What Is Sotorasib (Lumakras)? FDA Approval, Licensing and Reimbursement in Türkiye

• FDA Approved: Yes (first approval date: May 28, 2021)
• Brand Name: Lumakras
• Active Ingredient: Sotorasib
• Route of Administration: Oral tablets
• Class: RAS GTPase inhibitor (KRAS G12C inhibitor)
• Category: Antineoplastic agent
• Manufacturer: Amgen Inc.
• Distribution in Türkiye: Licensed in Türkiye.

1. Non-Small Cell Lung Cancer (NSCLC): In adults with locally advanced or metastatic KRAS G12C-mutated disease who have received at least one systemic treatment.
2. Colorectal Cancer: With panitumumab (Vectibix) in adults with metastatic KRAS G12C-mutated disease previously treated with specified chemotherapies.

Lumakras is the first approved targeted cancer drug for the KRAS G12C mutation. It is used particularly in previously treated non-small cell lung cancer (NSCLC) and selected colorectal cancers. By inhibiting the mutated intracellular KRAS protein, it stops tumor-cell proliferation.

KRAS is a GTPase involved in intracellular signaling that normally controls cell growth and differentiation. The G12C mutation keeps it continuously “active,” resulting in uncontrolled cell growth and cancer.

1. Binds specifically to mutant KRAS G12C: Targets only the mutated G12C KRAS isoform rather than normal KRAS.
2. Inactivates the GTP-bound active form: KRAS binds GTP when active. Sotorasib prevents G12C-mutated KRAS from binding GTP, locking it in the “inactive” GDP form.
3. Blocks downstream signaling: KRAS activates growth pathways such as MAPK/ERK and PI3K. Blocking these pathways interrupts proliferation and survival signals.
4. Stops tumor-cell growth and triggers cell death: This inhibitory effect slows or completely stops tumor growth.

• September 21, 2020: Phase 1 findings for Amgen's investigational KRAS G12C inhibitor sotorasib were published in the New England Journal of Medicine.
• October 5, 2020: Amgen announced positive topline phase 2 findings for sotorasib in advanced non-small cell lung cancer.
• December 8, 2020: The FDA granted sotorasib Breakthrough Therapy designation for advanced/metastatic KRAS G12C-mutated non-small cell lung cancer.
• January 28, 2021: Amgen's investigational sotorasib demonstrated rapid, deep, and durable responses in previously treated advanced non-small cell lung cancer.
• February 16, 2021: The FDA granted sotorasib Priority Review for locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer.
• April 28, 2021: Amgen shared updated information on a dose-comparison study of Lumakras (sotorasib).
• May 28, 2021: The FDA approved Lumakras (sotorasib) for locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer.
• December 26, 2023: Amgen issued an update on legal proceedings and the approval status of Lumakras.
• January 17, 2025: The FDA approved Lumakras (sotorasib) + Vectibix (panitumumab) for chemotherapy-resistant metastatic KRAS G12C-mutated colorectal cancer.

Lumakras (sotorasib) was licensed by Türkiye's Ministry of Health on October 28, 2022.

📋 Therapeutic Indications

Lumakras is indicated for patients with a KRAS G12C mutation, unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC), an ECOG performance status of 0 or 1, and no active brain metastases, who have received at least one chemotherapy line and immunotherapy either with chemotherapy or alone.

1. Reimbursement Status

• The Social Security Institution (SGK) currently does not reimburse Lumakras.

💵 Price Information

Current price: The retail price per box of Lumakras is 257952.14 TL .

1. Development of New Mutations Beyond KRAS G12C (On-Target Resistance): Tumor cells may develop new KRAS mutations that alter the sotorasib-binding site. Mutations such as KRAS Y96D and H95Q/R may reduce or completely block its effect. These “secondary mutations” change the target receptor's structure.
2. Activation of Alternative RAS Pathways (Off-Target Resistance): Tumor cells may activate related proteins such as NRAS or HRAS instead of KRAS, allowing signaling to continue through a different RAS protein.
3. Reactivation of Downstream Pathways: Despite KRAS inhibition, MAPK (MEK/ERK) or PI3K/AKT/mTOR signaling may be reactivated by other mutations or mechanisms, allowing continued growth.
4. Engagement of Bypass Pathways: Growth-factor receptors such as EGFR, MET, FGFR, and HER2 may sustain growth by bypassing KRAS. EGFR activation is a particularly important resistance mechanism in colorectal cancer.
5. Phenotypic Changes / Tumor Plasticity: Some cells may switch to another subtype, such as a mesenchymal phenotype, becoming less sensitive to the drug. This is also described as “adaptive resistance.”

