Heterogeneity Of Clinical Outcomes To Crizotinib In ALK-Rearranged Chinese Patients With Non-Small Cell Lung Cancer

Background and purpose:Lung cancer morbidity and mortality account for the first place in all malignant tumors,of which nearly 80%are non-small cell lung cancer?NSCLC?,more than80%of which are diagnosed as advanced lung cancer,and the 5-year survival rate is only 19.8%.Targeted therapy is an important component of advanced NSCLC precision therapy.The development of sequencing technology has facilitated the discovery of a variety of NSCLC-driven genes,and patients with positive driving genes can be treated with the corresponding targeted drugs.Anaplastic lymphoma kinase?ALK?is a common driving gene in advanced NSCLC,and echinoderm microtubule-associated protein-like 4?EML4?is the most common ALK fusion partner.Crizotinib is the first ALK tyrosine kinase inhibitor?TKI?approved by the Food and Drug Administration?FDA?to significantly prolong progress free survival?PFS?and overall survival?OS?in patients.However,there are significant differences in the efficacy of different patients after receiving Crizotinib.Which molecular mechanisms lead to the heterogeneity of efficacy is not yet clear.Several studies have reported a correlation between the different fusion variants of ALK and the clinical efficacy of Crizotinib,but have produced different results.This study retrospectively analyzed the distribution of different fusion variants in 110 patients with ALK positive in Chinese NSCLC population,and further explored its relevance to the clinical efficacy of Crizotinib.Method:We retrospectively analyzed the genomic profiles and clinical data of 1971NSCLC patients who visited the four tumor centers?Tianjin Medical University Cancer Institute and Hospital,Cancer Institute and Hospital of Chinese Academy of Medical Sciences,Peking Union Medical College Hospital,and Peking University Shenzhen Hospital?from December 2014 to May 2017.Samples were tested by next generation sequencing?NGS?in clinical laboratories accredited by the US Clinical Laboratory Improvement Act?CLIA?.Differences in the clinicopathologic characteristics between the groups were compared using chi-square or Fisher's exact test.Result:1.Our results showed that ALK rearrangements occurred in?110/1971,5.6%?NSCLC patients,and other ALK fusion partners were detected in?36/110,32.7%?patients.A total of?22/110,20%?patients were found to have multiple ALK rearrangements in the same sample,and a total of 134 ALK rearrangements and 39 different ALK fusion partners were detected.The most common ALK fusion partner is EML4?96/110,87.3%?,variant 3?41/96,42.7%?is the major EML4-ALK fusion subtype,followed by variant 1?39/96,40.6%?and variant 2?10/96,10.4%?,variant5 was detected in only 1 patient?1/96,1.0%?.2.Survival analysis of 110 patients with ALK-positive advanced NSCLC after Crizotinib treatment,mPFS?9.4 vs 14.5 months,P=0.207?and mOS?35.1 vs 35.5months?in patients with EML4-ALK rearrangement and non-EML4-ALK rearrangement,P=0.678)were not significantly different.Patients were further analyzed according to their age??40 and<40?,and there were no significant differences?7.3 vs 11.3 months,P=0.427;25.4 vs 35.5 months,P=0.686?.Survival analysis of patients with different treatment lines for Crizotinib showed no significant differences in mPFS and mOS between the groups(1^st vs 2^nd vs 3^rd line:11.3 vs 9.1vs 7.0 months,P=0.171;35.1 vs 35.5 months vs not reached,P=0.922).3.Survival analysis of patients with EML4-ALK positive?n=96?showed that both mPFS?8.6 vs 11.3 months,P=0.046?and mOS?31 vs 37.6 months,P=0.026?were significantly worse in patients with variants 3 and 5 than in other variants.Cox multivariate analysis showed that variant 3 and variant 5 were independent influencing factors for PFS?hazard ratio,2.0;95%CI,1.01-4.0;P=0.046?and OS?hazard ratio,2.99;95%CI,1.011-8.87;P=0.048?.In addition,we found that mPFS?7.2 vs 10.0 months,P=0.040?and mOS?20.0 vs 36.0 months,P=0.029?in patients with multiple ALK rearrangements were significantly worse than patients with single EML4-ALK rearrangement.Cox multivariate analysis showed that multiple ALK rearrangements were independent factors influencing PFS?hazard ratio,5.2;95%CI,2.16-12.7;P<0.001?and OS?hazard ratio,6.27;95%CI,1.787-22.04;P=0.004?.The baseline clinicopathological characteristics of the above groups were very balanced and the differences were not statistically significant.Conclusion:1.The detection rate of screening for ALK rearrangement by NGS in Chinese NSCLC population was 5.6%.The most common ALK fusion partner was EML4?87.3%?,variant 3 was the major EML4-ALK fusion subtype?42.7%?,followed by variant 1?40.6%?and variant 2?10.4%?.2.Variant 3 and variant 5 and multiple ALK rearrangements are independent factors influencing PFS and OS.Therefore,more precise stratification of patients with advanced NSCLC through different variants of ALK can help predict the clinical efficacy of different patients with Crizotinib.3.This study helps to explain the heterogeneity of clinical efficacy of Crizotinib in ALK-positive patients with advanced NSCLC,and a prospective multicenter study is needed to further clarify the relationship between ALK variant type and clinical efficacy of Crizotinib.