Introduction
Krazati (adagrasib) is an oral, small molecule kinase inhibitor specifically targeting KRAS G12C mutations. It represents a significant advancement in precision oncology for the treatment of certain advanced non-small cell lung cancers (NSCLC). Approved through the FDA's accelerated approval pathway in December 2022, Krazati offers a targeted therapeutic approach for patients with specific genetic alterations who have limited treatment options.
Mechanism of Action
Krazati functions as a covalent inhibitor that selectively and irreversibly binds to the cysteine residue of KRAS G12C mutant protein. This binding locks KRAS in its inactive GDP-bound state, preventing downstream signaling through the MAPK pathway (including RAF, MEK, and ERK). By inhibiting this oncogenic signaling cascade, Krazati reduces tumor cell proliferation and survival while potentially promoting apoptosis in KRAS G12C-mutant cancer cells.
Indications
Krazati is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.
Dosage and Administration
Standard dosing: 600 mg orally twice daily (approximately every 12 hours) with or without food Dose modifications:- For Grade 3 adverse reactions: Interrupt until resolves to Grade ≤1, then resume at 400 mg twice daily
- For recurrent Grade 3 or any Grade 4 adverse reactions: Permanently discontinue
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment (use caution in severe impairment)
- Hepatic impairment: No dosage adjustment recommended for mild impairment (not studied in moderate to severe impairment)
- Elderly patients: No specific dosage adjustment recommended
Pharmacokinetics
Absorption: Median Tmax is 6 hours; high-fat meal increases AUC by 36% and Cmax by 15% Distribution: Mean apparent volume of distribution is 278 L; protein binding is 93% Metabolism: Primarily metabolized via CYP3A4; also undergoes direct glucuronidation Elimination: Mean half-life is 23 hours; 75% excreted in feces (55% as unchanged drug) and 19% in urineContraindications
No absolute contraindications have been identified based on current clinical data. However, use is restricted to patients with confirmed KRAS G12C mutation.
Warnings and Precautions
Gastrointestinal toxicity: Severe nausea, vomiting, and diarrhea may occur; provide antiemetic and antidiarrheal prophylaxis QTc interval prolongation: Can cause dose-dependent QTc prolongation; monitor electrolytes and ECGs Hepatotoxicity: Drug-induced liver injury reported; monitor liver function tests regularly Interstitial lung disease/pneumonitis: Can be fatal; monitor for new or worsening respiratory symptoms Embryo-fetal toxicity: Can cause fetal harm; advise patients of reproductive potential to use effective contraceptionDrug Interactions
Strong CYP3A4 inhibitors: Avoid concomitant use (increases adagrasib exposure) Strong CYP3A4 inducers: Avoid concomitant use (decreases adagrasib exposure) CYP3A4 substrates: May increase exposure to sensitive substrates (monitor closely) P-gp substrates: May increase exposure to sensitive substrates QT-prolonging drugs: Avoid concomitant use with other drugs known to prolong QTcAdverse Effects
Most common (≥20%): Nausea (64%), diarrhea (58%), vomiting (53%), fatigue (47%), musculoskeletal pain (38%), hepatotoxicity (32%), renal impairment (32%), dyspnea (31%), edema (27%), decreased appetite (25%), cough (23%) Serious adverse reactions: Pneumonitis/ILD (3.8%), QT prolongation (2.1%), hepatotoxicity (1.6%)Monitoring Parameters
Baseline:- KRAS G12C mutation status confirmation
- Comprehensive metabolic panel (including liver and renal function)
- Electrolytes (potassium, magnesium, calcium)
- ECG with QTc measurement
- Pregnancy test for patients of reproductive potential
- Liver function tests every 3 weeks for first 3 months, then monthly
- Electrolytes prior to each dose for first month, then as clinically indicated
- ECG at Weeks 2, 4, and 8, and periodically thereafter
- Monitor for gastrointestinal toxicity, respiratory symptoms, and edema
- Tumor assessment every 6 weeks
Patient Education
- Take exactly as prescribed at approximately the same times each day
- Report any new or worsening symptoms immediately, especially nausea, vomiting, diarrhea, shortness of breath, or irregular heartbeat
- Use effective contraception during treatment and for 1 week after final dose
- Inform all healthcare providers about Krazati use before starting new medications
- Do not adjust dose or stop treatment without discussing with oncology team
- Maintain adequate hydration, especially if experiencing gastrointestinal side effects
- Regular monitoring through blood tests and ECGs is essential for safety
References
1. FDA Prescribing Information: KRAZATI® (adagrasib) tablets. December 2022. 2. Jänne PA, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022;387(2):120-131. 3. Ou SI, 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. 4. National Comprehensive Cancer Network (NCCN) Guidelines. Non-Small Cell Lung Cancer. Version 3.2023. 5. Hong DS, et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020;383(13):1207-1217. 6. ClinicalTrials.gov. Study of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation (KRYSTAL-1). NCT03785249.