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Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review
BACKGROUND AND OBJECTIVE: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programme...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989806/ https://www.ncbi.nlm.nih.gov/pubmed/36895930 http://dx.doi.org/10.21037/tlcr-22-639 |
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author | Santarpia, Mariacarmela Ciappina, Giuliana Spagnolo, Calogera Claudia Squeri, Andrea Passalacqua, Maria Ilenia Aguilar, Andrés Gonzalez-Cao, Maria Giovannetti, Elisa Silvestris, Nicola Rosell, Rafael |
author_facet | Santarpia, Mariacarmela Ciappina, Giuliana Spagnolo, Calogera Claudia Squeri, Andrea Passalacqua, Maria Ilenia Aguilar, Andrés Gonzalez-Cao, Maria Giovannetti, Elisa Silvestris, Nicola Rosell, Rafael |
author_sort | Santarpia, Mariacarmela |
collection | PubMed |
description | BACKGROUND AND OBJECTIVE: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. METHODS: In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. KEY CONTENT AND FINDINGS: KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. CONCLUSIONS: The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes. |
format | Online Article Text |
id | pubmed-9989806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-99898062023-03-08 Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review Santarpia, Mariacarmela Ciappina, Giuliana Spagnolo, Calogera Claudia Squeri, Andrea Passalacqua, Maria Ilenia Aguilar, Andrés Gonzalez-Cao, Maria Giovannetti, Elisa Silvestris, Nicola Rosell, Rafael Transl Lung Cancer Res Review Article BACKGROUND AND OBJECTIVE: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. METHODS: In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. KEY CONTENT AND FINDINGS: KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. CONCLUSIONS: The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes. AME Publishing Company 2023-02-20 2023-02-28 /pmc/articles/PMC9989806/ /pubmed/36895930 http://dx.doi.org/10.21037/tlcr-22-639 Text en 2023 Translational Lung Cancer Research. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Review Article Santarpia, Mariacarmela Ciappina, Giuliana Spagnolo, Calogera Claudia Squeri, Andrea Passalacqua, Maria Ilenia Aguilar, Andrés Gonzalez-Cao, Maria Giovannetti, Elisa Silvestris, Nicola Rosell, Rafael Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
title | Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
title_full | Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
title_fullStr | Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
title_full_unstemmed | Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
title_short | Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
title_sort | targeted therapies for kras-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989806/ https://www.ncbi.nlm.nih.gov/pubmed/36895930 http://dx.doi.org/10.21037/tlcr-22-639 |
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