Targeted therapy for advanced anaplastic lymphoma kinase (<i>ALK</i>)-rearranged non-small cell lung cancer

Cameron, Laird; Hitchen, Nadia; Chandran, Elias; Morris, Tessa Altair; Manser, Renée; Solomon, Benjamin; Jordan, Vanessa

doi:10.1002/14651858.cd013453.pub2

Cited by 32 publications

(21 citation statements)

References 178 publications

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“…The reviewed data suggest that introduction of targeted therapies brought a clear improvement of survival for the subgroups of cancers expressing an addressable target. For example, according to our analysis and the meta-analysis of Cameron et al, for the 4–7% of ALK + NSCLC, introduction of ALK inhibitors resulted in a large increase in PFS and increase of ORR including patients with measurable baseline brain metastases when compared to chemotherapy [ 8 ]. ALK inhibitors improved OS to a lesser degree than PFS.…”

Section: Discussionmentioning

confidence: 99%

State of affairs regarding targeted pharmacological therapy of cancers metastasized to the brain

et al. 2022

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In 1999 a visionary short article by The Wall Street Journal writers Robert Langreth and Michael Waldholz popularized the new term “personalized medicine,” that is to say, the targeting of drugs to each unique genetic profile. From today’s perspective, targeted approaches have clearly found the widest use in the antineoplastic domain. The current review was initiated to review the progress that has been made regarding the treatment of patients with advanced cancer and brain metastases. PubMed was searched for the terms brain metastasis, brain metastases, or metastatic brain in the Title/Abstract. Selection was limited to randomized controlled trial (RCT) and publication date January 2010 to February 2022. Following visual review, 51 papers on metastatic lung cancer, 12 on metastatic breast cancer, and 9 on malignant melanoma were retained and underwent full analysis. Information was extracted from the papers giving specific numbers for intracranial response rate and/or overall survival. Since most pharmacological trials on advanced cancers excluded patients with brain metastases and since hardly any information on adjuvant radiotherapy and radiosurgery is available from the pharmacological trials, precise assessment of the effect of targeted medication for the subgroups with brain metastases is difficult. Some quantitative information regarding the success of targeted pharmacological therapy is only available for patients with breast and lung cancer and melanoma. Overall, targeted approaches approximately doubled the lifespan in the subgroups of brain metastases from tumors with targetable surface receptors such as anaplastic lymphoma kinase (ALK) fusion receptor in non-small cell lung cancer or human epidermal growth factor receptor 2 (HER2)–positive breast cancer. For these types, overall survival in the situation of brain metastases is now more than a year. For receptor-negative lung cancer and melanoma, introduction of immune checkpoint blockers brought a substantial advance, although overall survival for melanoma metastasized to the brain appears to remain in the range of 6 to 9 months. The outlook for small cell lung cancer metastasized to the brain apparently remains poor. The introduction of targeted therapy roughly doubled survival times of advanced cancers including those metastasized to the brain, but so far, targeted therapy does not differ essentially from chemotherapy, therefore also facing tumors developing escape mechanisms. With the improved perspective of patients suffering from brain metastases, it becomes important to further optimize treatment of this specific patient group within the framework of randomized trials.

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Section: Discussionmentioning

confidence: 99%

State of affairs regarding targeted pharmacological therapy of cancers metastasized to the brain

et al. 2022

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“…ALK rearrangements in NSCLC have been initially diagnosed using break apart FISH assay, a time-consuming and operator-dependent technique often unlikely applicable in small biopsies with artifacts or cell blocks 3 , 7 , 21 , 22 . Following the demonstration of high concordance with the break apart ALK FISH assay, IHC with D5F3 clone using Ventana platform and Optiview amplification system has been approved by the US FDA as an alternative diagnostic tool for ALK rearrangements detection and TKI treatment 13 .…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemistry with 3 different clones in anaplastic lymphoma kinase fluorescence in situ hybridization positive non-small-cell lung cancer with thymidylate synthase expression analysis: a multicentre, retrospective, Italian study

