oncology team to follow up with the testing lab.
Krazati has accumulated 2 FDA accelerated approvals since its December 2022 first-in-class NSCLC accelerated approval. Both indications require KRAS G12C-mutation confirmation on tumor tissue or ctDNA.
KRAS G12C-mutated locally advanced or metastatic NSCLC, after at least one prior systemic therapy (monotherapy)
KRAS G12C-mutated locally advanced or metastatic colorectal cancer + cetuximab, after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
★ Krazati's clinical differentiator: documented CNS penetration
Adagrasib has documented blood-brain-barrier penetration and reported intracranial activity in KRYSTAL-1 NSCLC patients with brain metastases — an intracranial response rate was reported in the KRYSTAL-1 brain-metastases cohort, reflecting a more favorable CNS-penetration profile than sotorasib (Lumakras). For NSCLC patients with active or untreated brain metastases — a clinically common scenario, since lung cancer commonly metastasizes to the CNS — this is a meaningful differentiator that can influence drug selection.
A dedicated Phase 2 trial — NCT06248606 — is testing adagrasib + stereotactic radiosurgery (SRS) in KRAS G12C NSCLC patients with untreated brain metastases, leveraging this CNS-penetration advantage in a curative-intent local-therapy combination strategy.
Both adagrasib (Krazati, BMS via Mirati) and sotorasib (Lumakras, Amgen) are FDA-approved KRAS G12C-selective covalent inhibitors. Both have NSCLC monotherapy approval and CRC + anti-EGFR-antibody combination approval. The choice between them is a clinical conversation with the treating oncologist:
Curated list of 7 recruiting interventional Krazati (adagrasib) trials in the ClinTrialFinder corpus as of June 24, 2026. Trials are ordered by clinical significance.
Showing all 7 recruiting + not-yet-recruiting Krazati (adagrasib) interventional trials in the ClinTrialFinder corpus as of June 24, 2026. For the latest list: view all recruiting adagrasib trials on ClinicalTrials.gov.
Target: mutant KRAS G12C (cysteine-12), specifically in its GDP-bound inactive ('OFF') state.
Mechanism: Adagrasib is a small-molecule covalent inhibitor that diffuses into the cell and binds the switch-II pocket of KRAS — an allosteric pocket adjacent to the mutant cysteine that is only accessible in the GDP-bound 'OFF' conformation. Once positioned in the pocket, an electrophilic warhead on the drug forms a covalent bond with the sulfur atom on cysteine-12 of the mutant KRAS G12C protein. This covalent attachment locks KRAS G12C in the GDP-bound state, prevents nucleotide exchange to the GTP-bound 'ON' state, and blocks downstream activation of the MAPK pathway (RAF / MEK / ERK) and the PI3K / AKT pathway. Tumor cells that depend on mutant KRAS signaling for proliferation arrest and undergo apoptosis. Because the covalent bond requires the cysteine specifically, adagrasib is exquisitely selective for KRAS G12C — it does not target wild-type KRAS or other KRAS subtypes (G12D, G12V, G13D, Q61).
Class context: Adagrasib is the second FDA-approved KRAS G12C inhibitor (after sotorasib / Lumakras, Amgen, May 2021). The KRAS G12C class also includes the investigational divarasib (GDC-6036, Genentech), olomorasib (LY3537982, Eli Lilly), garsorasib (D-1553, InventisBio), glecirasib (JAB-21822, Jacobio), and calderasib (MK-1084, Merck). Adjacent investigational classes include KRAS G12D inhibitors (zoldonrasib RMC-9805, MRTX1133, setidegrasib ASP3082 degrader, HRS-4642) for the larger pancreatic / CRC G12D population, and pan-RAS RAS(ON) inhibitors (daraxonrasib RMC-6236, Revolution Medicines) that bind the GTP-bound ON state across multiple KRAS isoforms simultaneously. See the KRAS Inhibitors mechanism hub for the cross-drug comparison.
Acquired resistance to KRAS G12C inhibitors — including adagrasib — is well-described and heterogeneous. Resistance mechanisms fall into three broad categories:
At progression on adagrasib, clinical options depend on the resistance pattern. Discuss repeat tumor biopsy or cfDNA testing and clinical-trial options with your oncologist.
What is Krazati (adagrasib)?
Krazati is the brand name for adagrasib (MRTX849), an oral KRAS G12C-selective covalent inhibitor originally developed by Mirati Therapeutics and now part of Bristol Myers Squibb (following the Oct 2023 BMS acquisition of Mirati). Adagrasib received FDA accelerated approval December 2022 for KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) after at least one prior systemic therapy, based on the KRYSTAL-1 Phase 2 cohort. A second FDA accelerated approval followed June 2024 for KRAS G12C-mutated metastatic colorectal cancer (CRC) in combination with cetuximab after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, based on KRYSTAL-1 and KRYSTAL-10 data. Adagrasib works by covalently binding cysteine-12 on the GDP-bound (inactive 'OFF') state of mutant KRAS G12C, locking the protein in the inactive state and blocking downstream MAPK / PI3K signaling that drives tumor-cell proliferation. Adagrasib is taken by mouth (600 mg twice daily). Detection of the KRAS G12C subtype specifically is required — other KRAS mutations (G12D, G12V, G13D, Q61) are not targeted by adagrasib.
Which patients is Krazati FDA-approved for?
