TRK Inhibitors in Non-Small Cell Lung Cancer

Harada, Guilherme; Gongora, Aline Bobato Lara; Costa, Cesar Martins da; Santini, Fernando C.

doi:10.1007/s11864-020-00741-z

Cited by 14 publications

(16 citation statements)

References 36 publications

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“…Entrectinib is a multi-kinase inhibitor that targets the three TRK proteins in addition to ROS1 and ALK [ 14 ]. In contrast, larotrectinib, which is currently the most specific TRK inhibitor, is a selective inhibitor of the three TRK proteins [ 5 , 26 ]. Despite earlier discussion that multi-targeted agents may confer greater clinical benefits compared to single targeted agents [ 27 ], this difference in their mechanism of action could explain the observed differences in efficacy between the two treatments.…”

Section: Discussionmentioning

confidence: 99%

Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers

García‐Foncillas

Bokemeyer

Italiano

et al. 2022

Cancers

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Information regarding the comparative efficacy of first-generation receptor tyrosine kinase inhibitors is limited. This matching-adjusted indirect comparison (MAIC) evaluated differences in efficacy and safety across larotrectinib and entrectinib trials. Data from clinical trials for larotrectinib (LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431)) and entrectinib (ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)) were used. Adults (≥18 years) across trials were matched on available baseline characteristics. Outcomes evaluated included overall response rate (ORR), complete response (CR) rate, duration of response (DoR), overall survival (OS), progression-free survival (PFS), any serious treatment-related adverse events of grade ≥ 3 (TRAEs), and TRAEs leading to treatment discontinuation. The MAIC included 74 patients from entrectinib trials and 117 and 147 patients for the larotrectinib efficacy and safety populations, respectively. Post-matching, larotrectinib was associated with a significantly longer median duration of OS than entrectinib (p < 0.05) and a numerically longer median PFS (p = 0.07). ORR was similar for both agents (p = 0.63). The CR rate was higher (p < 0.05) and the DoR was longer for larotrectinib (p < 0.05). Safety outcomes were comparable and low for both treatments. Results were consistent in sensitivity analyses. These findings suggest favorable efficacy for larotrectinib and comparable safety profiles versus entrectinib in treating tropomyosin receptor kinase fusion cancer.

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Section: Discussionmentioning

confidence: 99%

Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers

García‐Foncillas

Bokemeyer

Italiano

et al. 2022

Cancers

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“…These observations, yielding new perspectives and a basis for understanding some mechanisms that regulate tumor cell behavior, suggest the possibility of considering these growth factors as potential therapeutic target molecules. From this point of view, in different adult and pediatric tumors, NTRK gene fusions are identified as oncogenic drivers [ 79 , 80 , 81 ]. In NSCLC, the prevalence is below 5%.…”

Section: Discussionmentioning

confidence: 99%

Adenocarcinomas of the Lung and Neurotrophin System: A Review

et al. 2022

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Neurotrophins (NTs) represent a group of growth factors with pleiotropic activities at the central nervous system level. The prototype of these molecules is represented by the nerve growth factor (NGF), but other factors with similar functions have been identified, including the brain derived-growth factor (BDNF), the neurotrophin 3 (NT-3), and NT 4/5. These growth factors act by binding specific low (P75) and high-affinity tyrosine kinase (TrkA, B, and C) receptors. More recently, these growth factors have shown effects outside the nervous system in different organs, particularly in the lungs. These molecules are involved in the natural development of the lungs, and their homeostasis. However, they are also important in different pathological conditions, including lung cancer. The involvement of neurotrophins in lung cancer has been detailed most for non-small cell lung cancer (NSCLC), in particular adenocarcinoma. This review aimed to extensively analyze the current knowledge of NTs and lung cancer and clarify novel molecular mechanisms for diagnostic and therapeutic purposes. Several clinical trials on humans are ongoing using NT receptor antagonists in different cancer cell types for further therapeutic applications. The pharmacological intervention against NT signaling may be essential to directly counteract cancer cell biology, and also indirectly modulate it in an inhibitory way by affecting neurogenesis and/or angiogenesis with potential impacts on tumor growth and progression.

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“…The application of tyrosine kinase inhibitors against specific gene targets (EGFR, ALK and ROS1) has revolutionized the treatment for lung adenocarcinoma (31). ALK inhibitors, such as Crizotinib and Ceritinib, have been widely used to treat cancers with mutations of ALK, especially for non-small cell lung cancers (32,33).…”

Section: Discussionmentioning

confidence: 99%

A Machine Learning Model Based on PET/CT Radiomics and Clinical Characteristics Predicts ALK Rearrangement Status in Lung Adenocarcinoma

et al. 2021

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ObjectivesAnaplastic lymphoma kinase (ALK) rearrangement status examination has been widely used in clinic for non-small cell lung cancer (NSCLC) patients in order to find patients that can be treated with targeted ALK inhibitors. This study intended to non-invasively predict the ALK rearrangement status in lung adenocarcinomas by developing a machine learning model that combines PET/CT radiomic features and clinical characteristics.MethodsFive hundred twenty-six patients of lung adenocarcinoma with PET/CT scan examination were enrolled, including 109 positive and 417 negative patients for ALK rearrangements from February 2016 to March 2019. The Artificial Intelligence Kit software was used to extract radiomic features of PET/CT images. The maximum relevance minimum redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) logistic regression were further employed to select the most distinguishable radiomic features to construct predictive models. The mRMR is a feature selection method, which selects the features with high correlation to the pathological results (maximum correlation), meanwhile retain the features with minimum correlation between them (minimum redundancy). LASSO is a statistical formula whose main purpose is the feature selection and regularization of data model. LASSO method regularizes model parameters by shrinking the regression coefficients, reducing some of them to zero. The feature selection phase occurs after the shrinkage, where every non-zero value is selected to be used in the model. Receiver operating characteristic (ROC) analysis was used to evaluate the performance of the models, and the performance of different models was compared by the DeLong test.ResultsA total of 22 radiomic features were extracted from PET/CT images for constructing the PET/CT radiomic model, and majority of these features used were based on CT features (20 out of 22), only 2 PET features were included (PET percentile 10 and PET difference entropy). Moreover, three clinical features associated with ALK mutation (age, burr and pleural effusion) were also employed to construct a combined model of PET/CT and clinical model. We found that this combined model PET/CT-clinical model has a significant advantage to predict the ALK mutation status in the training group (AUC = 0.87) and the testing group (AUC = 0.88) compared with the clinical model alone in the training group (AUC = 0.76) and the testing group (AUC = 0.74) respectively. However, there is no significant difference between the combined model and PET/CT radiomic model.ConclusionsThis study demonstrated that PET/CT radiomics-based machine learning model has potential to be used as a non-invasive diagnostic method to help diagnose ALK mutation status for lung adenocarcinoma patients in the clinic.

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TRK Inhibitors in Non-Small Cell Lung Cancer

Cited by 14 publications

References 36 publications

Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers

Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers

Adenocarcinomas of the Lung and Neurotrophin System: A Review

A Machine Learning Model Based on PET/CT Radiomics and Clinical Characteristics Predicts ALK Rearrangement Status in Lung Adenocarcinoma

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