Although targeted therapies are generally better tolerated than standard chemotherapy, there are some gastrointestinal side effects that should be kept in consideration. Most side effects are mild to moderate in severity, but some can be life threatening. Diarrhea is the most common side effects of tyrosine kinase inhibitors (TKIs). The majority of the cases can be managed with prophylactic and rescue use of anti-diarrhea medications. Aplastic lymphoma kinase (ALK) inhibitors, mesenchymal epithelial transition factor(c-MET) and poly ADP-ribose polymerase (PARP) inhibitors are known to cause nausea and vomiting. Most cases of nausea and vomiting can be managed by medications such as serotonin antagonists, NK-1 antagonists, dopamine antagonists or anti-anxiety medications. Prior to prescribing c-KIT TKIs (sunitinib, regorafenib), multi-TKIs (pazopanib), MEK inhibitors (trametinib), anti-HER-2 therapy (lapatinib) and anti-EGFR targeting agents (gefitinib, erlotinib), baseline liver function tests should be performed and then monitored periodically to prevent liver damage.
Read ArticleWelcome to ALK Research - the gateway to research that offers hope, treatment and advances to people with ALK-positive cancer. This blog provides links to articles, presentations, and videos related to ALK-positive cancer research. Some videos and articles have restricted access. Whether you are a medical professional, researcher, a patient or carer, we hope you will find this blog useful.
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Life Threatening haemoptysis in primary lung cancer-signet ring cell carcinoma
Primary signet ring cell carcinoma of the lung is a rare non-small cell carcinoma of the lung with extremely aggressive features and poor prognosis. The diagnosis mainly required tissue biopsy with immunohistochemical analysis and gene mutation studies. We describe a unique case of primary signet ring cell carcinoma of the lung presenting with life threatening haemoptysis along with literature review of prognosis and management of this rare clinical entity.
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Forced degradation of Ceritinib under stress conditions: Structural interpretation of novel degradants using HR-MS/MS and NMR
The current work describes the preparative isolation and structural interpretation of acid degradation product of ceritinib (CRB). The drug is exposed to different stress conditions (acid, base hydrolysis, oxidation, thermal and photolytic) as suggested by International Conference on Harmonisation guidelines (ICH). The degradation of drug (CRB) is observed when exposed to acidic condition whereas the drug is stable in remaining stress conditions. The separation between drug and acid degradant was attained on a C18 BEH UPLC column (50 mm × 2.1 mm, 1.7 μm) in a gradient separation mode. The mobile phase comprises of acetonitrile and 0.05% formic acid buffer at a flow rate of 0.6 mL/min and UV wavelength monitored at 215 nm. One novel degradation product formed in acidic condition was isolated by Preparative HPLC (Prep-HPLC). Structural interpretation and characterisation done by HR-MS/MS and NMR studies which is not yet described in the literature.
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Chapter 8 – Approach to Anaplastic Lymphoma Kinase (ALK) Gene Rearranged Non–Small Cell Lung Cancer (NSCLC)
Anaplastic lymphoma kinase (ALK) gene rearrangement occurs in 2%–4% of all non–small cell lung cancer (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses in these patients. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superior clinical benefit compared with chemotherapy. Eventually, all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site. Several next-generation ALK inhibitors were evaluated in crizotinib-treated patients and found to be effective. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Clinical efficacy observed with these agents, particularly in the CNS prompted evaluating these agents as front-line therapy. Recently, in two separate phase III trials, alectinib has demonstrated superior clinical efficacy as front-line therapy compared with crizotinib and has been accepted as a new standard of care. Further advances in the management of ALK positive NSCLC will require better understanding of mechanisms of resistance to ALK inhibitors that can form the basis for combination treatments. Despite the success observed with immune checkpoint inhibitors in some NSCLC patients, these agents have not demonstrated sufficient clinical activity in these patients. Assessment of the immunogenicity of the ALK positive NSCLC may allow evaluation of novel immunotherapy drugs for treatment of these patients. Finally, the role of ALK TKIs in the management of patients with earlier stage of cancer continues to be investigated.
