Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not rea..... READ ARTICLE

Signal Transduction and Targeted Therapy DOI:10.1038/s41392-021-00841-8

Authors: Shi, Y., Fang, J., Hao, X. et al.

Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies

Background: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK+) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome. Conclusions: Positive blood-based liquid rebiopsies in ALK+ NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of ALK resistance mutations with other features of the high-risk EML4-ALK V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment. READ ARTICLE

Transl Lung Cancer Research DOI:10.21037/tlcr-21-32

Authors: Petros Christopoulos, Steffen Dietz, Arlou K. Angeles, Stephan Rheinheimer, Daniel Kazdal, Anna-Lena Volckmar, Florian Janke, Volker Endris, Michael Meister, Mark Kriegsmann, Thomasz Zemojtel, Martin Reck, Albrecht Stenzinger, Michael Thomas, Holger Sültmann

Severe ulcerative esophagitis and colitis induced by crizotinib therapy: A case report

The expression of anaplastic lymphoma kinase (ALK), a target of tyrosine kinase is altered in several kinds of cancer, including in non-small cell lung cancer (NSCLC). For this reason, the use of crizotinib to treat locally advanced or metastatic ALK-positive NSCLC was approved by the US Food and Drug Administration in 2011. The reported adverse events during clinical trials with crizotinib included esophageal disorders in 11% of the patients, although none of them experienced severe events. Drug-induced esophagitis or more severe ulcerations are considerably rare according to the available case reports. We report a patient who presented with severe esophageal ulcers after 2-year treatment with crizotinib for metastatic, ALK-positive NSCLC. These clinical conditions improved after education on proper eating habits and an additional prescription of a proton pump inhibitor. Several months later, the patient developed colitis with severe diarrhea, which was successfully controlled with me..... READ ARTICLE

Advances in Digestive Medicine DOI:10.1177/1078155220961549

Authors: Wei-Wen Su,Hui-Ting Hsu,Po-Ke Hsu

Effect of bevacizumab on brain radiation necrosis in anaplastic lymphoma kinase-positive lung cancer

Central nervous system (CNS) metastases from anaplastic lymphoma kinase (ALK)-positive lung cancer often results in failure of ALK-tyrosine kinase inhibitor (TKI) therapy. Patients with uncontrolled CNS metastases receive radiation therapy, which sometimes causes brain radiation necrosis. We added bevacizumab (15 mg/kg, every 3–4 weeks) to the regimen of four ALK-positive lung cancer patients with brain radiation necrosis who were receiving ALK-TKI therapy. A decrease in brain radiation necrosis was seen in all the patients, and an improvement in symptoms was seen in three patients. In one patient who was receiving corticosteroid therapy, we could taper the dose and subsequently discontinue it. While one patient discontinued bevacizumab because of adverse events, the other three continued with the treatment. Therefore, the combination of bevacizumab with ALK-TKI seems to be an effective, manageable, and tolerable treatment for brain radiation necrosis. READ ARTICLE

Respirology Case Reports DOI:10.1002/rcr2.454

Authors: Kengo Tanigawa, Keiko Mizuno, Yusuke Kamenohara, Taiji Unoki, Shunsuke Misono, Hiromasa Inoue

Impact of Tyrosine Kinase Inhibitor Starting Dose on Outcomes in Patients With Non-Small Cell Lung Cancer

Background: Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can cause intolerable adverse events in patients with non-small cell lung cancer (NSCLC) and may be prescribed at a lower dose. Conclusion: Patients who initiated TKI therapy at a RD did not have different PFS and 15-month survival outcomes than patients who initiated TKI therapy at the FDA SD. READ ARTICLE

Journal of Pharmacy Practice DOI:10.1177/0897190019840596

Authors: Emily Miao, Nagashree Seetharamu, Kevin Sullivan, Stephen Eng, Chung-Shien Lee

Frequency, clinical features and differential response to therapy of concurrent ALK/EGFR alterations in Chinese lung cancer patients

Purpose: EGFR and anaplastic lymphoma kinase (ALK) alterations have been regarded as oncogenic drivers and incorporated into clinical practices to manage nonsmall cell lung cancer (NSCLC). Alterations of these two genes were traditionally considered to be mutually exclusive, but recent studies have suggested that they can occur concomitantly. Here, we investigated the prevalence, clinical features and outcomes in response to the treatment of NSCLC patients who harbor EGFR and ALK co-alterations. Conclusion: EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct clinical features and responses to EGFR-TKIs, suggesting that non-EML4-ALK co-alterations are likely to occur as a resistance mechanism to EGFR-TKI. In addition, dual-TKI therapy might be a better choice than single-TKI treatments for these co-altered patients. To the best of our knowledge, this is the largest dual-positive EGFR/ALK cohort study in People's Republic of China. READ ARTICLE

Drug Design and Development Therapies DOI:10.2147/DDDT.S196189

Authors: Jixian Liu, Zhimin Mu, Li Liu, Kang Li, Richeng Jiang, Peng Chen, Qiang Zhou, Meiling Jin, Yuxiang Ma, Yuancai Xie, Jianxing Xiang, Bing Li, Yafeng Ma, Xinru Mao, Lu Zhang, Tengfei Zhang, Da Wu

Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer

ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated.
Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17).
Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.024

Authors: Yongfeng Yu, Qiuxiang Ou, Xue Wu, Hairong Bao,
Yan Ding, Yang W. Shao, Shun Lu

ADAURA: Phase III, Double-blind, Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection

Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non–small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2018.04.004

Authors: Yi-LongWu, Roy S. Herbst, Helen Mann, Yuri Rukazenkov, Marcelo Marotti and MasahiroTsuboi