Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases

Zimmermann, Stefan; Dziadziuszko, Rafał; Peters, Solange

doi:10.1016/j.ctrv.2014.03.005

Cited by 130 publications

(104 citation statements)

References 88 publications

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“…By limiting the analysis to prospective studies, there was no significant difference in intracranial disease control and survival outcomes between concurrent upfront WBRT plus TKIs and TKIs alone. Thus, considering the high intracranial ORR, consistent with results from other reviews (99)(100)(101), TKIs alone may be used upfront before WBRT in those pts with EGFR mutated NSCLC and asymptomatic BM. With a similar strategy the side effects of WBRT may be potentially avoided as long as intracranial disease is well controlled by TKIs alone.…”

Section: Standard Schedulessupporting

confidence: 80%

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

Proto¹,

Imbimbo²,

Gallucci³

et al. 2016

Transl. Lung Cancer Res.

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Section: Standard Schedulessupporting

confidence: 80%

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

Proto¹,

Imbimbo²,

Gallucci³

et al. 2016

Transl. Lung Cancer Res.

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“…However, penetration may be increased in patients with more advanced brain metastases where BBB disruption has already occurred (20)(21)(22). In addition, there is a cumulative increase in brain metastases incidence in patients with EGFRm NSCLC over time (23).…”

Section: Introductionmentioning

confidence: 99%

“…Although many patients die of systemic progression, rather than brain lesion progression, quality of life is significantly worsened, both directly and as a result of whole brain radiotherapy (WBRT), which degrades cognitive function (24). In addition, as systemic therapies improve for patients with EGFRm NSCLC, the brain may increasingly become a sanctuary site where the BBB may offer protection from pharmacological agents (22). Therefore, there exists a clinical need for EGFR-TKIs with improved BBB penetration, and it is important that new mutant-selective agents, such as osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for sensitizing and T790M-resistance mutations (25,26), and rociletinib (CO-1686; ref.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Ballard

Yates

Yang³

et al. 2016

Clinical Cancer Research

574

472

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Purpose: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).Results: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11 C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11 C]rociletinib and [ 11 C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported.Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing.

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“…Several clinical trials with upfront platinum-based chemotherapy reported intracranial response rates (RRs) ranging from 23% to 50% (31-36) ( Table 1). Interestingly, in these studies intracranial RRs were correlated with and almost comparable to systemic RRs (37). On the other hand, when temozolomide, a drug that for its small size and lipophilic properties is deemed able to cross the BBB, was administered in a phase 2 study to NSCLC patients with or without BMs as firstline treatment, no objective responses were observed in the brain nor in the lung (38).…”

Section: Clinical Activity Of Chemotherapy Against Bms From Nsclcmentioning

confidence: 85%

State of the art of chemotherapy for the treatment of central nervous system metastases from non-small cell lung cancer

Inno¹,

Noia²,

D’Argento³

et al. 2016

Transl. Lung Cancer Res.

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Chemotherapy is the mainstay of treatment of advanced non-small cell lung cancer (NSCLC) without molecular drivers. Despite a low penetration of central nervous system (CNS), chemotherapy drugs demonstrated encouraging activity against CNS metastases from NSCLC. Based on the available data, chemotherapy should be considered as an important part of the multidisciplinary treatment of CNS metastases. Particularly, platinum-based regimens represent the most active combinations and pemetrexed is associated with a meaningful clinical benefit for patients with non-squamous histology. How to integrate chemotherapy and radiotherapy for newly diagnosed brain metastases (BMs) is still debated. Although flawed by some limitations, the available evidence suggests a role for upfront chemotherapy for the treatment of NSCLC patients with synchronous, asymptomatic BMs, thus allowing a delay of radiotherapy. Despite the introduction of modern and more effective chemotherapy, however, the prognosis of NSCLC patients with CNS metastases remains poor, especially for those with progressive BMs or leptomeningeal carcinomatosis (LC).

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Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases

Cited by 130 publications

References 88 publications

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

State of the art of chemotherapy for the treatment of central nervous system metastases from non-small cell lung cancer

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