The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.713530

Authors: Yue Pan, Chao Deng, Zhenhua Qiu, Chenghui Cao and Fang Wu

Therapeutic Sequencing in ALK+ NSCLC

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a cur..... READ ARTICLE

Pharmaceuticals DOI: 10.3390/ph14020080

Authors: Elsayed M., Christopoulos P.

Review PaperKirk SmithJanuary 21, 2021ALK, NSCLC, TKI, EML4-ALK fusion variant 3, chemotherapy, sequential treatment

Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive pa.....READ ARTICLE

Pharmaceuticals DOI: 10.3390/ph13110371

Author: Maximilian J. Hochmair, Hannah Fabikan ,Oliver Illini, Christoph Weinlinger ,Ulrike Setinek, Dagmar Krenbek , Helmut Prosch , Markus Rauter ,Michael Schumacher ,Ewald Wöll ,Romana Wass ,Elmar Brehm ,Gudrun Absenger , Tatjana Bundalo , Peter Errhalt , Matthias Urban and Arschang Valipour

Real-World OutcomesKirk SmithNovember 1, 2020ALK, ROS1, tyrosine kinase inhibitor, sequential treatment, lorlatinib

OA0206 The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L)

Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primar..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.415

Authors: S. Watanabe, T. Yamanaka, K. Ito, S. Sakata, H. Daga, T. Kijima, K. Hirano, I. Okamoto, A. Nakamura, T. Kozuki, M. Ishihara, K. Azuma, T. Seto, T. Yokoyama, Y. Oya, H. Kobayashi, K. Nishino, Y. Hattori, K. Nakagawa, N. Yamamoto