et al. 2022

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Summary Introduction ALK rearrangement is the only druggable oncogenic driver detectable by immunohistochemistry (IHC) not requiring further confirmation of positivity in accessing first-line specific inhibitors. ALK-positive patients experience clinical benefit from pemetrexed-based chemotherapy possibly due to lower thymidylate synthase (TS) levels. This study assesses agreement with three different ALK IHC clones in 37 FISH-positive NSCLC. TS expression by real time (RT)-PCR was compared with ALK FISH-negative cases. Materials and methods 37 ALK FISH-positive NSCLC cases diagnosed between 2010 and 2015 in 7 Italian centres were investigated with ICH using three different anti-ALK antibodies (ALK1, 5A4 and D5F3). Staining for ALK1 and 5A4 was graded as 0+,1+,2+, and 3+, while the scoring for D5F3 was recorded as negative or positive. Proportion agreement analysis was done using Cohen’s unweighted kappa (k). TS and β-actin expression levels were analysed by quantitative RT-PCR. Comparison between TS expression in ALK FISH-positive specimens and a control cohort of ALK FISH-negative ones was performed with the Mann-Whitney and Kruskal-Wallis tests. Results Considering 2+ and 3+ as positive, the proportion of IHC agreement was 0.1691 (95% CI 0-0.4595) for ALK1/5A4, 0.1691 (95% CI 0-0.4595) for ALK1/D5F3, and 1 for D5F3/5A4. Considering 3+ as positive, it was 0.1543 (95% CI 0-0.4665) for ALK1/ 5A4, 0.0212 (95% CI 0-0.1736) for ALK1/D5F3, and 0.2269 (95% CI 0-0.5462) for 5A4/D5F3. Median TS expression was 6.07 (1.28-14.94) and ALK-positive cases had a significant lower TS expression than ALK-negative tumours (p = 0.002). Conclusions IHC proved to be a reliable tool for the diagnosis of ALK-rearranged NSCLC. D5F3 and 5A4 clones have the highest percentage of agreement. TS levels are significantly lower in FISH-positive patients.

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“…Crizotinib is an orally active aminopyridine-derived small molecule competitive inhibitor ( 10 ). The study showed that, in patients with advanced EML4-ALK fusion gene-positive NSCLC, the objective response rate (ORR; 53%) and progression-free survival (PFS) time (8.5 months) of patients receiving crizotinib were significantly higher than those of patients receiving standard platinum-based chemotherapy ( 67 , 68 ). The results showed that targeted therapy with crizotinib was more effective than traditional standard chemotherapy and did not increase the number of serious adverse reactions ( 69 , 70 ).…”

Section: Targeted Therapy For Eml4-alkmentioning

confidence: 99%

EML4‑ALK fusion gene in non‑small cell lung cancer (Review)

Lei

Shi

et al. 2022

Oncol Lett

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Non-small cell lung cancer (NSCLC) is a malignant tumor with a high morbidity and mortality rate that is a threat to human health. With the development of molecular targeted research, breakthroughs have been made on the molecular mechanism of lung cancer. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is one of the most important pathogenic driver genes of NSCLC discovered thus far. Four generations of targeted drugs for EML4-ALK have been developed, with patients benefiting significantly from these drugs. Therefore, EML4-ALK has become a research hotspot in NSCLC. The aim of the present study is to introduce the current research progress of EML4-ALK and its association with NSCLC. Contents 1. Introduction 2. EML4-ALK fusion gene 3. Clinical features of EML4-ALK in NSCLC 4. EML4-ALK detection method 5.

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Targeted therapy for advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer

Cited by 32 publications

References 178 publications

State of affairs regarding targeted pharmacological therapy of cancers metastasized to the brain

State of affairs regarding targeted pharmacological therapy of cancers metastasized to the brain

Immunohistochemistry with 3 different clones in anaplastic lymphoma kinase fluorescence in situ hybridization positive non-small-cell lung cancer with thymidylate synthase expression analysis: a multicentre, retrospective, Italian study

EML4‑ALK fusion gene in non‑small cell lung cancer (Review)

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