Sotorasib: first KRAS G12C inhibitor in NSCLC

Sotorasib (brand name Lumykras in the EU, Lumakras in the USA) is the first targeted substance against the KRAS G12C mutation. KRAS belongs to the family of RAS proto-oncogenes and is one of the most frequently mutated genes in solid tumours. The point mutation G12C, in which glycine at position 12 is mutated to cysteine, is found in about 13 % of non-small cell lung cancers (NSCLC) and in some colorectal cancers.

Until the approval of sotorasib, KRAS was long considered undruggable, that is, not accessible to classic inhibitors. Only the discovery of a reactive pocket at the mutated G12C position, accessible only in the GDP-bound inactive form of KRAS, enabled the development of covalent inhibitors. Sotorasib was approved in 2021 in the USA and 2022 in the EU for pretreated NSCLC with KRAS G12C mutation.

Mechanism of action

KRAS works as a molecular switch between an active (GTP-bound) and inactive (GDP-bound) form. In the active form KRAS activates downstream pathways such as RAF, MEK and ERK, which control cell growth and proliferation. Mutations like G12C keep KRAS predominantly in the active form, leading to uncontrolled tumour growth.

Sotorasib uses the unique cysteine side chain of the G12C mutation as a target. The substance binds covalently and irreversibly to this cysteine in the GDP-bound form of KRAS. KRAS is thereby held in the inactive form, the switch into the active form is no longer possible and the downstream signalling cascade is interrupted.

Clinically, the phase 2 study CodeBreaK 100 showed a tumour response rate of about 37 % and a median progression-free survival of about 6.8 months in pretreated KRAS G12C positive NSCLC.

Indications

• Pretreated locally advanced or metastatic non-small cell lung cancer (NSCLC): with proven KRAS G12C mutation, after at least one prior systemic therapy
• Colorectal cancer: in combination with panitumumab approved in the USA, under EU evaluation or in trials
• Other KRAS G12C positive solid tumours: trials are ongoing in pancreatic cancer, endometrial cancer, cholangiocarcinoma

A prerequisite is always the proof of the KRAS G12C mutation through validated molecular diagnostics (NGS or PCR-based tests).

Dosing and administration

Standard dose: 960 mg once daily orally, continuously, until disease progression or unacceptable toxicity.

The dose of 960 mg corresponds to 8 tablets of 120 mg each, taken at the same time of day. Take regardless of meals. The tablets can be swallowed or dispersed in water, which facilitates intake when there are swallowing difficulties.

Missed dose: if less than 6 hours remain until the next regular dose, skip; otherwise take.

Dose reductions: for specific side effects (hepatotoxicity, pneumonitis, gastrointestinal complaints), the dose is reduced stepwise to 480 or 240 mg. With recurrence, possibly stop therapy.

Side effects

Very common: diarrhoea, nausea, vomiting, abdominal pain, fatigue, rise in ALT and AST, hepatotoxicity, cough.

Common: anaemia, peripheral oedema, pneumonitis (interstitial lung disease), increased alkaline phosphatase, hyponatraemia, raised bilirubin, respiratory tract infections.

Uncommon: acute hepatitis up to liver failure, severe pneumonitis requiring therapy interruption, QT prolongation.

Rare: Stevens Johnson syndrome, severe skin reactions.

Hepatotoxicity:

• More common with prior immune checkpoint inhibitor therapy
• Close monitoring of liver values (AST, ALT, ALP, bilirubin) every 1 to 3 weeks during the first 3 months, then monthly
• With significant rise, interrupt therapy, dose reduction or steroid therapy

Pneumonitis:

• Symptoms: new cough, dyspnoea, fever
• Imaging: high-resolution CT in case of suspicion
• Treatment: pause, steroids, possibly permanent discontinuation

Interactions

Sotorasib is a substrate of CYP3A4, P-glycoprotein, BCRP and an inhibitor of CYP3A4 and P-gp.

• Strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, ritonavir): raised levels, caution or dose reduction
• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): falling levels, avoid combination if possible
• Acid-suppressive substances (PPI, H2 blockers, antacids): reduced absorption of sotorasib, antacids 4-hour interval, avoid PPIs if possible or replace with famotidine taken with a time interval
• P-gp substrates with narrow therapeutic index (digoxin, dabigatran): raised levels, careful monitoring
• Other CYP3A4 substrates: sotorasib induces CYP3A4 weakly; levels of e.g. midazolam, oral contraceptives or certain statins can fall
• QT-prolonging substances: additive QT prolongation, ECG checks

Special considerations

Pregnancy: contraindicated, teratogenic based on animal studies. Women of childbearing potential must use reliable contraception during therapy and for at least 7 days after the end of therapy.

Breastfeeding: not recommended.

Pretreatment with immune checkpoint inhibitors: hepatotoxicity is markedly more common; a time interval is recommended, ideally at least 6 weeks before starting sotorasib.

Pretherapy checks: molecular proof of the KRAS G12C mutation, liver values, lung status, ECG, pregnancy test.

Resistance development: secondary resistance often arises through point mutations in KRAS or activation of parallel signalling pathways. Trials investigate combinations with MEK inhibitors, EGFR inhibitors or immunotherapy.

Quality of life: sotorasib is an oral therapy delivered on an outpatient basis. Patients report acceptable tolerability and good integration into daily life, especially compared with classic chemotherapy.

Related substances

• Dasatinib, tyrosine kinase inhibitor in CML
• Sunitinib, multikinase inhibitor
• Regorafenib, multikinase inhibitor in colorectal cancer
• Fruquintinib, VEGFR TKI in colorectal cancer

Frequently asked questions

Sources

• EMA Lumykras (sotorasib) EPAR
• BfArM Federal Institute for Drugs and Medical Devices
• AWMF S3 lung cancer guideline
• Gelbe Liste sotorasib monograph