Sotoxen

Approved Indications:

• Non-Small Cell Lung Cancer (NSCLC):
  Sotorasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy (e.g., chemotherapy or immune checkpoint inhibitors).

Off-label/Investigational Uses (Clinically Accepted):

• KRAS G12C-mutated Colorectal Cancer (CRC):
  Being explored as monotherapy or in combination with EGFR inhibitors in patients with advanced colorectal cancer harboring KRAS G12C mutation.
• Other Solid Tumors with KRAS G12C Mutation:
  Investigated in pancreatic, ovarian, endometrial, and gastrointestinal cancers where KRAS G12C mutations are detected.

Adults (Standard Regimen):

• Recommended Dose:
  960 mg orally once daily until disease progression or unacceptable toxicity.
• Route:
  Oral administration with or without food.
• Administration Instructions:
  Tablets should be swallowed whole; do not chew, crush, or split. Missed doses can be taken within 6 hours; otherwise, skip.

Renal Impairment:

• Mild to Moderate Impairment:
  No dose adjustment required.
• Severe Renal Impairment:
  Use with caution; insufficient data for adjustment recommendations.

Hepatic Impairment:

• Mild Impairment (Child-Pugh A):
  No dose adjustment needed.
• Moderate or Severe (Child-Pugh B/C):
  Use with caution; exposure may increase—monitor closely.

Pediatrics:
Safety and efficacy have not been established in patients under 18 years.

Elderly:
No specific dose adjustments required; monitor for tolerability.

Sotorasib is a KRAS G12C inhibitor. It binds covalently and irreversibly to the cysteine residue (C12) in the KRAS G12C mutant protein in its inactive GDP-bound form. This prevents the activation of KRAS signaling pathways (e.g., MAPK and PI3K), which are critical for cancer cell proliferation and survival. By locking KRAS in an inactive state, Sotorasib halts downstream oncogenic signaling and promotes apoptosis of tumor cells harboring this specific mutation.

• Absorption:
  Rapidly absorbed; peak plasma concentration (Tmax) occurs in 1–2 hours post-dose.
• Bioavailability:
  Absolute bioavailability is not fully established, but oral absorption is adequate for therapeutic effect.
• Distribution:
  Volume of distribution (Vd): 211 L. Highly protein-bound (89%).
• Metabolism:
  Metabolized mainly by CYP3A4, with contributions from non-CYP enzymes and glucuronidation (UGT1A1).
• Elimination:
• Half-life (t½): ~5 hours
• Excretion: Primarily via feces (~74%), and minor renal excretion (~6%).

• Pregnancy:
  There is no FDA-assigned pregnancy category. Based on animal studies, embryo-fetal toxicity is possible. Use only if clearly needed and benefits outweigh potential risks.
• Lactation:
  It is unknown if sotorasib is excreted in human milk. Due to potential harm to a nursing infant, breastfeeding is not recommended during treatment and for 1 week after the last dose.
• Contraception:
  Females of reproductive potential should use effective contraception during treatment and for 1 week after.

• Primary Class:
  Targeted Antineoplastic Agent
• Subclass:
  KRAS G12C Covalent Inhibitor (First-in-class)

• Known hypersensitivity to sotorasib or any of its components
• Coadministration with strong CYP3A4 inducers (e.g., rifampin), due to reduced efficacy
• Severe hepatic impairment (relative contraindication; safety not well-established)

• Hepatotoxicity:
  Monitor liver enzymes (ALT, AST) before and during therapy. Interrupt, reduce, or discontinue if Grade 3 or higher elevations occur.
• Interstitial Lung Disease (ILD) / Pneumonitis:
  Discontinue immediately if suspected; can be fatal.
• Gastrointestinal Toxicity:
  Diarrhea, nausea, and vomiting are common; ensure adequate hydration and consider antiemetics.
• QT Prolongation Risk:
  Caution in patients with existing QT prolongation or those on QT-prolonging drugs.
• Drug Resistance Monitoring:
  Resistance mutations (e.g., secondary KRAS mutations) may develop; molecular monitoring recommended.

Common Adverse Effects (≥10%):

• Gastrointestinal: Diarrhea, nausea, vomiting, constipation, abdominal pain
• Hepatic: Increased ALT/AST, bilirubin elevation
• Respiratory: Cough, dyspnea
• General: Fatigue, decreased appetite

Less Common / Serious:

• Pneumonitis / ILD
• Hepatotoxicity
• QT prolongation
• Hypersensitivity reactions

Timing:
Most side effects begin within the first few weeks of therapy. Hepatic monitoring is critical during the first 3 months.

• CYP3A4 Inducers (e.g., Rifampin, Phenytoin):
  May decrease sotorasib plasma levels—avoid coadministration.
• CYP3A4 Inhibitors:
  May increase systemic exposure—monitor for toxicity if necessary.
• P-gp and BCRP substrates (e.g., digoxin, rosuvastatin):
  Caution advised; sotorasib may increase exposure of these agents.
• Acid-Reducing Agents (e.g., PPIs, antacids):
  May reduce sotorasib absorption—separate administration by several hours or avoid if possible.
• Warfarin or DOACs:
  Monitor INR or bleeding risk due to possible metabolic interference.

• FDA Approval Status:
  Sotorasib received accelerated FDA approval in May 2021 for KRAS G12C-mutated NSCLC.
• EMA Conditional Authorization:
  European Medicines Agency has also granted conditional marketing authorization.
• Ongoing Trials:
  Combination regimens with EGFR inhibitors or immunotherapies are being investigated in colorectal and other KRAS G12C-mutant cancers.
• ASCO/NCCN Guidelines:
  Sotorasib is now included in NCCN guidelines for NSCLC with confirmed KRAS G12C mutations, typically after progression on standard therapies.

• Storage Temperature:
  Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity/Light:
  Keep in original bottle to protect from moisture and light.
• Handling Instructions:
  Do not crush or split tablets. Keep bottle tightly closed and out of reach of children.
• Shelf Life:
  Follow expiration as printed on the label; discard unused tablets post-expiry.