Adagrasib

KRAZATI, as a single-agent, 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. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial.

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.

• Recommended dosage: 600 mg orally twice daily. • Swallow tablets whole with or without food. Patient Selection 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. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of a KRAS G12C mutation is available at: https://www.fda.gov/CompanionDiagnostics

None. None.

• Gastrointestinal Adverse Reactions: Monitor patients for diarrhea, nausea and vomiting and provide supportive care as needed. Withhold, reduce the dose or permanently discontinue based on severity. • QTc Interval Prolongation: Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Monitor ECG and electrolytes particularly potassium and magnesium, in patients at risk, and in patients taking medications known to prolong the QT interval. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue based on severity. • Hepatotoxicity: Monitor liver laboratory tests prior to the start of KRAZATI and monthly for 3 months after and as clinically indicated. Reduce the dose, withhold, or permanently discontinue based on severity.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Gastrointestinal Adverse Reactions • QTc Interval Prolongation • Hepatotoxicity • Interstitial Lung Disease (ILD)/Pneumonitis • The most common adverse reactions (≥ 25%) were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite. The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils and increased alkaline phosphatase.

See full prescribing information for clinically significant drug interactions with KRAZATI. • Strong CYP3A4 Inducers: Avoid concomitant use. • Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state. • 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.

Store tablets at room temperature, 20°C to 25°C (68°F to 77°F). Temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted.