Lymphoma Kinase-rearranged Non-small Cell Lung Research Articles

Review of Therapeutic Strategies for Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer.

Simple SummaryAnaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) was first reported in 2007. Following the development of crizotinib as a tyrosine kinase inhibitor (TKI) targeting ALK, the treatment of advanced NSCLC with ALK-rearrangements has made remarkable progress. Currently, there are five ALK-TKIs approved by the FDA, and the development of new agents, including fourth-generation TKI, is ongoing. Clinical trials with angiogenesis inhibitors and immune checkpoint inhibitors are also underway, and further progress in the treatment of ALK-rearranged advanced NSCLC is expected. The purpose of this manuscript is to provide information on the recent clinical trials of ALK-TKIs, angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy, to describe tissue and liquid biopsy as a method to investigate the mechanisms of resistance against ALK-TKIs and suggest a proposed treatment algorithm.Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK) was first reported in 2007. ALK-rearranged NSCLC accounts for about 3–8% of NSCLC. The first-line therapy for ALK-rearranged advanced NSCLC is tyrosine kinase inhibitors (TKI) targeting ALK. Following the development of crizotinib, the first ALK-TKI, patient prognosis has been greatly improved. Currently, five TKIs are approved by the FDA. In addition, clinical trials of the novel TKI, ensartinib, and fourth-generation ALK-TKI for compound ALK mutation are ongoing. Treatment with angiogenesis inhibitors and immune checkpoint inhibitors is also being studied. However, as the disease progresses, cancers tend to develop resistance mechanisms. In addition to ALK mutations, other mechanisms, including the activation of bypass signaling pathways and histological transformation, cause resistance, and the identification of these mechanisms is important in selecting subsequent therapy. Studies on tissue and liquid biopsy have been reported and are expected to be useful tools for identifying resistance mechanisms. The purpose of this manuscript is to provide information on the recent clinical trials of ALK-TKIs, angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy to describe tissue and liquid biopsy as a method to investigate the mechanisms of resistance against ALK-TKIs and suggest a proposed treatment algorithm.

The impact of baseline brain metastases on clinical benefits and progression patterns after first-line crizotinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer.

Baseline brain metastasis (BBM) commonly occurs in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Crizotinib prolongs the survival of patients with ALK rearrangement but lacks significant effect on brain metastasis. It remains unclear whether BBM and local therapy affect therapeutic outcomes and progression patterns during crizotinib treatment.Patients with ALK-positive (immunotherapy) non-small cell lung cancer were screened from West China Hospital between May 2013 and January 2019. A total of 155 patients were enrolled in this research, with entirely recorded statistics to analyze retrospectively.Baseline brain metastasis occurred in 64 patients (55.7%). Thirty-seven patients received local therapy, while 24 patients did not. We observed higher overall response rate in patients receiving local therapy (70.2% vs. 41.7%, P = .026), but no statistical difference was found in median progression free survival (mPFS) (12.0 months vs 13.0 months, P = .633). A significantly shorter mPFS was found in patients not receiving local treatment compared with the 16.5 months mPFS of patients without BBM (P = .029). Intracranial progressions were recorded in 35 patients with BBM (71%) and 16 patients who don’t have (30%). As for extracranial progression, there is a higher occurrence rate (75.5%) in patients who had baseline extracranial metastases versus 49.0% in BBM patients. A significantly higher occurrence rate of multiple progression was noted in patients with BBM (14/49 vs. 6/53).Baseline intracranial metastasis changes the location and number of progressions after the first-line crizotinib and results in poor prognosis. There is no evidence that local treatment for brain metastasis had a protective effect on intracranial progression.

504P - A single center report for safety and efficacy of CT-707 in Chinese patients with advanced, anaplastic lymphoma kinase-rearranged non-small cell lung cancer or other tumours