Krazati (adagrasib) is FDA-approved in two settings, both requiring KRAS G12C-mutation confirmation on tumor tissue or ctDNA. First indication (NSCLC, December 2022, accelerated approval): adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer who have received at least one prior systemic therapy — adagrasib as monotherapy. Second indication (colorectal cancer, June 2024, accelerated approval): adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy — adagrasib in combination with cetuximab. KRAS G12C is detected in approximately 13% of NSCLC adenocarcinomas and approximately 3% of colorectal cancers, with smaller percentages in pancreatic, endometrial, and other tumor types. The KRAS subtype specifically matters: a patient whose tumor is KRAS-mutated but NOT G12C (e.g., G12D, G12V, G13D, Q61) is not eligible for adagrasib. Comprehensive KRAS mutation testing reporting the exact codon and substitution is needed before adagrasib eligibility can be established.
How is Krazati (adagrasib) different from Lumakras (sotorasib)?
Both Krazati (adagrasib, Bristol Myers Squibb) and Lumakras (sotorasib, Amgen) are KRAS G12C-selective covalent inhibitors that lock mutant KRAS G12C in the GDP-bound 'OFF' state, and both are FDA-approved for KRAS G12C-mutated NSCLC after at least one prior systemic therapy (sotorasib May 2021, adagrasib December 2022). Both are also FDA-approved for KRAS G12C metastatic colorectal cancer in combination with an anti-EGFR antibody — adagrasib + cetuximab (Jun 2024) and sotorasib + panitumumab (Jan 2025, based on CodeBreaK 300). The most clinically relevant difference is CNS penetration: adagrasib has documented intracranial activity in KRYSTAL-1 patients with NSCLC brain metastases, reflecting a more favorable blood-brain-barrier penetration profile than sotorasib. For patients with active or untreated brain metastases, the CNS-penetration data is a meaningful differentiator and the dedicated NCT06248606 trial is testing adagrasib + stereotactic radiosurgery for KRAS G12C NSCLC patients with untreated brain metastases. Other differences: dosing schedule (adagrasib 600 mg twice daily; sotorasib 960 mg once daily), QTc prolongation signal (adagrasib has a documented QTc-prolongation warning), and hepatotoxicity (both have liver-monitoring requirements; profiles differ). For patients in the eligibility window for both drugs, your oncologist should weigh CNS disease status, cardiac history (QTc baseline), liver function, and concurrent medications. Both are appropriate options — ask your oncologist about both.
What are the main side effects of Krazati?
The most common side effects in the KRYSTAL-1 and KRYSTAL-10 trials were gastrointestinal: diarrhea, nausea, and vomiting (reported in roughly half or more of patients all-grade, typically mild to moderate). Other common adverse events: fatigue, decreased appetite, AST / ALT elevation, hyponatremia, hypomagnesemia and other electrolyte abnormalities, and edema. Two adverse events have specific monitoring implications. First, QTc prolongation: adagrasib is associated with a documented QTc-prolongation signal in its FDA label — baseline and on-treatment ECG plus electrolyte (potassium, magnesium) monitoring are recommended, and concurrent QTc-prolonging medications should be reviewed and avoided where possible. This is distinct from sotorasib's adverse-event profile. Second, hepatotoxicity: AST / ALT elevations are common and severe hepatitis has been reported — liver function (AST, ALT, total bilirubin) monitoring at baseline and at routine intervals is required. Drug-drug interactions: adagrasib is a CYP3A4 substrate — strong CYP3A4 inhibitors (ketoconazole, clarithromycin, grapefruit juice) can increase exposure, and strong CYP3A4 inducers (rifampin, St. John's Wort) can decrease it. Adagrasib also inhibits / induces multiple CYP enzymes and is a P-glycoprotein inhibitor — review all concomitant medications with the oncology team and pharmacist.
What if my tumor develops resistance to Krazati?
Acquired resistance to Krazati (adagrasib) is well-described and includes both on-target and off-target mechanisms. On-target: secondary KRAS mutations — most notably Y96 in the switch-II pocket adjacent to the covalent cysteine, plus H95Q and other secondary mutations — that interfere with covalent binding. Switching to the other FDA-approved KRAS G12C inhibitor (sotorasib) is unlikely to overcome on-target Y96 resistance because cross-resistance is expected. Off-target / pathway-bypass: receptor tyrosine kinase (RTK) reactivation (EGFR, MET, FGFR, AXL, HER2), KRAS amplification, alternative KRAS alleles emerging (new G12V, G12D, Q61 clones), NF1 loss-of-function, BRAF / MAP2K1 mutations, and (rare) adeno-to-squamous lineage switching in NSCLC. Polyclonal resistance: cfDNA studies show multiple co-occurring resistance mechanisms in the same patient at progression — meaning no single second-line targeted strategy is universally effective. Clinical options at progression depend on the resistance pattern. Combination strategies under clinical investigation include adagrasib + SHP2 inhibitor, adagrasib + EGFR antibody (FDA-approved CRC backbone), adagrasib + checkpoint inhibitor (NCT06875310 1L KRYSTAL-12 + chemo, NCT06412198 CRC + cetuximab + cemiplimab), and pan-RAS RAS(ON) inhibitors (daraxonrasib RMC-6236) that may bypass on-target G12C-specific resistance by targeting the GTP-bound active state across multiple KRAS isoforms simultaneously. Discuss repeat tumor biopsy or cfDNA testing and clinical-trial options with your oncologist at progression.
Find Krazati and KRAS G12C Inhibitor Trials Matched to Your Situation
Use ClinTrialFinder's AI-powered matching to find Krazati (adagrasib) and other KRAS-targeted trials based on your specific cancer type, exact KRAS mutation, prior therapy history, and country.
Find Matching Trials