Dramatic response to brigatinib in a lung adenocarcinoma patient harboring EML4-ALK fusion and a G1202R de novo gene mutation

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors are the preferred initial treatment for ALK rearranged non-small cell lung cancer (NSCLC). While initial responses to next-generation inhibitors are robust, acquired resistance is expected for nearly all patients. The emergence of the G1202R mutation represents a significant concern for oncologists, as it predicts resistance to almost all ALK inhibitors (ALKi) other than lorlatinib. However, we report the first case of ALK de novo mutation in a patient with advanced NSCLC that responded to brigatinib. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2022.02.001

Authors: Yue Pan, Yue Zeng, Yurong Peng, Xiaohan Liu, Yizheng Li, Fang Wu

Case StudyKirk SmithApril 1, 2022Brigatinib, lung adenocarcinoma, EML4-ALK, G1202R, gene mutation

A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU-MP-5 as a new-generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU-MP-5. In addition, XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological eff..... READ ARTICLE

EMBO Molecular Medicine
DOI:10.15252/emmm.202114296

Authors: Yue Lu, Zhenzhen Fan, Su-Jie Zhu, Xiaoxing Huang, Zhongji Zhuang, Yunzhan Li, Zhou Deng, Lei Gao, Xuehui Hong, Ting Zhang, Li Li, Xihuan Sun, Wei Huang, Jingfang Zhang, Yan Liu, Baoding Zhang, Jie Jiang, Fu Gui, Zheng Wang, Qiyuan Li, Siyang Song, Xin Huang, Qiao Wu, Lanfen Chen, Dawang Zhou, Jianming Zhang, Cai-Hong Yun, Liang Chen and Xianming Deng

A Compound L1196M/G1202R ALK Mutation in a Patient with ALK-Positive Lung Cancer with Acquired Resistance to Brigatinib Also Confers Primary Resistance to Lorlatinib

We report here the case of a 70-year-old patient with ALK-positive NSCLC treated with crizotinib as part of the ALTA-1L trial.4 The patient relapsed after a partial response. After crizotinib failure, the patient was crossed over to brigatinib, which led to a second partial response lasting 9 months. After progression, the patient was shifted to lorlatinib but the clinical conditions worsened and the patient died. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.06.028

Authors: Geeta G. Sharma, Diego Cortinovis, Francesco Agustoni, Giulia Arosio, Matteo Villa, Nicoletta Cordani, Paolo Bidoli, William H. Bisson, Fabio Pagni, Rocco Piazza, Carlo Gambacorti-Passerini, Luca Mologni

PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor.
Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against
all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore,
PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse
survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a
variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment
of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors
because of secondary ALK kinase domain mutations and/or brain metastases. READ ARTICLE

Cell Cancer DOI: 10.1016/j.ccell.2015.05.010

Authors: Helen Y. Zou, Luc Friboulet, David P. Kodack, Lars D. Engstrom, Qiuhua Li, Melissa West, Ruth W. Tang, Hui Wang, Konstantinos Tsaparikos, Jinwei Wang, Sergei Timofeevski, Ryohei Katayama, Dac M. Dinh, Hieu Lam, Justine L. Lam, Shinji Yamazaki, Wenyue Hu, Bhushankumar Patel, Divya Bezwada, Rosa L. Frias, Eugene Lifshits, Sidra Mahmood, Justin F. Gainor, Timothy Affolter, Patrick B. Lappin, Hovhannes Gukasyan, Nathan Lee, Shibing Deng, Rakesh K. Jain, Ted W. Johnson, Alice T. Shaw, Valeria R. Fantin and Tod Smeal

Pre-ClinicalKirk SmithJuly 2, 2015lorlatinib, G1202R, PF-06463922, ALK TKI