Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation

Skoulidis, Ferdinandos; Li, Bob T.; Dy, Grace K.; Price, Timothy; Falchook, Gerald S.; Wolf, Jürgen; Italiano, Antoîne; Schüler, Martin; Borghaei, Hossein; Barlési, Fabrice; Kato, Terufumi; Curioni-Fontecedro, Alessandra; Sacher, Adrian G.; Spira, Alexander I.; Ramalingam, Suresh S.; Takahashi, Toshiaki; Besse, Benjamin; Anderson, Abraham; Ang, Agnes; Tran, Qui; Mather, Omar; Henary, H.; Ngarmchamnanrith, Gataree; Friberg, Gregory; Velcheti, Vamsidhar; Govindan, Ramaswamy

doi:10.1056/nejmoa2103695

Cited by 902 publications

(548 citation statements)

References 38 publications

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“…The phase II portion of the CodeBreak 100 multicenter trial took place between the dates of August 2019 and February 2020. 17 This phase included subjects 18 years or older with locally advanced or metastatic KRAS G12C NSCLC who had disease progression after programmed death-1 (PD-1), programmed death ligand-1 (PDL-1), and/ or a platinum-based chemotherapy. A total of 126 subjects, 117 of whom were current or former smokers, were included.…”

Section: Phase II Portion Of the Codebreak 100 Trialmentioning

confidence: 99%

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Zhang

Nagasaka

2021

LCTT

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Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRAS G12C mutation has proven to be challenging due to the abundance of GTP in the cytoplasm, rapid hydrolysis of GTP, and difficulty designing small molecules to achieve sufficient concentration for KRAS inhibition. Based on promising results in both preclinical and clinical trials, sotorasib, a novel KRAS G12C inhibitor, was given conditional approval by the FDA in May 2021. The Phase I portion of the clinical trial produced 32% confirmed response with 56% of patients with stable disease. About 91.2% of patients who received the highest dose of 960mg daily achieved disease control. The Phase II portion, which used 960mg daily dosing resulted in 37.1% of patients with confirmed response and 80.6% of patients with disease control. Both phase I and phase II had similar progression-free survival, in 6.3 months and 6.8 months, respectively. In both phases, grade 4 adverse events occurred in only one patient. The most common adverse events were elevations in LFTs, which down-trended upon dose reduction and steroid treatment. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, resistance mutations to sotorasib are increasingly common. Many proposals have been made to address this, such as the use of combination therapy for synthetic lethality, which are producing encouraging results. Here, we explore in further detail the development of sotorasib, its efficacy, mechanism of resistance, and strategies to overcome these resistances.

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Section: Phase II Portion Of the Codebreak 100 Trialmentioning

confidence: 99%

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Zhang

Nagasaka

2021

LCTT

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“…KRAS G12C substitution is characteristic for smoking-related NSCLCs, accounting for approximately one out of six NSCLCs in this category of patients. The first clinical trials on KRAS G12C inhibitors provided highly satisfactory results [32,33] and resulted in the approval of sotorasib [34]. The remaining RAS mutations are not druggable.…”

Section: Non-small Cell Lung Cancer (Nsclc)mentioning

confidence: 99%

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Aleksakhina

Imyanitov

2021

IJMS

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The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.

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“…Biochemically, these agents capture KRAS in its inactive GDP-bound state and lock it in this conformation, thereby inhibiting downstream pro-tumorigenic signaling that translates to preclinical antitumor responses. In clinical trials, two potent, selective, and irreversible small-molecule KRAS G12C inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), have demonstrated promising single-agent activity across cancers harboring KRAS G12C [7,8]. In spite of the initial positive response in patients with KRAS G12C mutant lung cancer treated with these inhibitors, both adaptive and acquired resistance can limit their efficacy.…”

Section: Kras Dependency and Response To Kras G12c Inhibitorsmentioning

confidence: 99%

“…Unfortunately, these methodologies have demonstrated suboptimal efficacies. Furthermore, while recent success in developing KRAS G12C inhibitors has proved that mutant KRAS is, in fact, druggable, the clinical activity of KRAS G12C inhibitors is underwhelming when compared to EGFR and ALK inhibitors [7]. Unlike patients with lung cancer harboring EGFR mutations or ALK translocations, diseases for which targeted agents typically achieve 60 to 80% response rates, KRAS G12C inhibitors such as sotorasib and adagrasib typically yield 40 to 50% response rates [8].…”

Section: Introductionmentioning

confidence: 99%

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Abe

Kimura

Hirade

et al. 2021

Cancers

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Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.

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Sotorasib for Lung Cancers with KRAS p.G12C Mutation

Cited by 902 publications

References 38 publications

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

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