Phase 1 Study of Ceritinib Combined With Trametinib in Patients With Advanced ALK- or ROS1-Positive NSCLC

Lara, Matthew S.; Gubens, Matthew A.; Bacaltos, Bianca; Daran, Lea; Lim, Steffany; Li, Tianhong; Gandara, David R.; Bivona, Trever G.; Riess, Jonathan W.; Blakely, Collin M.

doi:10.1016/j.jtocrr.2022.100436

Cited by 3 publications

(3 citation statements)

References 8 publications

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“…Combining ROS1-targeted agents with other targeted therapies or immunotherapies has been investigated to enhance treatment efficacy and overcome resistance. For example, combining ROS1 inhibitors with MEK inhibitors or immune checkpoint inhibitors has shown potential in preclinical and clinical studies ( 142 , 143 ).…”

Section: Targeted Therapy Resistance In Nsclcmentioning

confidence: 99%

Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges

Xiang,

Liu,

Wang

et al. 2024

Front. Immunol.

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Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.

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Section: Targeted Therapy Resistance In Nsclcmentioning

confidence: 99%

Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges

Xiang,

Liu,

Wang

et al. 2024

Front. Immunol.

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“…On-target resistance Off-target resistance Additional resistance ATP site Gatekeeper mutations [64] KRAS-exon 3 mutation [52] Anti-apoptotic pathways [93] ATP site solvent-front mutations (e.g. : G1202R) [64] MET amplification [64] Histological transformation [94] Second-site mutations [46,95] MEK activation [96] Epigenetics [97] Compound mutations PIK3CA mutations [98] Tumour microenvironment [29] Oncogene amplification [46] IGF-1R activation [56] Oncogene loss [46] KRAS G12C mutation [46] ALK-exon 23 mutation [52] RET fusion [52] MAPK pathway [68] TP53 mutation [44] PI3K-AKT pathway [99] JAK-STAT pathway [60] SRC activation [100] EGFR activation [58] KIT activation [64] HER family activation [58] YAP activation [62,66] ROS1+ NSCLC patients [69]. A study by Chuang et al highlighted the importance of SERPINB4, a protease inhibitor protein, in EML4-ALK and other ALK fusions.…”

Section: Types Of Resistance Mechanismsmentioning

confidence: 99%

“…For example, RAS‐MAPK is critical for the survival of EML4‐ALK variant 1 cells, and a combination of the MEK inhibitor trametinib enhanced response and delayed resistance to crizotinib and ceritinib in relevant in vitro and in vivo models [ 68 ]. In fact, a phase 1 clinical study is currently investigating the combination of an ALK‐TKI, ceritinib, with a MEK inhibitor, trametinib, in ALK+ or ROS1+ NSCLC patients [ 69 ]. A study by Chuang et al.…”

Section: Combination Therapymentioning

confidence: 99%

EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries

Elshatlawy,

Sampson,

Clarke

et al. 2023

Molecular Oncology

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Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point-mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule-associated protein-like 4 (EML4) in non-small cell lung cancer (NSCLC). EML4-ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta-propeller domain in variant 1 confers solid-like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK-TKIs are beneficial for most patients with EML4-ALK fusions. However, resistance to ALK inhibitors can occur via point-mutations within the kinase domain of the EML4-ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4-ALK variants, their impact on treatment response, ALK-TKI drug resistance mechanisms and potential combination therapies.

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New perspectives for targeting therapy in ALK-positive human cancers

Zhao

Xia

et al. 2023

Oncogene

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Phase 1 Study of Ceritinib Combined With Trametinib in Patients With Advanced ALK- or ROS1-Positive NSCLC

Cited by 3 publications

References 8 publications

Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges

Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges

EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries

New perspectives for targeting therapy in ALK-positive human cancers

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