The Challenges of Third-Generation EGFR Tyrosine Kinase Inhibitors in the Therapy of Advanced NSCLC

Wang, Fen; Zhou, Qing

doi:10.1016/j.jtho.2022.01.007

Cited by 10 publications

(5 citation statements)

References 36 publications

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“…Additionally, in vivo studies demonstrated that the second-generation EGFR-TKI afatinib achieved a superior performance than others in all the rare mutations we tested, which is probably because it irreversibly targets all homodimers and heterodimers of the ErbB family. Although third-generation EGFR-TKIs also have been shown with promising clinical outcome against EGFR rare mutations in multiple studies, a direct comparison between second-and third-generation EGFR-TKIs is still needed (37). Currently the guidelines from NCCN, ESMO and CSCO all have suggested preferred choice of afatinib or osimertinib for the rst-line treatment of NSCLC patients with EGFR rare mutations, but these mutations were still limited to well established EGFR S768I, L861Q, and/or G719X, which are not that "rare"; our results suggest it's worth trying to extend this principle to other rare mutations, including the compounding mutations as well Structural variations were identi ed in 20.5% of HNCH patients, including ampli cations of EGFR, MET or ERBB2, and gene rearrangements involving ALK, ROS1 or RET.…”

Section: Discussionmentioning

confidence: 99%

Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

Zhang

Guan

et al. 2022

Preprint

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Background: Lung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cancer characterized by driver mutations detected in a substantial proportion of the cases. Tyrosine kinase inhibitors (TKIs) are standard care for the patients with these mutations. In this study, we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive Chinese LUAD patients who are treatment-naïve. Material and methods: Targeted sequencing covering the hotspot regions of eight LUAD driver genes was performed across 853 treatment-naïve LUAD patients. Logistic regression analysis was used to determine the factors associated with presence of these mutations. Genetically modified LUAD PC9 cells were established to evaluated the sensitivity of selected EGFRcompound mutations to different EGFR-TKIs in-vivo. Results: A total of 574 single nucleotide variants, 270 InDels, 88 amplifications, and 87 rearrangements were identified in this study, with EGFR and KRAS being the most frequently mutated genes. Females, mostly life-long non-smokers, had significantly higher EGFRmutation rates than males and had a T>A conversion signature, for which the etiological factor is still unknown. Males, primarily smokers, more frequently had KRAS mutations and a smoking-associated signature of C>A conversions. Rare EGFR compound mutations identified in this study (Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873) conferred genetically modified PC9 cells, constantly and consistently, more sensitive to second-generation EGFR-TKI afatinib in-vivo. Conclusion: Over 70% of Chinese treatment-naïve LUAD patients are TKIs-targetable. Patients with rare EGFR compound mutations might conside second-generation EGFR-TKIs for treatment.

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Section: Discussionmentioning

confidence: 99%

Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

Zhang

Guan

et al. 2022

Preprint

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“…The NCT02330367 trial of abivertinib (AC0010) was a phase 1/2, open-label, single-arm, clinical study in China, evaluating the efficacy and safety of abivertinib as second-line treatment in patients with NSCLC who had previously received treatment and had EGFR T790M mutations. The ORR was 52.2%, DCR was 88.0%, mDoR was 8.5 months, mPFS was 7.5 months, mOS was 24.9 months, and treatment-related AEs of grade 3 or above were 32.6% (62,63). The most common AEs were elevated ALT (7.0%), elevated AST (4.8%), diarrhea (4.4%) and neutropenia (3.5%).…”

Section: Rociletinib (Also Named Co1686mentioning

confidence: 99%

The advance of the third‑generation EGFR‑TKI in the treatment of non‑small cell lung cancer (Review)

Cheng,

Cui,

Wang

et al. 2023

Oncol Rep

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Lung cancer is currently the second most common type of cancer with the second incidence rate and the first mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of cases of lung cancers. Concerning the treatment of NSCLC, targeted therapy has become a research hotspot in recent years because of its favorable efficacy, high selectivity and minimal adverse reactions. Among the drugs used in targeted therapy, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most common and are categorized into four generations. The use of first and second-generation drugs leads to drug resistance within 8-14 months. This resistance is primarily caused by the T790M mutation, which is the most observed mechanism. A third-generation drug has been developed to address this issue and a fourth-generation drug is expected to overcome multiple resistance mechanisms, including third-generation drug resistance. However, the fourth-generation drug has not been launched yet. At present, multiple third-generation targeted drugs have been launched globally, with three being launched in China and several being at research and clinical trial stages. The present article provides a review of the development process, mechanism of action and clinical trials of the third-generation EGFR-TKIs, aiming to provide some reference and suggestions for the clinical treatment of NSCLC and scientific research on third-generation targeted drugs. Contents 1. Introduction 2. History of the EGFR-targeted drugs 3. Mechanism 4. Third-generation EGFR-TKIs 5. Comparison of drug efficacy and clinical plan recommendations 6. Advantages and disadvantages of the third-generation EGFR TKIs 7. Prospects

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“…This higher selectivity for mutated EGFR may be associated with a decreased incidence of toxicities compared with the first and second generations. 16,46,52,53,57,61,62,69 Combination strategies with first-generation EGFR-TKI have consistently shown no difference in the rate of diarrhea. Two randomized trials explored first-generation EGFR-TKIs administered in combination with platinumbased chemotherapy in the first-line setting and did not find an increase in the incidence of allgrade diarrhea, ranging from 35.3 to 42%.…”

Section: Incidence Of Diarrhea According To Type Of Egfr-tkis and Con...mentioning

confidence: 99%

“…This higher selectivity for mutated EGFR may be associated with a decreased incidence of toxicities compared with the first and second generations. 16 , 46 , 52 , 53 , 57 , 61 , 62 , 69 …”

Section: Incidence Of Diarrhea According To Type Of Egfr-tkis and Con...mentioning

confidence: 99%

Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma

Cárdenas-Fernández,

Soberanis Pina,

Turcott

et al. 2023

Ther Adv Med Oncol

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The identification of Epidermal Growth Factor Receptor (EGFR) mutations in lung adenocarcinoma has facilitated the development of personalized medicine based on oncogenic drivers. EGFR-Tyrosine Kinase Inhibitors (TKIs) are part of the targeted therapy; they impede the phosphorylation of the intracellular tyrosine kinase component of EGFR and consequently block signal transduction pathways. These drugs inhibit the proliferation and survival of tumor cells, leading to long-term progression-free survival and overall survival. Diarrhea is one of the most frequent adverse events associated with EGFR-TKIs, affecting at least 18% of patients and reaching up to 95% in some cases. Diarrhea should be managed carefully given its association with important complications, treatment interruptions, and dose reductions. Moreover, nutritional status and quality of life (QoL) can deteriorate due to severe diarrhea. Changes in diet, such as increment of fiber, supplementation with glutamine, and use of probiotics, may contribute to a decrease in the incidence of diarrhea. Improving the control of diarrhea can provide a significant benefit to the QoL of patients.

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The Challenges of Third-Generation EGFR Tyrosine Kinase Inhibitors in the Therapy of Advanced NSCLC

Cited by 10 publications

References 36 publications

Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

The advance of the third‑generation EGFR‑TKI in the treatment of non‑small cell lung cancer (Review)

Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma

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