BackgroundIt is proved that anaplastic lymphoma kinase-rearranged non–small-cell lung cancer (ALK-rearranged NSCLC) is sensitive to ALK inhibitors while the chemotherapy resistance is unavoidable. In this study, safety and antitumor activity of the novel ALK inhibitor (ALKi) CT-707 is evaluated in Chinese patients with advanced ALK-rearranged NSCLC. MethodsThis Multi-center, open-label phase I study (NCT02695550) recruited adult patients with ALK-rearrangement (confirmed by fluorescence in situ hybridization and/or immunohistochemistry) of locally advanced/metastatic malignancies including non–small-cell lung cancer. This study consisted of a dose escalation study and a dose expansion study. CT-707 was administered orally once a day for 21 days. The Lung Cancer Center of Peking Union Medical College Hospital of Chinese Academy of Medical Sciences summarized the safety and effectiveness of the cases enrolled in this center. ResultsThirteen patients who were treated with CT-707 from 450 to 600mg (in the dose increasing phase) were enrolled in this trial (two patients were previously treated with crizotinib). Twelve patients were diagnosed with lung adenocarcinoma and one patient was malignant pleural mesothelioma. After treatment, grade 3 diarrhea (600 mg QD) was found as dose-limiting toxicity (DLT). The most common adverse events included diarrhea (92%), elevated aspartate aminotransferase (61%), elevated alanine aminotransferase (54%), hair loss (38%), and vomiting (31%).ORR and disease control rate among patients were 10 of 13 (77%) and 11 of 13 (85%). The median progression-free survival was 13 months (95% CI:9.98-16.00).The overall survival rate of 12 months was 85%, which has not yet reached the median overall survival. Among all patients, ten patients observed partial response (PR). One patient reached a complete response (CR). However, no response of the disease was observed in patients with malignant pleural mesothelioma. ConclusionsCT-707 is effective in Chinese patients with tumors harboring ALK rearrangements. It has reliable safety and tremendous clinical application value. Clinical trial identificationNCT02695550; March 2016. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: update and perspectives.

We describe recent developments in the rapidly evolving field of anaplastic lymphoma kinase-targeting agents. Five targeted drugs are currently available in the clinic via regular approval or named patient programs, including crizotinib, ceritinib, alectinib, brigatinib and lorlatinib. Further drugs are tested in clinical trials. This review summarizes published data, together with drug-specific information on dosing and toxicity. Moreover, we discuss different clinical scenarios and potential treatment options in patients with tumor progression, based on current literature and our own experience. Patients with metastatic, anaplastic lymphoma kinase-rearranged nonsmall cell lung cancer should be managed by interdisciplinary expert teams. New drugs with enhanced brain activity are available, and some patients may benefit from local therapies.

A step forward in the management of a rare disease, the anaplastic lymphoma kinase-rearranged non-small cell lung cancer

The discovery of the anaplastic lymphoma kinase (ALK) gene rearrangement as an oncogenic driver in thoracic oncology has permitted to identify a subpopulation of non-small cell lung cancer (NSCLC) that can be considered as a rare oncologic disease.

Directed Therapies in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) rearrangements were first implicated as driving mutations in non-small cell lung cancer in 2007. Since then, a number of novel, small-molecule inhibitors directed against the ALK receptor have demonstrated superiority over standard chemotherapies in the treatment of ALK rearrangement-positive lung cancer. Of considerable importance when considering such therapies is the ability of each to overcome mutations conferring acquired resistance, as well as penetrate the central nervous system (CNS), the most common site of metastasis and traditionally the most difficult to breach. Herein is a review of the efficacy, indications, and degree of CNS penetration for the ALK-targeting agents crizotinib, ceretinib, alectinib, brigatinib, and lorlatinib, as well as a summary of ongoing clinical trials comparing these drugs.

Development of a new choroidal metastasis in resistance to crizotinib therapy in anaplastic lymphoma kinase-rearranged non-small cell lung cancer.

Development of a new choroidal metastasis in resistance to crizotinib therapy in anaplastic lymphoma kinase-rearranged non-small cell lung cancer.

A crowded, but still varied, space: brigatinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer

Considering that, as recently as 10 years ago, physicians caring for patients with advanced lung cancer had only a handful of conventional cytotoxic agents from which to choose, the field’s recent development and competition seem truly remarkable. A prime example of this shifting and crowded landscape is immunotherapy. Since 2015, three different checkpoint inhibitors targeting programmed death 1 (PD-1) or PD-1 ligand (PD-L1) have received U.S. FDA approval, with several others currently in clinical trials. While these drugs may differ by specific target (PD-1 versus PD-L1), antibody species (humanized versus fully human), and IgG subclass (IgG1 versus IgG4), it remains unclear whether there are clinically meaningful differences in efficacy or toxicity between these agents.

P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.

The lessons of failure

The lessons of failure