The first KRAS inhibitor received accelerated FDA approval today to treat non-small cell lung cancer

▎The content team editor of WuXi AppTec today, the US Food and Drug Administration announced that it has accelerated the approval of Lumakras (sotorasib) developed by Amgen for the treatment of non-small cell lung cancer (NSCLC) patients whose tumors carry the KRAS G12C mutation.

These patients have received at least one pre-systemic treatment.

This is the first anti-cancer therapy targeting specific KRAS gene mutations.

KRAS gene mutation is one of the most common oncogene mutations in cancer patients.

However, it is also a well-known "non-drugable" target, and Lumakras' approval represents a major milestone in the development of drugs for this target.

It is worth mentioning that Amgen and BeiGene have reached a cooperation and will jointly carry out the development of Lumakras in China.

The FDA's approval of Lumakras is based on the results of a subgroup of patients in the CodeBreaK 100 clinical trial.

This subgroup includes 124 patients with KRAS G12C mutation-positive NSCLC who have received immunotherapy and/or chemotherapy after disease progression.

The results of the trial showed that the overall response rate of patients treated with Lumakras at a dose of 960 mg was 36% (95% CI: 28-45), and the disease control rate reached 81% (95% CI: 73-87), with a median response rate.
The duration is 10 months.

The most common adverse reactions are diarrhea, musculoskeletal pain, nausea, fatigue, liver toxicity and cough.

Nine percent of patients had adverse reactions that led to the permanent discontinuation of Lumakras.

Lung cancer is one of the most common types of cancer in the world and the leading cause of cancer deaths.

KRAS gene mutations occur in approximately 25% of NSCLC patients, and 13% of patients carry KRAS G12C mutations.

Lumakras is a covalent inhibitor that specifically targets KRAS G12C mutants.
It locks KRAS in an inactive state by binding to KRAS G12C mutants, thereby irreversibly inhibiting the activity of KRAS.

It has been granted breakthrough therapy designation by the US FDA.

In China, sotorasib, jointly declared by Amgen and BeiGene, has also planned to be included in the breakthrough treatment category.

"For a long time, KRAS mutations have been difficult to target by drugs, representing a truly unmet need for patients with certain types of cancer," Dr.
Richard Pazdur, director of the U.
S.
FDA Center for Oncology Excellence and Acting Director of the U.
S.
FDA Center for Drug Evaluation and Research, Office of Oncology and Diseases Said, "Today's approval represents another major advancement in individualized therapy.

" The most common side effects of Lumakras include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.

Lumakras should be discontinued if the patient has symptoms of interstitial lung disease, and Lumakras should be permanently discontinued if the diagnosis of interstitial lung disease is made.

Before starting Lumakras and while using Lumakras, healthcare professionals should monitor the patient's liver function tests.

If the patient develops liver damage, Lumakras should be discontinued, the dose reduced, or the drug should be permanently discontinued.

When taking Lumakras, patients should avoid taking acid-lowering agents, drugs that induce or act as substrates for certain enzymes in the liver, and drugs that act as substrates for P-glycoprotein.

Image source: Reference materials [3] In addition to Lumakras, there are currently a number of KRAS inhibitors in clinical development.
Among them, adagrasib developed by Mirati Therapeutics has entered the critical clinical trial stage.
Data released in October 2020 show that it is in treatment A 96% disease control rate is achieved in NSCLC patients.

In addition, Boehringer Ingelheim, Lilly, Novartis and many other companies are also developing innovative therapies that directly target KRAS or KRAS signaling pathway targets.

Nearly 40 years ago, scientists discovered the relationship between KRAS gene mutations and cancer for the first time.
With the unremitting efforts of scientists and drug developers, we finally witnessed a milestone in breaking KRAS's "non-drugability".

We wish the development of more KRAS-targeted therapies go smoothly and benefit the majority of cancer patients.

Reference: [1] FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy.
Retrieved May 28, 2021, from https:// -therapy-for-lung-cancer-mutation-previously-considered-resistant-to-drug-therapy-301301797.
html[2] FDA Approves LUMAKRAS™ (Sotorasib), The First And Only Targeted Treatment For Patients With KRAS G12C-Mutated Locally Advanced Or Metastatic Non-Small Cell Lung Cancer.
Retrieved May 28, 2021, from https:// treatment-for-patients-with-kras-g12c-mutated-locally-advanced-or-metastatic-non-small-cell-lung-cancer-301301808.
html[3] Liu et al.
, (2019).
Targeting the untargetable KRAS in cancer therapy.
Acta Pharmaceutica Sinica B, https://doi.
org/10.
1016/j.
apsb.
2019.
03.
002 Note: This article aims to introduce the progress of medical and health research, not a treatment plan recommendation.

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