Yudong Su1, Xiang Long2, Yang Song3, Peng Chen1, Shanqing Li3, Huaxia Yang4, Pancheng Wu3, Yanyu Wang3, Zhongxing Bing3, Zhili Cao3, Lei Cao3, Yijun Wu3, Zhe Zhang5, Jing Liu5, Bing Li5, Jianxing Xiang5, Ke Ma5, Tengfei Zhang5, Lu Zhang5, Xinru Mao5, Hao Liu5, Puyuan Xing6, Naixin Liang7. 1. Key Laboratory of Cancer Prevention and Therapy, Department of Thoracic Medical Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China. 2. Department of Respiratory Medicine, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China. 3. Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 9 Dongdan Santiao, Dongcheng District, Beijing, 100730, China. 4. Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China. 5. Burning Rock Biotech, Guangzhou, 510000, Guangdong, China. 6. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. xingpuyuan@163.com. 7. Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 9 Dongdan Santiao, Dongcheng District, Beijing, 100730, China. pumchnelson2018@163.com.
Abstract
BACKGROUND: ALK-rearranged non-small cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a US Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor for treating ALK-rearranged NSCLC, has shown remarkable response in ALK-positive NSCLC. However, heterogeneity of clinical responses exists among different ALK fusion partners. Several small studies have investigated the correlation between fusion partners and efficacy, but not yielded consistent results. OBJECTIVE: We investigated the prevalence of ALK rearrangements in a Chinese NSCLC population, and correlated clinical outcomes of crizotinib with different ALK partners/variants. PATIENTS AND METHODS: We retrospectively reviewed genomic profiling and clinical data of 110 ALK-rearranged NSCLC patients from five centers. The clinical response to crizotinib and survival data in ALK-positive patients was retrospectively analyzed. RESULTS: A total of 134 ALK rearrangements with 39 partners were identified in 110 patients (5.6%) among a cohort of 1971 NSCLC patients. The most frequently occurring ALK fusion partner was EML4, which was identified in 71.6% (96/134) of all of the rearrangements in 87.3% (96/110) patients, and with variant 3 (41/96, 42.7%) as the main variant type. No statistically significant differences in terms of progression-free survival (PFS) and overall survival (OS) were found between EML4-ALK and non-EML4-ALK NSCLC patients in our cohort (PFS, p = 0.207; OS, p = 0.678). Outcomes did not differ significantly between patients above and below 40 years of age (PFS, p = 0.427; OS, p = 0.686), nor between patients treated with crizotinib in different lines of therapy (PFS, p = 0.171; OS, p = 0.922). For EML4-ALK-positive NSCLC (n = 96), patients harboring variant 3 or variant 5 displayed significantly lower PFS and OS than those with other variants (PFS, 8.6 vs. 11.3 months, p = 0.046; OS, 31.0 vs. 37.6 months, p = 0.026). In addition, patients with a single EML4-ALK rearrangement event displayed favorable PFS (10.0 vs. 7.2 months, p = 0.040) and OS (36.0 vs. 20.0 months, p = 0.029) compared to those harboring multiple ALK rearrangements. CONCLUSIONS: This study illustrates the patterns of ALK fusion variants present in Chinese NSCLC patients and might help explain heterogeneous clinical outcomes to crizotinib treatment according to different ALK fusion variants.
BACKGROUND:ALK-rearranged non-small cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a US Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor for treating ALK-rearranged NSCLC, has shown remarkable response in ALK-positive NSCLC. However, heterogeneity of clinical responses exists among different ALK fusion partners. Several small studies have investigated the correlation between fusion partners and efficacy, but not yielded consistent results. OBJECTIVE: We investigated the prevalence of ALK rearrangements in a Chinese NSCLC population, and correlated clinical outcomes of crizotinib with different ALK partners/variants. PATIENTS AND METHODS: We retrospectively reviewed genomic profiling and clinical data of 110 ALK-rearranged NSCLCpatients from five centers. The clinical response to crizotinib and survival data in ALK-positive patients was retrospectively analyzed. RESULTS: A total of 134 ALK rearrangements with 39 partners were identified in 110 patients (5.6%) among a cohort of 1971 NSCLCpatients. The most frequently occurring ALK fusion partner was EML4, which was identified in 71.6% (96/134) of all of the rearrangements in 87.3% (96/110) patients, and with variant 3 (41/96, 42.7%) as the main variant type. No statistically significant differences in terms of progression-free survival (PFS) and overall survival (OS) were found between EML4-ALK and non-EML4-ALKNSCLCpatients in our cohort (PFS, p = 0.207; OS, p = 0.678). Outcomes did not differ significantly between patients above and below 40 years of age (PFS, p = 0.427; OS, p = 0.686), nor between patients treated with crizotinib in different lines of therapy (PFS, p = 0.171; OS, p = 0.922). For EML4-ALK-positive NSCLC (n = 96), patients harboring variant 3 or variant 5 displayed significantly lower PFS and OS than those with other variants (PFS, 8.6 vs. 11.3 months, p = 0.046; OS, 31.0 vs. 37.6 months, p = 0.026). In addition, patients with a single EML4-ALK rearrangement event displayed favorable PFS (10.0 vs. 7.2 months, p = 0.040) and OS (36.0 vs. 20.0 months, p = 0.029) compared to those harboring multiple ALK rearrangements. CONCLUSIONS: This study illustrates the patterns of ALK fusion variants present in Chinese NSCLCpatients and might help explain heterogeneous clinical outcomes to crizotinib treatment according to different ALK fusion variants.
Authors: Aaron McKenna; Matthew Hanna; Eric Banks; Andrey Sivachenko; Kristian Cibulskis; Andrew Kernytsky; Kiran Garimella; David Altshuler; Stacey Gabriel; Mark Daly; Mark A DePristo Journal: Genome Res Date: 2010-07-19 Impact factor: 9.043
Authors: Daniel C Koboldt; Qunyuan Zhang; David E Larson; Dong Shen; Michael D McLellan; Ling Lin; Christopher A Miller; Elaine R Mardis; Li Ding; Richard K Wilson Journal: Genome Res Date: 2012-02-02 Impact factor: 9.043
Authors: A T Shaw; A M Varghese; B J Solomon; D B Costa; S Novello; M Mino-Kenudson; M M Awad; J A Engelman; G J Riely; V Monica; B Y Yeap; G V Scagliotti Journal: Ann Oncol Date: 2012-08-10 Impact factor: 32.976
Authors: Mehtap Derya Aydemirli; Jaap D H van Eendenburg; Tom van Wezel; Jan Oosting; Willem E Corver; Ellen Kapiteijn; Hans Morreau Journal: Endocr Relat Cancer Date: 2021-05-11 Impact factor: 5.678