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Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature
Background: Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%–90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy… Conclusions: Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation.
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Special issue “The advance of solid tumor research in China”: Real-world clinical outcomes of alectinib for advanced non-small-cell lung cancer patients with ALK fusion in China.
Global phase 3 trials have demonstrated the priority of several next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). However, clinical studies are conducted with specific populations that differ from the real world. The study aimed to evaluate the clinical outcomes of alectinib in real-world settings. Patients with advanced non-small-cell lung cancer (NSCLC) and EML4-ALK fusion were enrolled from two medical centers between June 2018 and June 2020. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) to alectinib. The secondary endpoint was response of brain metastases. The risk factors for disease progression were also investigated. In total, 127 patients with advanced NSCLC were enrolled into this study. Of them, 54.3% received first-line alectinib. The 1- and 2-year PFS rates were 77.4% and 68.3%, respectively. ORR and disease control rate (DCR) were 53.5% and 91.3%, respectively. Among patients with brain metastases, intracranial ORR and DCR were 63.6% and 88.6%, respectively. In addition, we found that “crizotinib pretreatment”, “liver metastasis”, and “TP53 co-mutation” were individually associated with shorter PFS in alectinib treatment. In conclusion, this study confirms the salient clinical outcomes of alectinib for ALK-fusion-driven NSCLC patients with or without brain metastases, adding real-world evidence to the priority of alectinib in clinical practice.
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Genomic and transcriptomic analysis of neuroendocrine transformation in ALK-rearranged lung adenocarcinoma after treatments with sequential ALK inhibitors: a brief report
Introduction
Neuroendocrine transformation has been reported in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) patients after ALK inhibition, but unlike epidermal growth factor receptor (EGFR)-mutant NSCLC, the exact mechanism of neuroendocrine (NE) transformation in ALK-rearranged NSCLC is poorly studied.
Methods
We collected the matched pre- and post-transformation samples from a patient with ALK-rearranged lung adenocarcinoma (LUAD) and performed targeted panel sequencing, whole-exome sequencing (WES) and bulk RNA sequencing.
Results
Multiple mutations were shared between the pre- and post-transformation samples. Neither RB1 nor TP53 mutation was detected, but CDKN2A deletion and CDK4 amplification were found instead. Mismatch repair (MMR)-associated mutational signature was significantly enriched after transformation. Genes associated with Notch signaling and PI3K/AKT pathway were significantly upregulated, whereas genes related to lymphocyte activation and NF-kappa B signaling were downregulated. Signatures relating to homologous recombination (HR), MMR and Notch signaling pathway were enriched, which were further validated in TCGA cohorts. Macrophages M2 showed prominently higher abundance in the tumor immune microenvironment after NE transformation.
Conclusions
The mechanism of NE transformation in ALK-rearranged LUAD may be different from that in EGFR-mutant LUAD.
Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management
The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on-target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off-target’ mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.
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Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001
Background: ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy.
Methods: In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment.
Results: Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively.
Conclusions: Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib.
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Systematic identification of ALK substrates by integrated phosphoproteome and interactome analysis
The sensitivity of phosphorylation site identification by mass spectrometry has improved markedly. However, the lack of kinase–substrate relationship (KSR) data hinders the improvement of the range and accuracy of kinase activity prediction. In this study, we aimed to develop a method for acquiring systematic KSR data on anaplastic lymphoma kinase (ALK) using mass spectrometry and to apply this method to the prediction of kinase activity. Thirty-seven ALK substrate candidates, including 34 phosphorylation sites not annotated in the PhosphoSitePlus database, were identified by integrated analysis of the phosphoproteome and crosslinking interactome of HEK 293 cells with doxycycline-induced ALK overexpression. Furthermore, KSRs of ALK were validated by an in vitro kinase assay. Finally, using phosphoproteomic data from ALK mutant cell lines and patient-derived cells treated with ALK inhibitors, we found that the prediction of ALK activity was improved when the KSRs identified in this study were used instead of the public KSR dataset. Our approach is applicable to other kinases, and future identification of KSRs will facilitate more accurate estimations of kinase activity and elucidation of phosphorylation signals.
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