Sotorasib target analysis for cancer and global drug purchase price guide

What kind of medicine is sotolaxib? KRAS G12C抑制领域的首个里程碑

Sotorasib (R&D code AMG 510, trade name LUMAKRAS) was developed by the American company Amgen and is the world's first targeted small molecule drug approved for the treatment of KRAS G12C mutated tumors.这类突变长期以来被认为是“不可成药”的顽固靶点。索托拉西布的问世，不仅标志着靶向治疗进入KRAS新时代，也为部分无有效治疗选项的患者带来了全新希望。

KRAS G12C mutations are mainly found in solid tumors such as non-small cell lung cancer (NSCLC), colorectal cancer (mCRC), and pancreatic cancer, and are especially more common in lung adenocarcinoma in smokers. It keeps the KRAS protein in an active state, activates the MAPK signaling pathway, and promotes cell proliferation and cancer progression.

Scope of indications for sotoraxib:FDA has identified two major categories of tumor groups

1. KRAS G12C mutated non-small cell lung cancer (NSCLC)

According to the 2021 FDA approval results, LUMAKRAS is approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer carrying KRAS G12C mutations who have disease progression after at least one systemic therapy. As an oral targeted therapy, sotoracib provides an accurate alternative to chemotherapy and immunotherapy for these advanced patients.

2. KRAS G12C mutated metastatic colorectal cancer (mCRC)

In 2023, the FDA further approved sotoracib combined with panitumumab (anti-EGFR monoclonal antibody) for patients with KRAS G12C mutated metastatic colorectal cancer (mCRC) who have progressed after receiving treatment with fluoropyrimidine, oxaliplatin, and irinotecan.该联合方案基于临床试验CodeBreaK 101的积极结果，显著提升了缓解率，成为结直肠癌精准治疗的重要里程碑。

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用法用量与用药建议：每日一次，空腹状态下给药

The recommended oral dosage of sotoraxib is once daily,960mg，建议在空腹状态下服用，即服药前2小时或服药后1小时内不进食。 This dose has been proven to have good tolerability and efficacy in clinical trials. However, if intolerable adverse reactions occur (such as elevated liver enzymes, diarrhea, vomiting, etc.), dose adjustment can be considered. Common dose reduction steps are 720mg, 480mg or 240mg.在临床实践中，需监测肝功能、肾功能及常规血象，以便及时评估是否需要减量或暂时停药。

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创新机制解析：靶向不可成药的KRAS G12C突变位点

As a covalent and irreversible type of KRAS G12C inhibitor, sotoracib has a mechanism of action that is different from traditional pan-inhibitory RAS regulatory pathway drugs. Sotorasiibby selectively bindingG12C mutated cysteine u200bu200bresidues, locks the KRAS protein in its inactive GDP-binding state, thereby inhibiting its continued activation of the downstream MAPK pathway and achieving the purpose of inhibiting tumor cell proliferation.相比于MEK或RAF抑制剂，索托拉西布因其靶点更精确，副作用相对可控。此外，其不依赖T细胞免疫激活路径，亦可与免疫检查点抑制剂联合使用，进一步扩大其治疗潜力。

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索托拉西布在临床实践中的疗效表现

According to CodeBreaK 100 study data, sotoracib has shown significant efficacy in KRAS G12C mutated advanced non-small cell lung cancer, with a median progression-free survival (PFS) of 6.8 months, an overall survival (OS) of approximately 12.5 months, and an objective response rate of 37.1%. Although some patients may develop resistance within months after taking the drug, researchers have begun to develop second-generation KRAS G12C inhibitors and combination regimens (such as in combination with EGFR or SHR inhibitors) to overcome the resistance mechanism.

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索托拉西布价格对比：原研药与仿制药的价格差异显著

目前索托拉西布原研药在中国大陆尚未上市，因此尚未进入医保目录，也无正规药房销售渠道。 In Hong Kong, China, Lumakras is already on the market. The specification is 120mg*240 tablets and the price is about 80,000 yuan, but the price will fluctuate with the exchange rate.在欧洲市场，同等规格药品价格在4万人民币左右，远低于香港市场售价。

For patients with limited financial capacity, they may also consider purchasing the generic version from Lucius Pharmaceutical Factory in Laos. The drug consists of 120 mg x 56 tablets of sotorasibu, and the price ranges from about 1,000 to 2,000 yuan. The active ingredients of the generic drug will be basically the same as the original drug. However, the purchase of generic drugs in some areas involves drug import and export policy restrictions. Patients may choose channels with legal overseas medical purchase qualifications and use them rationally under the guidance of specialists.

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Interpretation of the original drug market and the legality of generic drugs

The original research of sotorasibu was developed by the American company Amgen (Amgen). It has complete patent protection and FDA/EMA approval qualifications and is widely used in the United States, the European Union, Japan and other places. Sales have also been registered in Hong Kong and Taiwan. Since mainland China has not yet completed the registration application, patients can only purchase drugs "at their own expense and cross-border" through Hong Kong and other places. Under the premise of legal compliance, third-party overseas pharmacies may provide a certain degree of drug source protection, such as the Yaode official website.

As for generic drugs, for example, the versions produced in countries such as Laos and India are currently mostly drugs that have not been approved by the China Food and Drug Administration, but they are legally registered generics in these countries. Although the price is low, its clinical data support is limited, so you should choose carefully after fully understanding the source and risks of the drug.

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The future development direction of sotorasiib: the path of exploration from single drug to combination therapy

In order to deal with the possible resistance mechanisms that may arise after sotorasiib is used as a single agent, researchers are actively exploring its combination treatment strategy. Includes:

In combination with immune checkpoint inhibitors (such as pembrolizumab)

In combination withEGFR inhibitors (especially suitable for mCRC)

In combination withSHR or MEK inhibitors (used in various solid tumors)

In addition,Amgen is also advancing the development of second-generation KRAS inhibitors and deploying a wider range of RAS family mutation targets, such as G12D and G13C, to provide patients with more precise treatment options.

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Summary:Sotorasibuleads a new era of KRAS targeted drugs, still waiting for domestic launch

The advent of sotorasiib marks a major breakthrough in the treatment of KRAS G12C mutant tumors. Its unique mechanism and clinical data have brought new hope to many late-stage patients. However, because it has not yet been launched in mainland China, the drug purchase cost is high and it cannot be included in medical insurance reimbursement. It is urgent to speed up the domestic marketing approval and medical insurance negotiation process. At the same time, although the price advantage of generic drugs is obvious, issues of efficacy and compliance cannot be ignored. In the future, with the advent of more KRAS-targeted drugs and the in-depth development of combination treatment strategies, patients with KRAS mutations are expected to see longer-term survival benefits.

References:

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-sotorasib-kras-g12c-mutated-non-small-cell-lung-cancer

https://www.amgen.com/products/lumakras

https://www.nejm.org/doi/full/10.1056/NEJMoa2103695

https://www.ema.europa.eu/en/medicines/human/EPAR/lumykras