Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non-small cell lung cancer

Here, we aimed to assess the association of ALK variants and alterations with ensartinib response duration in NSCLC, and explore the potential value of computed tomography (CT) radiomic features in predicting progression-free survival (PFS). We enrolled 88 patients with identified ALK variant NSCLC in a multicenter phase 2 trial, and assessed the impact of ALK variants and secondary ALK alterations on the clinical outcome (response duration) of patients receiving ensartinib. Our study showed that secondary ALK alterations were adversely associated with ensartinib efficacy, and that ALK variants might not correlate with PFS. The quantitative radiomic signature provided added prognostic prediction value to the clinicopathological features. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14083

Authors: Donghui Hou, Xiaomin Zheng, Wei Song, Xiaoqing Liu, Sicong Wang, Lina Zhou, Xiuli Tao, Lv Lv, Qi Sun, Yujing Jin,Zewei Zhang, Lieming Ding, Ning Wu, Shijun Zhao

The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Review providing a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. READ ARTICLE

Pharmaceuticals (Basel) DOI: 10.3390/ph13120474

Authors: Valerio Gristina, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, Viviana Bazan

Review PaperKirk SmithDecember 13, 2020ALK inhibitor, NSCLC, TKI, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib

Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial

Background: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. Interpretation: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. READ ARTICLE

The Lancet Respiratory Medicine DOI:10.1016/S2213-2600(19)30252-8

Authors: Yunpeng Yang, Jianya Zhou, Jianying Zhou, Jifeng Feng, Wu Zhuang, Prof Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Prof Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Prof Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Prof Yunpeng Liu, Zhendong Zheng, Prof Gaofeng Li, Prof Ning Wu, Prof Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Prof Li Mao, Giovanni Selvaggi, Xiaobin Yuan, Yuanqing Fu, Tao Wang, Shanshan Xiao, Li Zhang

$P114-57 Post-Ensartinib Outcomes in Refractory Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC)$

P114-57 Post-Ensartinib Outcomes in Refractory Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC)

With the advent of novel ALK inhibitors utilized in sequence, the survival of patients with ALK-rearranged tumors has improved dramatically. This case series serves to compare tumor response rates and long-term survival outcomes among four patients treated with ensartinib over the course of four years at our institution.We found that ensartinib is well tolerated and has clinical activity in advanced ALK-rearranged NSCLC patients with brain metastases, despite previously progressing on crizotinib, with durable post-ensartinib survival on subsequent next-generation ALK inhibitors such as brigatinib and lorlatinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.5455/jpma.3142. PMID: 32296229.

Authors: H. Kim, P. Vu, K. Harrow, C. Liang, G. Selvaggi, E. Weihe, W. Mitchell, L. Bazhenova, S. Patel

Conference PaperKirk SmithOctober 1, 2019NSCLC, ALK, ensartinib

P114-43 A Novel Patient Derived Synchronous Cell Pair with Different Mutations in an ALK-Rearranged Lung Adenocarcinoma Underlines Tumor Heterogeneity

ALK targeted therapy can provide prolonged clinical response rates in ALK-rearranged lung adenocarcinoma (ADC) patients. However, most tumors relapse within a few years of treatment pressure due to a variety of resistance mechanisms, including intratumoral heterogeneity. Understanding these mechanisms is of utmost importance to more precisely tailor future targeted therapies.This study is the first evidence of the synchronous establishment of two highly distinct patient-derived ALK translocated lung ADC cell lines carrying different resistant mutations. This concept supports the paramount significance of spatiotemporal intratumoral heterogeneity under targeted therapy. Furthermore, our findings showed that HDAC inhibition could enhance sensitivity of resistant tumor cells to ALK targeted therapy in vitro. Altogether, our findings provide strong evidence for the synchronous emergence of multiple resistance mechanisms and emphasize the importance of multiple site re-biopsies to better identify acquired resistance mechanisms under targeted therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1194

Authors: P. Stockhammer, C.S.L. Ho, A. Bankfalvi T. Plönes, L. Hegedus, M. Schuler, C. Aigner, A. Schramm, B. Hegedus

P114-32 Rash and Efficacy in Anaplastic Lymphoma Kinase Positive (ALK+) Non-Small Cell Lung Cancer Patients Treated with Ensartinib

In a phase 1/2 study, ensartinib was generally well tolerated and demonstrated good clinical activity in pts with ALK+ non-small cell lung cancer (NSCLC). This post hoc analysis sought to determine the relationship between ensartinib-related rash and clinical benefit. The study found that ensartinib was associated with mild to moderate rash that was easily managed. Preliminary findings suggest that rash is potentially associated with better clinical benefit with ensartinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1183

Authors: H. Wakelee, K. Reckamp, T. Leal, A. Chiappori, S. Waqar, K. Zeman, J. Neal, C. Liang, K. Harrow, A. Holzhausen, J. Zhou, G. Selvaggi, L. Horn

Conference PaperKirk SmithOctober 1, 2019ALK, rash, clinical benefit, ensartinib

Circulating tumor (ct) DNA analysis to monitor response and resistance to ensartinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC)

Background: Pts with anaplastic lymphoma kinase (ALK)-rearranged NSCLC have benefited from ALK tyrosine kinase inhibitors (TKIs); however, most pts eventually acquire resistance. Identification of resistance mutations informs subsequent therapy but has typically required invasive repeat biopsies. Here, we assessed the utility of ctDNA analysis and the ability to monitor response longitudinally and detect resistance mutations during therapy with ensartinib, a potent second-generation ALK TKI. Conclusions: Overall, the data suggest that plasma ctDNA analysis can potentially identify a subgroup of pts with ALK+ NSCLC who may derive clinical benefit from ensartinib. Furthermore, serial assessments of ctDNA during therapy offer a convenient method to track tumor response and identify the mutational landscape of acquired resistance. READ ARTICLE

Annals of Oncology DOI:10.1093/annonc/mdz063.010

Authors: L. Horn, J. G. Whisenant, H. Wakelee, K. L. Reckamp, H. Qiao, L. Du, J. Hernandez, V. Huang, S. N. Waqar, S. Patel, R. E. Sanborn, T. Shaffer, K. Garg, A. Holzhausen, K. Harrow, C. Liang, L. P. Lim, M. Li, C. M. Lovly