Sotorasib (AMG-510) – the world's first targeted drug specifically targeting KRAS mutations

Lung cancer is one of the most common malignant tumors in the world, and it is also the disease
with the highest incidence and mortality among malignant tumors in China.
More than 80% of all lung cancers are non-small cell lung cancer (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, which have the characteristics of
slow growth and division, late spread and metastasis.
KRAS (Kirsten rat sarcoma virus oncogene homology) mutation is one of the most common mutations (about 25%) in non-small cell lung cancer.

What is the KRAS gene?

The KRAS gene encodes uridine triphephatase (GTPase), an enzyme that normally acts as a molecular switch that regulates signal transduction by coupling the cell membrane growth factor receptor to intracellular signaling pathways and transcription factors
.
When KRAS is mutated, the intrinsic activity of GTPase is destroyed, and the active guanosine triphosphate (GTP) is converted to inactive guanosine diphosphate (GDP), which is involved in the growth and survival
of tumor cells.
In addition, KRAS mutations are often associated
with targeted therapy resistance and poor prognosis in tumor patients.

Among them, KRAS G12C is a specific KRAS submutation, which is the most common type of KRAS mutation (41%), which may lead to resistance to a variety of targeted drugs including gefitinib, erlotinib, crizotinib
, etc.
KRAS G12C mutations occur not only in non-small cell lung cancer (13%), but also in colorectal cancer (3%) and other solid tumor patients
.

The treatment of KRAS mutations is not ideal

Although KRAS G12C mutations are common in patients with non-small cell lung cancer (one in eight patients with non-small cell lung cancer is a KRAS G12C mutation), treatment options are limited and chemotherapy remains the mainstay of
treatment.
After first-line treatment failure, there are not many
follow-up treatment options.

The world's first targeted drug against KRAS gene mutations

Turn things around

On May 28, 2021, the US FDA accelerated the approval of Sotorasib (trade name: Lumakras, drug code: AMG-510) developed by Amgen for the treatment of patients with non-small cell lung cancer (NSCLC) with KRAS G12C mutation, who have received at least one systemic therapy
.
The drug is the first KRAS-targeted therapy approved after nearly 40 years of research and the only targeted drug
approved for the treatment of locally advanced or metastatic non-small cell lung cancer patients with KRAS G12C mutations.

Applicable people

For the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer who have been tested to have a KRAS G12C mutation and who have received at least one prior systemic therapy
.

Clinical trial data:

(1) Sotolasib's accelerated approval by the FDA is based on the results of a Phase I/II clinical study based
on CodeBreaK 100.

(2) Sotoraxib was approved in the European Union for a Phase II clinical trial study
based on CodeBreaK 100.

Mechanism of action

Sotorasib specifically and irreversibly inhibits KRAS G12C, blocking KRAS signaling, inhibiting cell growth and promoting apoptosis
only in KRAS G12C tumor cell lines.
Moreover, Sotolasib's inhibition of KRAS G12C works
both in vivo and in vitro.

Method of use and dosage

Recommended Dosage:

How to Use:

Note:

Adverse reactions

Most common adverse effects (≥20%)

Diarrhea, musculoskeletal pain, nausea, fatigue, liver toxicity, and cough
.

The most common abnormal laboratory tests (≥25%)

Lymphopenia, decreased hemoglobin, elevated aspartate aminotransferase, elevated alanine aminotransferase, decreased calcium, elevated alkaline phosphatase, increased proteinuria, and decreased sodium
.

Precautions

1.
Liver toxicity

Lumakras can cause hepatotoxicity
.
Monitor liver function (ALT, AST, and total bilirubin) every 3 weeks for the first three months after initiation, followed by monthly monitoring or more frequently in patients with elevated aminotransferases and/or bilirubin as clinically
indicated.
Depending on the severity of the adverse reaction, the dose is suspended, reduced or permanently discontinued Lumakras
.

2.
Interstitial lung disease (ILD)/pneumonia

Lumakras can cause severe ILD/pneumonia
.
Monitor patients for new or worsening pulmonary symptoms (e.
g.
, dyspnea, cough, fever, etc.
); Discontinue Lumakras
immediately in patients with suspected ILD/pneumonia and permanently if no other underlying cause of ILD/pneumonia is identified.

Drug interactions

1.
Acid suppressants

Avoid combination with proton pump inhibitors (PPIs) and H2 receptor antagonists
.
If antacids cannot be avoided, take Lumakras
4 hours before or 10 hours after topical antacid suppressant use.

2.
Powerful YP3A4 inducer

Avoid combination with potent YP3A4 inducers
.

3.
CYP3A4 substrate

Avoid combination with CYP3A4 substrates
.
Minimal concentration changes may cause the "fifth therapy" to fail
.
If the combination cannot be avoided, adjust the substrate dose
according to the prescribing information.

4.
P-gp substrate

Avoid combination with P-gp substrates
.
Minimal changes in concentration can cause severe toxicity
.
If the combination cannot be avoided, reduce the substrate dose
according to the prescribing information.

Use by specific groups of people

Lactation: Breastfeeding
is not recommended.

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