TY - JOUR
T1 - Targeted therapies for KRAS-mutant non-small cell lung cancer
T2 - from preclinical studies to clinical development-a narrative review
AU - Santarpia, Mariacarmela
AU - Ciappina, Giuliana
AU - Spagnolo, Calogera Claudia
AU - Squeri, Andrea
AU - Passalacqua, Maria Ilenia
AU - Aguilar, Andrés
AU - Gonzalez-Cao, Maria
AU - Giovannetti, Elisa
AU - Silvestris, Nicola
AU - Rosell, Rafael
N1 - 2023 Translational Lung Cancer Research. All rights reserved.
PY - 2023/2/28
Y1 - 2023/2/28
N2 - 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.
AB - 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.
U2 - https://doi.org/10.21037/tlcr-22-639
DO - https://doi.org/10.21037/tlcr-22-639
M3 - Review article
C2 - 36895930
SN - 2218-6751
VL - 12
SP - 346
EP - 368
JO - Translational Lung Cancer Research
JF - Translational Lung Cancer Research
IS - 2
ER -