Progress in the Management of Advanced Thoracic Malignancies in 2017

Ferrara, Roberto; Mezquita, Laura; Besse, Benjamin

doi:10.1016/j.jtho.2018.01.002

Cited by 45 publications

(37 citation statements)

References 130 publications

(162 reference statements)

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“…13), osimertinib significantly improved PFS compared with first-generation EGFR-TKIs. Based on these two pivotal trials, osimertinib has become a standard of care for T790M-mutant NSCLC or a preferred option for treatment-na€ ve EGFR-mutant NSCLC (14).…”

Section: Introductionmentioning

confidence: 99%

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

Yun

Hong

Kim

et al. 2019

Clinical Cancer Research

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Purpose: Given that osimertinib is the only approved thirdgeneration EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (NSCLC), additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models.Experimental Design: Antitumor activity of YH25448 was investigated in vitro using mutant EGFR-expressing Ba/F3 cells and various lung cancer cell lines. In vivo antitumor efficacy, ability to penetrate the blood-brain barrier (BBB), and skin toxicity of YH25448 were examined and compared with those of osimertinib using cell lines and PDX model.Results: Compared with osimertinib, YH25448 showed a higher selectivity and potency in kinase assay and mutant EGFR-expressing Ba/F3 cells. In various cell line models har-boring EGFR activating and T790M mutation, YH25448 effectively inhibited EGFR downstream signaling pathways, leading to cellular apoptosis. When compared in vivo at equimolar concentrations, YH25448 produced significantly better tumor regression than osimertinib. Importantly, YH25448 induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. YH25448 rarely suppressed the levels of p-EGFR in hair follicles, leading to less keratosis than osimertinib in animal model. The potent systemic and intracranial activity of YH25448 has been shown in an ongoing phase I/II clinical trial for advanced EGFR T790M mutated NSCLC (NCT03046992).Conclusions: Our findings suggest that YH25448 is a promising third-generation EGFR inhibitor, which may be more effective and better tolerated than the currently approved osimertinib. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Introductionmentioning

confidence: 99%

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

Yun

Hong

Kim

et al. 2019

Clinical Cancer Research

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“…Lung cancer is the leading global cause of cancer‐related mortality, and the high mortality rate is historically attributed to advanced stage at initial diagnosis and limited therapeutic options for metastatic disease . However, in the last two decades there has been an improvement in survival of a subset of patients with advanced non‐small cell lung cancer due to the discovery of new molecular targets, histology‐directed chemotherapeutic regimens and immunotherapy . Additionally, lung cancer screening with low‐dose computed tomography (LDCT) has been found in randomised clinical trials to improve detection of early stage lung cancers, particularly adenocarcinoma (ACA), and has recently been implemented .…”

Section: Introductionmentioning

confidence: 99%

“…2 However, in the last two decades there has been an improvement in survival of a subset of patients with advanced non-small cell lung cancer due to the discovery of new molecular targets, histology-directed chemotherapeutic regimens and immunotherapy. 3 Additionally, lung cancer screening with low-dose computed tomography (LDCT) has been found in randomised clinical trials to improve detection of early stage lung cancers, particularly adenocarcinoma (ACA), [4][5][6] and has recently been implemented. 7 Thus, it has never been more critical to consistently classify early-stage lung ACA for the prediction of patient outcomes and identification of patients who may benefit from adjuvant therapy.…”

Section: Introductionmentioning

confidence: 99%

Problems in the reproducibility of classification of small lung adenocarcinoma: an international interobserver study

et al. 2019

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Aims The 2015 WHO classification for lung adenocarcinoma (ACA) provides criteria for adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (INV), but differentiating these entities can be difficult. As our understanding of prognostic significance increases, inconsistent classification is problematic. This study assesses agreement within an international panel of lung pathologists and identifies factors contributing to inconsistent classification. Methods and results Sixty slides of small lung ACAs were reviewed digitally by six lung pathologists in three rounds, with consensus conferences and examination of elastic stains in round 3. The panel independently reviewed each case to assess final diagnosis, invasive component size and predominant pattern. The kappa value for AIS and MIA versus INV decreased from 0.44 (round 1) to 0.30 and 0.34 (rounds 2 and 3). Interobserver agreement for invasion (AIS versus other) decreased from 0.34 (round 1) to 0.29 and 0.29 (rounds 2 and 3). The range of the measured invasive component in a single case was up to 19.2 mm among observers. Agreement was excellent in tumours with high‐grade cytology and fair with low‐grade cytology. Conclusions Interobserver agreement in small lung ACAs was fair to moderate, and improved minimally with elastic stains. Poor agreement is primarily attributable to subjectivity in pattern recognition, but high‐grade cytology increases agreement. More reliable methods to differentiate histological patterns may be necessary, including refinement of the definitions as well as recognition of other features (such as high‐grade cytology) as a formal part of routine assessment.

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“…This novel CSDW signature stratified "driver gene-negative" lung adenocarcinoma patients into two distinct high-and lowrisk subgroups. In general, high-risk patients should receive highfrequency surveillance and corresponding treatment to prevent disease progression (30). In this study, most of the disease progression occurred within 20 months after resection for highrisk patients, which may reflect a true recurrence of lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 80%

Development and Validation of a Novel Signature to Predict Overall Survival in “Driver Gene–negative” Lung Adenocarcinoma (LUAD): Results of a Multicenter Study

Cui

Fang

et al. 2019

Clinical Cancer Research

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Purpose: Examining the role of developmental signaling pathways in “driver gene–negative” lung adenocarcinoma (patients with lung adenocarcinoma negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as “driver gene–negative”) may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of “driver gene–negative” lung adenocarcinoma. Experimental Design: In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature. Results: Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “driver gene–negative” lung adenocarcinoma. Furthermore, the Wnt/β-catenin pathway–based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin pathway–based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3, and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46–16.79; P < 0.001) than patients with low-risk scores. Conclusions: The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for “driver gene–negative” lung adenocarcinoma.

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Progress in the Management of Advanced Thoracic Malignancies in 2017

Cited by 45 publications

References 130 publications

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

Problems in the reproducibility of classification of small lung adenocarcinoma: an international interobserver study

Development and Validation of a Novel Signature to Predict Overall Survival in “Driver Gene–negative” Lung Adenocarcinoma (LUAD): Results of a Multicenter Study

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