Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

Tan, Aaron C.; Teh, Yi Lin; Lai, Gillianne; Tan, Daniel Shao-Weng

doi:10.1080/14737140.2019.1604228

Cited by 12 publications

(11 citation statements)

References 36 publications

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“…In the VM-negative group, ORR of TKIs was 83.3% compared with 39.3% for chemotherapy (P < 0.001) (c). The red bar indicates chemotherapy therapy was superior to platinum-based chemotherapy in both ORR and PFS, which is consistent with the available data [23]. On the other hand, the PFS of patients with VM was significantly lower than that of no-VM, regardless of the first-line treatments.…”

Section: Discussionsupporting

confidence: 86%

Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status

You

Ding

et al. 2021

BMC Cancer

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Background Vascular mimicry (VM) was associated with the prognosis of cancers. The aim of the study was to explore the association between VM and anticancer therapy response in patients with lung adenocarcinoma. Methods This was a single-center retrospective study of patients with lung adenocarcinoma between March 1st, 2013, to April 1st, 2019, at the Second People’s Hospital of Taizhou City. All included patients were divided into the VM and no-VM groups according to whether VM was observed or not in the specimen. Vessels with positive PAS and negative CD34 staining were confirmed as VM. The main outcome was progression-free survival (PFS). Results Sixty-six (50.4%) patients were male. Eighty-one patients received chemotherapy as the first-line treatment, and 50 patients received TKIs. Forty-five (34.4%) patients were confirmed with VM. There was no difference regarding the first-line treatment between the VM and no-VM groups (P = 0.285). The 86 patients without VM had a median PFS of 279 (range, 90–1095) days, and 45 patients with VM had a median PFS of 167 (range, 90–369) days (P < 0.001). T stage (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.10–1.71), N stage (HR = 1.43, 95%CI: 1.09–1.86), M stage (HR = 2.85, 95%CI: 1.76–4.61), differentiation (HR = 1.85, 95%CI: 1.29–2.65), therapy (HR = 0.32, 95%CI: 0.21–0.49), VM (HR = 2.12, 95%CI: 1.33–3.37), and ECOG (HR = 1.41, 95%CI: 1.09–1.84) were independently associated with PFS. Conclusion The benefits of first-line TKIs for NSCLC with EGFR mutation are possibly better than those of platinum-based regimens in patients without VM, but there is no difference in the benefit of chemotherapy or target therapy for VM-positive NSCLC harboring EGFR mutations.

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Section: Discussionsupporting

confidence: 86%

Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status

You

Ding

et al. 2021

BMC Cancer

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“…Additionally, NGS also has the benefit of detecting the fusion variant and partner, which in ALK rearranged NSCLC, may have prognostic and therapeutic implications [43]. NGS may therefore have a role, not only in detecting actionable alterations, but also in stratifying patients for therapy, given the expanding number of combinations currently available [44].…”

Section: Discussionmentioning

confidence: 99%

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis

et al. 2020

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“…Third-generation TKIs, including lazertinib and osimertinib, have better selectivity for mutant EGFR over wild-type EGFR than earlier generations of TKIs. 16 , 27 This increased selectivity has the potential to enhance the therapeutic index and reduce side effects, thereby improving the safety profile. 28 Nevertheless, a recent analysis of the Food and Drug Administration Adverse Events Reporting System pharmacovigilance data indicates increased risk of cardiotoxicity with osimertinib compared with other TKIs (erlotinib, afatinib, gefitinib).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR Mutation-Positive Advanced NSCLC and Preclinical Studies

Jang

Kim

Sim

et al. 2021

JTO Clinical and Research Reports

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Introduction Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild-type–sparing third-generation EGFR tyrosine kinase inhibitor (TKI), creating a wide therapeutic index. Cardiovascular adverse events (AEs), including QT prolongation, decreased left ventricular ejection fraction (LVEF), and heart failure, have emerged as potential AEs with certain EGFR TKI therapies. Methods Cardiac safety of lazertinib was evaluated in TKI-tolerant adults with EGFR mutation-positive locally advanced or metastatic NSCLC receiving lazertinib (20–320 mg/d). QT intervals corrected with Fridericia’s formula (QTcF) prolongation, time-matched concentration-QTcF relationship, change of LVEF, and cardiac failure-associated AEs were evaluated. The clinical findings were supplemented by the following three preclinical studies: an in vitro hERG inhibition assay, an ex vivo isolated perfused rabbit heart study, and an in vivo telemetry-instrumented beagle dog study. Results Preclinical evaluation revealed little to no physiological effect on the basis of electrocardiogram, electrophysiological, proarrhythmic, and hemodynamic parameters. Clinical evaluation of 181 patients revealed no clinically relevant QTcF prolongation by centralized electrocardiogram in any patient and at any dose level. The predicted magnitude of QTcF value increase at maximum steady-state plasma concentration for the therapeutic dose of lazertinib (240 mg/d) was 2.2 msec (upper bound of the two-sided 90% confidence interval: 3.6 msec). No patient had clinically relevant LVEF decrease (i.e., minimum postbaseline LVEF value of <50% and a maximum decrease in LVEF value from baseline of ≥10 percentage points). Cardiac failure-associated AE occurred in one patient (grade 2 decreased LVEF) and resolved without any dose modifications. Conclusions Our first-in-human study, together with preclinical data, indicates that lazertinib is not associated with increased cardiac risk.

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Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

Cited by 12 publications

References 36 publications

Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status

Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis

Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR Mutation-Positive Advanced NSCLC and Preclinical Studies

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