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

Shannon S Zhang,1 Misako Nagasaka1– 3 1Department of Medicine, University of California Irvine School of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USA; 3St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako NagasakaDepartment of Medi...

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Autores principales:	Zhang S, Nagasaka M
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	sotorasib amg 510 lumakras non-small cell lung cancer codebreak 100 krasg12c Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/55c194b34a7344bf91660bf05a256637
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spelling	oai:doaj.org-article:55c194b34a7344bf91660bf05a2566372021-12-02T18:07:10ZSpotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer1179-2728https://doaj.org/article/55c194b34a7344bf91660bf05a2566372021-10-01T00:00:00Zhttps://www.dovepress.com/spotlight-on-sotorasib-amg-510-for-krasg12c-positive-non-small-cell-lu-peer-reviewed-fulltext-article-LCTThttps://doaj.org/toc/1179-2728Shannon S Zhang,1 Misako Nagasaka1– 3 1Department of Medicine, University of California Irvine School of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USA; 3St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako NagasakaDepartment of Medicine, University of California Irvine School of Medicine, Orange, CA, USAEmail nagasakm@hs.uci.eduAbstract: Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRASG12C 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 KRASG12C 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 KRASG12C 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.Keywords: sotorasib, AMG 510, Lumakras, non-small cell lung cancer, CodeBreak 100, KRASG12CZhang SNagasaka MDove Medical Pressarticlesotorasibamg 510lumakrasnon-small cell lung cancercodebreak 100krasg12cNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENLung Cancer: Targets and Therapy, Vol Volume 12, Pp 115-122 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	sotorasib amg 510 lumakras non-small cell lung cancer codebreak 100 krasg12c Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	sotorasib amg 510 lumakras non-small cell lung cancer codebreak 100 krasg12c Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Zhang S Nagasaka M Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
description	Shannon S Zhang,1 Misako Nagasaka1– 3 1Department of Medicine, University of California Irvine School of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USA; 3St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako NagasakaDepartment of Medicine, University of California Irvine School of Medicine, Orange, CA, USAEmail nagasakm@hs.uci.eduAbstract: Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRASG12C 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 KRASG12C 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 KRASG12C 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.Keywords: sotorasib, AMG 510, Lumakras, non-small cell lung cancer, CodeBreak 100, KRASG12C
format	article
author	Zhang S Nagasaka M
author_facet	Zhang S Nagasaka M
author_sort	Zhang S
title	Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
title_short	Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
title_full	Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
title_fullStr	Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
title_full_unstemmed	Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer
title_sort	spotlight on sotorasib (amg 510) for krasg12c positive non-small cell lung cancer
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/55c194b34a7344bf91660bf05a256637
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Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer

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