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      Targeted drugs for systemic therapy of lung cancer with brain metastases

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      Author(s): 2 , 3 , 4 , 5 , 1
      Publication date (Electronic):
      Journal: Oncotarget
      Publisher: Impact Journals LLC
      Keywords: brain metastases, lung cancer, target drug, EGFR-TKI, ALK

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          Abstract

          Brain metastases are very common in lung cancer patients. The condition of these patients is complicated and difficult to treat, and adverse reactions following treatment can affect the nervous system, which severely reduces quality of life. Lung cancers are categorized as small cell lung cancers and non-small cell lung cancers. Patients with brain metastasis of small cell lung cancers are generally treated with brain radiotherapy and systemic chemotherapy, but stage III/IV patients with brain metastasis of non-small cell lung cancers are generally not responsive to radiotherapy or chemotherapy. With the recent development of targeted drugs, tumor molecular profile detection allows the selection of appropriate targeted drugs for adjuvant pharmacological treatment of brain metastasis in lung cancer patients. In recent years, immune checkpoint inhibitors have emerged and have been approved by the Food and Drug Administration (FDA) for the treatment of certain cancers, but their efficacy in lung cancer patients with brain metastases still needs to be confirmed. This paper focuses on highlighting drugs for targeted therapy of brain metastasis in lung cancer patients and their molecular targets and mechanisms of drug resistance.

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          Small-cell lung cancer.

          Jan P Van Meerbeeck, Dean Fennell, Dirk De Ruysscher (2011)
          The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis relies on histology, with the use of immunohistochemical studies to confirm difficult cases. Typical patients are men older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities. Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to define disease as metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling pathways have been identified that might yield new drug targets. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.

            Martin Reck, Joachim von Pawel, Petr Zatloukal … (2009)
            Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting. Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351). PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation. Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.
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              Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.

              Dong-Wan Kim, Marcello Tiseo, Myung-Ju Ahn … (2017)
              Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 12 January 2018
                Publication date (Electronic): 22 December 2017
                Volume: 9
                Issue: 4
                Pages: 5459-5472
                Affiliations
                1 Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China
                2 Shandong Cancer Hospital and Institute, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
                3 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
                4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
                5 University of South Carolina, Computer Science and Engineering Department, Columbia, SC, USA
                Author notes
                Correspondence to: Wen-Juan Liu, 122liuwenjuan@ 123456163.com
                Article
                Publisher ID: 23616
                DOI: 10.18632/oncotarget.23616
                PMC ID: 5797064
                PubMed ID: 29435193
                SO-VID: 75b6f347-259f-4c88-a956-14bf7243885b
                Copyright © Copyright: © 2018 Sun et al.
                License:

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 20 July 2017
                Date accepted : 28 October 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: brain metastases,lung cancer,target drug,egfr-tki,alk
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: brain metastases, lung cancer, target drug, egfr-tki, alk

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