Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor.
Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy.
Eleven patients were enrolled between September 2015 and February 2020. Mos..... READ ARTICLE

ESMO Open, Cancer Horizons DOI:10.1016/j.esmoop.2021.100342

Authors: J.J. Lin, A. Muzikansky, E. Kennedy, I. Dagogo-Jack, A.T. Shaw, J.F. Gainor

Prognostic Markers of Survival among Japanese Patients with Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Receiving First-Line Alectinib.

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Mean-while, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associat..... READ ARTICLE

Diagnostics DOI:10.3390/diagnostics11122170

Authors: Takeda T, Yamada T, Tanimura K, Nakano T, Ishida M, Tachibana Y, Shiotsu S, Horiuchi S, Hibino M, Okada A, Chihara Y, Takayama K.

Testing for EGFR Mutations and ALK Rearrangements in Advanced Non-Small-Cell Lung Cancer: Considerations for Countries in Emerging Markets

The treatment of patients with advanced non-small-cell lung cancer (NSCLC) in recent years has been increasingly guided by biomarker testing. Testing has centered on driver genetic alterations involving the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements. The presence of these mutations is predictive of response to targeted therapies such as EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs. However, there are substantial challenges for the implementation of biomarker testing, particularly in emerging countries. Understanding the barriers to testing in NSCLC will be key to improving molecular testing rates worldwide and patient outcomes as a result. In this article, we review EGFR mutations and ALK rearrangements as predictive biomarkers for NSCLC, discuss a selection of appropriate tests and review the literature with respect to the global uptake of EGFR and ALK testing. To help improve testing rates and unify procedures, we review our exp..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S313669

Authors: Mercedes L Dalurzo, Alejandro Avilés-Salas, Fernando Augusto Soares, Yingyong Hou, Yuan Li, Anna Stroganova, Büge Öz, Arif Abdillah, Hui Wan and Yoon-La Choi

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

"Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement"

Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint
inhibitor (ICI) treatment e cacy. The clinical e cacy of ICIs for non-small-cell lung cancer (NSCLC)
patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped
190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab
monotherapy, and examined the e cacy in NSCLC patients with or without major mutations.
Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients
had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients
had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the
rate of high PD-L1 expression ( 50%) was significantly higher in patients with ALK mutations.
The progression-free survival was 0.6 (95% CI: 0.2–2.1) months for ALK-positive patients and 1.8 (95%
CI: 1.2–2.1) months for EGFR-positive patients. All patients..... READ ARTICLE

International Journal of Molecular Sciences DOI:10.3390/ijms21072623

Authors: Yuko Oya, Hiroaki Kuroda, Takeo Nakada, Yusuke Takahashi, Noriaki Sakakura, Toyoaki Hida

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45−) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM− CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were obs..... READ ARTICLE

Cancers DOI:10.3390/cancers12010127

Authors: Mina Zeinali, Maggie Lee, Arthi Nadhan, Anvya Mathur, Casey Hedman, Eric Lin, Ramdane Harouaka, Max S. Wicha, Lili Zhao, Nallasivam Palanisamy, Mathias Hafner, Rishindra Reddy, Gregory P. Kalemkerian, Bryan J. Schneider, Khaled A. Hassan, Nithya Ramnath, Sunitha Nagrath

P201-35 Acquired MET-Aberrance Is a Mechanism of Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer

Totally 136 ALK-positive advanced NSCLC patients were screened for ALK rearrangement detected by tumor tissue or plasma Next-generation sequencing (NGS) at the Guangdong Lung Cancer Institute from January 2016 to December 2018. MET-aberrance was defined as c-Met overexpression performed by immunohistochemical(IHC) staining method with SP44 antibody and MET amplification assessed by tumor tissue or plasma Next-generation sequencing (NGS) or fluorescent in situ hybridization (FISH)The study found acquired MET-aberrance maybe a mechanism of acquired resistance to the second-generation ALK-TKIs for ALK-rearranged advanced NSCLC patients. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1379

Authors: Q. Deng, J. Kang, H. Wang, J. Yang, H. Yan, Z. Wang

Meta-analysis comparing incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer

Aim: Using the available literature, this meta-analysis aimed to compare reports of the incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with ALK-positive NSCLC. Conclusion: This meta-analysis of Phase III randomized clinical trials found no significant difference in the incidence of grade 3–4 neutropenia among patients with ALK-positive NSCLC treated with either an ALK inhibitor or chemotherapy, and this was not affected by adjusting for baseline tumor stage. READ ARTICLE

FUTURE ONCOLOGY
DOI:10.2217/fon-2018-0863

Authors: Bernardo Rapoport, Ramin B Arani, Nicola Mathieson, Andriy Krendyukov

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4–ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC...... READ ARTICLE

Nature DOI:10.1038/nature05945

Authors: Manabu Soda, Young Lim Choi, Munehiro Enomoto, Shuji Takada, Yoshihiro Yamashita, Shunpei Ishikawa, Shin-ichiro Fujiwara, Hideki Watanabe, Kentaro Kurashina, Hisashi Hatanaka, Masashi Bando, Shoji Ohno, Yuichi Ishikawa, Hiroyuki Aburatani, Toshiro Niki, Yasunori Sohara, Yukihiko Sugiyama & Hiroyuki Mano

Pre-ClinicalKirk SmithJuly 11, 2007EML4-ALK fusion, non-small-cell lung cancer (NSCLC)