Overview
11 DESCRIPTION Adagrasib is an irreversible inhibitor of KRAS G12C and belongs to the RAS GTPase family. The molecular formula is C 32 H 35 ClFN 7 O 2 and the molecular weight is 604.1 g/mol. The chemical name is {(2 S )-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2 S )-1-methylpyrrolidin-2-yl]- methoxy}-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl}acetonitrile.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibited tumor cell growth and viability in cells harboring KRAS G12C mutations and resulted in tumor regression in KRAS G12C-mutated tumor xenograft models with minimal off-target activity. Adagrasib in combination with cetuximab had increased antitumor activity in some cell line-derived and patient-derived KRAS G12C-mutant CRC tumor xenograft models compared to adagrasib or cetuximab alone. 12.
Indications
- 1 INDICATIONS AND USAGE KRAZATI is an inhibitor of the RAS GTPase family indicated for: Non-small cell lung cancer (NSCLC)* • As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. ( 1.1 ) Colorectal cancer (CRC)* • In combination with cetuximab, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-,...
Common Doses
- 600 mg
- 400 mg
Dosage
2 DOSAGE AND ADMINISTRATION • Recommended dosage as a single agent for NSCLC and in combination with cetuximab for CRC: 600 mg orally twice daily. ( 2.2 ) • Swallow tablets whole with or without food. ( 2.2 ) 2.1 Patient Selection Non-Small Cell Lung Cancer Select patients for treatment of locally advanced or metastatic NSCLC with KRAZATI based on the presence of KRAS G12C mutation in plasma or tumor specimens [see Clinical Studies (14.1) ] . If no mutation is detected in a plasma specimen, test tumor tissue.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ] • QTc Interval Prolongation [see Warnings and Precautions (5.2) ] • Hepatotoxicity [see Warnings and Precautions (5.3) ] • Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.4) ] • Single agent use in NCSLC: The most common adverse reactions (≥ 25%) were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased...
Interactions
- 7 DRUG INTERACTIONS See full prescribing information for clinically significant drug interactions with KRAZATI. ( 7 ) • Strong CYP3A4 Inducers : Avoid concomitant use. ( 7.1 ) • Strong CYP3A4 Inhibitors : Avoid concomitant use until adagrasib concentrations have reached steady state. ( 7.1 ) • Sensitive CYP3A4 Substrates : Avoid concomitant use with sensitive CYP3A4 substrates. ( 7.2 ) • 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...