Absorption: Taken orally. Bioavailability is approximately 37%, and maximum plasma levels (Tmax) are reached in approximately 1 hour. A fatty meal can substantially increase sotorasib plasma levels. It may be taken with or without food, although taking it with food may be preferred.

Distribution: The volume of distribution (Vd) is approximately 211 L, indicating extensive tissue distribution. Plasma protein binding is approximately 89%, meaning much of the circulating drug is protein-bound.

Metabolism: The liver is the main site of metabolism, primarily through CYP3A4. Glucuronidation (UGT1A1) and hydrolysis also contribute.

Elimination: The elimination half-life (t1/2) is approximately 5 hours, supporting once-daily use. Excretion is mainly in feces (approximately 74%), with approximately 6% in urine. Most excreted drug is unchanged active ingredient.

1. KRAS G12C-Mutated Non-Small Cell Lung Cancer

• Recommended dose: 960 mg / day (8 tablets of 120 mg)
• Treatment duration: Until disease progression or intolerable toxicity.
• Administration: Take 1 time daily, swallowing the tablets whole without chewing. They may be taken with or without food, preferably at the same time each day.

2. KRAS G12C-Mutated Metastatic Colorectal Cancer

• Combination: Given as Lumakras + panitumumab (Vectibix).
• Sotorasib dose: 960 mg / day (oral, as with monotherapy).
• Panitumumab dose: 6 mg/kg IV every 14 days (standard regimen).
• Clinical note: Used in patients previously treated with at least two chemotherapy lines. The combination is preferred to prevent resistance by bypassing EGFR signaling.

Drug Interaction Parameters:

• Lumakras is mainly metabolized by CYP3A4. Strong CYP3A4 inducers such as rifampin may lower blood levels and reduce efficacy. Strong CYP3A4 inhibitors such as ketoconazole may increase levels and the risk of adverse reactions. Concurrent use with these agents should be avoided.
• Sotorasib absorption is sensitive to gastric pH. Acid-suppressing drugs, including proton pump inhibitors such as omeprazole and H2 receptor antagonists such as famotidine, may reduce absorption and efficacy. If essential, they should be given hours before or after Lumakras.
• Antacids containing aluminum or magnesium may briefly increase gastric pH and reduce absorption. At least 4 hours should separate antacids and sotorasib.
• As a substrate of P-glycoprotein (P-gp) and BCRP transporters, it may interact with drugs affecting these transporters. It may also inhibit OATP1B1/3, increasing blood levels of statins such as atorvastatin and rosuvastatin and raising muscle-toxicity risk.

Important Clinical Warnings:

• Mutation Confirmation: Lumakras works only in tumors with a KRAS G12C mutation. Its presence must be confirmed by molecular testing before treatment.
• Monitoring for Hepatotoxicity: Sotorasib can cause liver injury. AST, ALT, and bilirubin should be checked regularly during treatment. Severe enzyme elevations may require treatment interruption or dose reduction.
• Risk of Pneumonitis: Rarely, it may cause interstitial lung disease or drug-related pneumonia. New shortness of breath, dry cough, or chest imaging changes require treatment discontinuation and appropriate medical management.
• Gastrointestinal Symptoms: Mild to moderate diarrhea, nausea, vomiting, and abdominal pain are common. Severe cases require hydration and supportive care.
• Pregnancy and Breastfeeding: It may have teratogenic effects during pregnancy. Women of reproductive age should use effective contraception during and after treatment. Use during breastfeeding is not recommended.
• Kidney and Liver Impairment: No dose adjustment is needed in mild to moderate kidney impairment. Pharmacokinetics may change in severe liver disease, requiring close monitoring and follow-up.
• Regular Use: Taken 1 time daily without missed doses. In overdose, the patient should be monitored closely and supportive treatment provided.

Adverse reactions and frequencies observed in clinical trials of sotorasib are: