2021年9月1日 · In 2021, the U.S. Food and Drug Administration (FDA) accelerated the approval of sotorasib as the first KRAS-G12C blocking drug for the treatment of adult patients with NSCLC.

2021年11月15日 · Recently, there has been light on the horizon for one specific mutation, KRAS (G12C). With the discovery of a new allosteric site of KRAS (G12C), several irreversible covalently binding...

2021年6月4日 · Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of...

2020年9月20日 · We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was...

Analyzing amino acid-specific KRAS mutations in the three cancer types responsible for most KRAS mutations, the most common KRAS mutation in NSCLC adenocarcinoma subtype is KRAS G12C (glycine to cysteine) (33.4%), while the most common KRAS mutation in colon and rectal adenocarcinoma and pancreatic ductal adenocarcinoma is KRAS G12D (glycine to ...

2024年4月18日 · The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents—sotorasib and adagrasib.

The ongoing research into new KRAS G12C inhibitors and their mechanisms offers hope for overcoming these barriers and achieving more durable responses.

One such alteration in non-small cell lung cancer is the Kirsten Rat Sarcoma (KRAS) oncogene. KRAS mutations are the most common oncogenic driver in NSCLC, representing roughly 20–25% of cases. The mutation is almost exclusively detected in adenocarcinoma and is found among smokers 90% of the time.

Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRAS G12C has revolutionized the treatment of KRAS G12C-mutated NSCLC patients.

2022年7月4日 · Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD- (L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options.

2020年11月12日 · Recent advances in medicinal chemistry have established inhibitors targeting KRAS (G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers.

2022年3月23日 · KRAS G12C was most prevalent in patients with non–small-cell lung cancer, appendiceal, colorectal, tumor of unknown origin, small bowel, and pancreatic cancers. KRAS G12C tumors were genomically distinct from KRAS non-G12C tumors, including variations in STK11, KEAP1, and other gene frequencies.

2021年1月13日 · We studied the distribution of KRASG12C mutations in 32,138 patients with cancer across race (Asian, Black, and White) and sex and in 10 cancer types (Table S1.1 in Supplementary Appendix 2). A...

2024年12月11日 · Here, we show that MRTX849, a covalent inhibitor targeting the KRAS-G12C mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma.

2025年1月13日 · KRAS G12C inhibitors represent a significant breakthrough in the treatment of cancers driven by KRAS mutations. Sotorasib (AMG 510), also marketed as Lumakras, is the first FDA-approved inhibitor specifically target the KRAS G12C mutation, which is prevalent in NSCLC.

2025年1月17日 · The KRAS G12C mutation is present in approximately 3-5% of colorectal cancers, emphasizing the important role of comprehensive biomarker testing in mCRC. By detecting an actionable mutation, eligible patients are now able to receive a corresponding targeted therapy that may lead to improved responses.

2025年1月16日 · The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur:. On January 16, 2025, the Food and Drug Administration approved sotorasib (Lumakras, Amgen Inc.) with panitumumab (Vectibix, Amgen Inc.) for adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC), as determined by an …

With the expansion of these inhibitors to other solid malignancies and the reported promising outcomes (20,21), KRAS G12C mutation has the potential to become the next agnostic cancer biomarker in the era of precision oncology.

6 天之前 · The mOS in KRAS G12C mutation, RAS non-G12C mutations, BRAF V600E mutation, and RAS/BRAF V600E WT was 65 months (m), 55m, 19m and 105m respectively. Compared to RAS non-G12C, the mOS of CRC patients with KRAS G12C was (65m vs 55m, p=0.54) .

2020年7月8日 · Acute and sustained degradation of KRAS G12C in multiple cancer cell lines renders LC-2 a valuable tool compound to interrogate KRAS biology and represents a significant step toward the development of PROTAC-based candidate therapeutics that function by inducing oncogenic KRAS degradation.

2021年6月23日 · Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS G12C)....

6 天之前 · In this blog, we take a deep dive into the Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations (NCT06412198) clinical trial alongside Drs. Christine Parseghian and Bennett Caughey.Special thanks to Drs. Christine Parseghian and Bennett Caughey for their contributions to this blog …

2025年1月22日 · The p.G12C mutation in KRAS is commonly found in many cancers and was previously untreatable until drugs like sotorasib were developed. However, up to 15% of patients treated with sotorasib have experienced hepatobiliary adverse events. To investigate whether these side effects are more common among sotorasib users, a pharmacovigilance study is ...

5 天之前 · The recommended dose of Lumakras for KRAS G12C-mutated mCRC is 960mg orally once daily in combination with panitumumab until disease progression or unacceptable toxicity. The first dose of ...

Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer.

Purpose: The p.G12C mutation in KRAS is commonly found in many cancers and was previously untreatable until drugs like sotorasib were developed. However, up to 15% of patients treated with sotorasib have experienced hepatobiliary adverse events. To investigate whether these side effects are more common among sotorasib users, a pharmacovigilance study is necessary.

2022年6月3日 · Adagrasib, a KRAS G12C inhibitor, irreversibly and selectively binds KRAS G12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in...

4 天之前 · In patients with lung cancer with KRAS-G12C mutations, resistance to G12Ci can result from secondary KRAS mutations . We examined seven common mutations in codons 12 and 13 (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) and found no mutations other than G12D in the G12Di Ref and G12Di Sen tumors

3 天之前 · KRAS G12C mutations, present in approximately 13% of lung adenocarcinoma cases, are associated with limited responses to current KRAS G12C inhibitor treatments such as adagrasib and sotorasib, with overall response rates ranging between 34% and 43%.

2022年12月21日 · We conducted an international, multicenter, open-label, phase 1–2 trial to evaluate the efficacy and safety of sotorasib as monotherapy in patients with KRAS p.G12C–mutated pancreatic...

2025年1月17日 · Mutations in KRAS gene stands out as one of the most widespread driver mutations, occurring in 60–70% of pancreatic cancers and 20–30% of colorectal malignancies. KRAS mutations predominantly affect Glycine at the 12th amino acid position, presented as G12C, G12D, or G12V variants. Adoptive transfer of T cell receptor (TCR) T cells has ...