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About KRAS G12C Heading
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WHAT TO KNOW

JUMP TO:

Poor prognosis ↓

Determining KRAS G12C status ↓

Continuous inhibition ↓

KRAZATI properties ↓

KRAS G12C: The Unmet Need

3 reasons KRAS G12C is a challenging mutation

1

KRAS G12C is a driver mutation with poor prognosis in advanced CRC1,2

Woman standing near water
Man standing near rocks
2

Continuous regeneration of KRAS G12C may require continuous inhibition in advanced CRC​3-5

3

Heavily pretreated patients need an option that may offer a response* to their KRAS G12C-mutated advanced CRC6

Man standing near rocks

*Based on the phase 1/2 KRYSTAL-1 trial; confirmatory trials remain ongoing.

Not actual patients.

KRAZATI is intentionally designed to meet the challenge of KRAS G12C

INCREASED ANTITUMOR ACTIVITY WHEN COMBINED WITH CETUXIMAB IN mCRC6,7

KRAZATI + cetuximab had increased antitumor activity in some KRAS G12C-mutated CRC models compared to KRAZATI or cetuximab alone.

LONGEST HALF-LIFE OF ANY APPROVED KRAS G12C INHIBITOR6

A ~24-hour half-life allowed drug levels to be maintained above a target threshold.†‡

IRREVERSIBLE INHIBITION6

KRAZATI covalently binds to the mutant cysteine in KRAS G12C and locks the protein in its inactive state, preventing downstream signaling without affecting wild-type KRAS protein.

OTHER PROPERTY:
CNS PENETRANT8-10

KRAZATI CSF/free plasma concentration ratio was consistent with other agents with known CNS penetration.

Krazati + cetuximab mechanism of action in CRC, illustration

†Clinical relevance of pharmacokinetic data is unknown. KRAZATI half-life is 23 hours.6
‡This is a target threshold in preclinical models; target exceeded at KRAZATI 600 mg BID.11

BID=twice-daily; CNS=central nervous system; CRC=colorectal cancer; CSF=cerebrospinal fluid; EGF=epidermal growth factor; EGFR=epidermal growth factor receptor; GDP=guanosine diphosphate; GTP=guanosine triphosphate; mCRC=metastatic colorectal cancer; OS=overall survival.

Learn how testing can help identify patients  →

References:

  1. Zhu G, Pei L, Xia H, et al. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer. 2021;20(1):143.
  2. Fakih M, Tu H, Hsu H, et al. Real-world study of characteristics and treatment outcomes among patients with KRAS p.G12C-mutated or other KRAS mutated metastatic colorectal cancer. Oncologist. 2022;27(8):663-674.
  3. Stites EC, Shaw AS. Quantitative systems pharmacology analysis of KRAS G12C covalent inhibitors. CPT Pharmacometrics Syst Pharmacol. 2018;7(5):342-351.
  4. Shukla S, Allam US, Ahsan A, et al. KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation. Neoplasia. 2014;16(2):115-128.
  5. Bergo MO, Gavino BJ, Hong C, et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J Clin Invest. 2004;113(4):539-550.
  6. KRAZATI®. Prescribing information. Princeton, NJ. Mirati Therapeutics, Inc., a Bristol Myers Squibb company; 2024.
  7. Hallin J, Calinisan A, Hargis L, et al. The anti-tumor activity of KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models. Cancer Res. 2020;80(16 Suppl):Abstract nr LB-098.
  8. Sabari JK, Velcheti V, Shimizu K, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRAS G12C-mutant non-small cell lung cancer. Clin Cancer Res. 2022;28(15):3318-3328.
  9. Colclough N, Chen K, Johnström P, et al. Preclinical comparison of the blood-brain barrier permeability of osimertinib with other EGFR TKIs. Clin Cancer Res. 2021;27(1):189-201.
  10. Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130-5140.
  11. Ou SI, Jänne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRASG12C solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530-2538.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

 

  • KRAZATI can cause severe gastrointestinal adverse reactions

  • Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity

QTc Interval Prolongation

 

  • KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death

  • Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation

  • Monitor ECGs and electrolytes, particularly potassium and magnesium, prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that are known to prolong the QT interval. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity

Hepatotoxicity

 

  • KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis

  • Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity

Interstitial Lung Disease/Pneumonitis

 

  • KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal

  • Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified

ADVERSE REACTIONS

 

  • Serious adverse reactions occurred in 30% of 94 patients who received adagrasib in combination with cetuximab. The most common adverse reactions in CRC patients (≥20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy

DRUG INTERACTIONS

 

  • Strong CYP3A4 Inducers: Avoid concomitant use.

  • Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state (after ~8 days).

  • Sensitive CYP3A4 Substrates: Avoid concomitant use with sensitive CYP3A4 substrates.

  • Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates: Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions.

  • Drugs That Prolong QT Interval: Avoid concomitant use with KRAZATI.

Please see Drug Interactions Section of the Full Prescribing Information for additional information.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential

 
  • Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential

Lactation

 
  • Advise not to breastfeed

Please see Full Prescribing Information.

 

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