According to the American Cancer Society, non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 80-85% of all cases worldwide. [1] The main subtypes of this type of lung cancer are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Although these subtypes start from different types of lung cells, they are grouped together as NSCLC because their treatment and prognoses are often very similar.

Genes responsible that ‘messages’ between cells are transmitted accurately include the RAS family of genes, KRAS, NRAS, and HRAS. Grouped together, these genes are part of the MAPK/ERK signaling pathway and encode proteins that have a pivotal cytoplasmic role in cell signaling. When these genes are mutated, cells grow uncontrollably and evade death signals. Mutations can also make cells resistant to some available cancer therapies.

The KRAS mutation was one of the first oncogenes discovered. It is also the most commonly mutated oncogene. Overall, cancers stemming from RAS mutations account for nearly a quarter of all human cancers and contribute to 1 million deaths per year worldwide. Among the RAS family of oncogenes, KRAS gene mutations are the most common, making up 85% of all RAS mutations.

Unfortunately, efforts to produce direct inhibitors of KRAS have largely failed, earning the member of the RAS gene family the title of “undruggable.”

However, drug developers have, in recent years, been successful in developing and producing subtype-specific inhibitors. As a result, several KRASG12C inhibitors have reached clinical trials, including adagrasib (MRTX849; Mirati Therapeutics) and sotorasib (Amgen), which have shown early evidence of efficacy in patients.

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Most common KRAS mutation
KRAS G12C is the most common KRAS mutation in NSCLC [2][]3] This mutation is a biomarker of poor prognosis in patients diagnosed with NSCLC, which may be improved by G12C-specific inhibitors [4]

The KRAS G12C mutation occurs in 13% of patients diagnosed with non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. The mutation is generally found in smokers. [4][5]

To date, no therapies for targeting KRAS mutations in cancer have been approved. Sotorasib, an investigational small molecule that selectively and irreversibly targets KRASG12C, is being developed by Amgen for the treatment of advanced or metastatic NSCLC in this patient population.

In an OpEd, published in the New England Journal of Medicine, Patricia M. LoRusso, D.O., and Judith S. Sebolt-Leopold, Ph.D, write that the overall survival among patients with advanced-stage KRASG12C NSCLC or colorectal cancer is approximately 1 to 2 years.

Four decades of research
In their article, published in the September 24, 2020 edition of the journal, the authors highlight how this startling statistic has fueled nearly four decades of research dedicated to the search for a KRAS-targeted drug.

However, these challenges in cancer research have resulted in the development of sotorasib, the first KRASG12C inhibitor to enter the clinic.[8]

CodeBreaK100
The investigational drug is being studied in the broadest clinical program exploring 10 combinations with global sites spanning four continents. In just over two years, the sotorasib clinical trial program has also established the deepest clinical data set with nearly 700 patients studied across 13 tumor types, bringing hope to patients.

The development program consists of multiple clinical trials, including the CodeBreak100 trial program, the first Phase I and II, first-in-human, open-label multicenter studies.

These trials enrolled patients with KRAS G12C-mutant solid tumors. To be eligible, patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of the disease. The primary endpoint for the Phase II study was centrally assessed objective response rate. The Phase II trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline. The Phase 2 trial in colorectal cancer is fully enrolled and topline results are expected in 2021.

A global Phase III randomized active-controlled study comparing sotorasib to docetaxel in patients with KRAS G12C-mutated NSCLC (CodeBreaK 200) is currently recruiting.

The drug is also studied in more than 10 Phase 1b combination studies across various advanced solid tumors (CodeBreaK 101) open for enrollment.

In patients with heavily pretreated advanced solid tumors harboring the KRASG12C mutation, the results from the CodeBreaK100 trial demonstrated that sotorasib showed encouraging, durable, anticancer activity with a positive benefit-risk profile,

Eligible patients participating in the trial received sotorasib orally once daily. The primary endpoint was safety. Key secondary endpoints were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

In the study, treatment with sotorasib demonstrated durable anticancer activity] The study results were presented at the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer (WCLC) Presidential Symposium on Friday, January 29, 2021.

Breakthrough Therapy Designation
Based on the preliminary trial results, the investigational drug was granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA).

The designation is for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy. This is the first BTD submission for Amgen in China, as well as the first under Amgen’s strategic collaboration with BeiGene.

“Given that Breakthrough Therapy Designation is a new pathway in China, we are pleased to receive this designation for sotorasib,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen.

“This designation underscores the importance of sotorasib and we look forward to working with regulatory authorities in China to bring the first potential targeted therapy to NSCLC patients with the KRAS G12C mutation.”

The Breakthrough Therapy Designation was supported by the positive CodeBreaK 100 Phase II results in patients with advanced NSCLC whose cancer had progressed despite prior treatment with chemotherapy and/or immunotherapy.

Expedite the development
The NMPA’s BTD process is designed to expedite the development and review of therapies that are intended for the prevention or treatment of serious life-threatening diseases for which there is no existing treatment and where preliminary evidence indicates advantages of the therapy over available treatment options. [7] This designation shows the potential for sotorasib to become the first targeted treatment available in China for KRAS G12C-mutated NSCLC.

Clinical trials
A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreak 100) – NCT03600883 [Clinical trial]

References
[1] What is Lung cancer? American Cancer Society. Online. last accessed on January 2021.
[2] Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018 Aug 9;3(15):e120858. doi: 10.1172/jci.insight.120858. PMID: 30089719; PMCID: PMC6129126.
[3] Arbour KC, Jordan E, Kim HR, Dienstag J, Yu HA, Sanchez-Vega F, Lito P, Berger M, Solit DB, Hellmann M, Kris MG, Rudin CM, Ni A, Arcila M, Ladanyi M, Riely GJ. Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2018 Jan 15;24(2):334-340. doi: 10.1158/1078-0432.CCR-17-1841. Epub 2017 Oct 31. PMID: 29089357; PMCID: PMC5771996.
[4] Liu SY, Sun H, Zhou JY, Jie GL, Xie Z, Shao Y, Zhang X, Ye JY, Chen CX, Zhang XC, Zhou Q, Yang JJ, Wu YL. Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients. Biomark Res. 2020 Jun 25;8:22. doi: 10.1186/s40364-020-00199-z. PMID: 32607238; PMCID: PMC7318746.
[5] Loong, et al. Transl Lung Cancer Res. 2020 Oct; 9(5): 1759–1769.
[6] AMGEN, 2020. [On file]
[7] China Drug Registration Regulation [Article]
[8] Kim D, Xue JY, Lito P. Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients. Cell. 2020 Nov 12;183(4):850-859. doi: 10.1016/j.cell.2020.09.044. Epub 2020 Oct 15. PMID: 33065029; PMCID: PMC7669705.

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