Clinical Efficacy,Survival Outcomes And Gene Profile Analysis Of Crizotinib In ALK-Positive Advanced Non-Small-Cell Lung Cancer

Part Ⅰ Impact of crizotinib on long-term survival of ALK-positive advanced NSCLCBackground:Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC)in clinical trials.However,large-scale data on the clinical application and patient outcomes associated with crizotinib in China are still limited.We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in,to our knowledge,the largest cohort of patients with ALK-positive advanced NSCLC.Methods:We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017.Clinical and pathologic data,therapeutic regimen,objective response rate(ORR),progression-free survival(PFS)and overall survival(OS)were analyzed.Results:A total of 428 eligible ALK-positive NSCLC patients were enrolled,273(63.8%)of whom received crizotinib as first-line treatment.The PFS and OS from the initiation of crizotinib treatment were 14.4 months(95%confidence interval[CI]:12.35-16.37)and 53.4 months(95%CI:33.70-73.06),respectively.In subgroup analyses,patients who received crizotinib as first-line treatment showed a higher disease control rate(DCR)(94.8%vs 89.0%,P=0.038)and a longer median OS(OS not reached vs 40.5 months,P=0.023)compared with second-/further-line crizotinib treatment.For 261 patients with Response Evaluation Criteria In Solid Tumors(RECIST)defined progressive disease(PD),multivariate COX analysis revealed that in patients who received first-line crizotinib therapy,continued crizotinib beyond progressive disease(CBPD)and next-generation ALK inhibitors after crizotinib failure were associated with improved survival.Conclusions:This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients.CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.Part Ⅱ Clinical Features and Outcomes of ALK-positive NSCLC with Primary Resistance to CrizotinibBackground:A subset of patients harboring ALK rearrangement show a poor response to crizotinib and patients with primary resistance to crizotinib are rarely reported.We aimed to analyzed the clinical features and outcomes of these patients,and explore effective treatment regimen to overcome primary resistance to crizotinib.Methods:We collected the clinical features and survival outcomes of 28 primary-resistant responders(PRR)that have progression-free survival(PFS)of<3 months on crizotinib and compared with 78 long-term responders(LTR)that achieved>24 months PFS as control group.Results:The primary resistance was observed in 6.5%of the patients(28/428).The median PFS of PRR and LTR groups was 1.2 months(95%confidence inverval[CI]:0.70-1.73)and 47.0 months(95%CI:34.39-59.64)respectively,and a better Eastern Cooperative Oncology Group performance status(ECOG PS)score was significantly associated with longer PFS(odds ratio[OR]0.06,95%CI:0.01-0.33,P=0.001).The median overall survival(OS)of PRR group was 8.4 months(95%CI:3.47-13.42)and crizotinib as first-line treatment was an independent prognostic factor for survival outcome(P=0.005).Patients administered ALK-tyrosine kinase inhibitors(TKIs)after crizotinib progression have significantly longer survival than the PRR group treated with best supportive care(P=0.007),but no significant difference was found between ALK-TKIs and single chemotherapy(P=0.944).A novel LTBP1-ALK fusion and co-existing TP53 mutation with EML4-ALK fusion were detected by next-generation sequencing(NGS)in the tumor specimen of two patients with primary resistance to crizotinib.Conclusion:Patients with primary resistance to crizotinib displayed unfavorable survival outcomes and the underlying mechanism cannot be identified in clinical features.Nevertheless,next-generation ALK-TKIs and chemotherapy after crizotinib progression could confer a therapeutic and survival benefit in this population.Part Ⅲ Analysis of ctDNA gene profiling in ALK-positive non-small cell lung cancer patients treated with crizotinibBackground:Tumor tissue biopsy is considered as the "gold standard" for cancer dignosis,but is limited in practice due to the risk of operation,the difficulty of getting tissue samples,being unable to determine in real-time,tumor heterogeneity and so on.Circulating tumor DNA(ctDNA)can longitudinal monitor the genetic alterations and overcome many of the limitations of tissue sampling.Plasma ctDNA genotyping by next-generation sequencing(NGS)can simultaneously interrogate multiple genes and identify a broad range of molecular alterations,including chromosomal rearrangements.It can be optimally positioned for investigating the genetic profile and molecular mechanism of resistance in anaplastic lymphoma kinase(ALK)-positive non-small cell lung cancer(NSCLC)patients.Here,we performed longitudinal ctDNA analysis using a hybrid-capture based NGS plasma genotyping platform to assess tissue-plasma concordance and study the evolution of resistance in ALK-positive NSCLC patients treated with crizotinib.Methods:We performed analysis of plasma specimens from 69 ALK-positive patients with crizotinib treatment using a 63-gene capture-based next-generation sequencing(NGS)assay,to detect and quantify ALK fusion along with other driver mutation variants in plasma ctDNA.And we assessed the relationship between different molecular alterations and therapeutic response and survival outcomes in ALK-positive patients treated with crizotinib.Results:The proportion of patients with ALK fusion gene detected in baseline tissues and blood samples was 40.6%(28/69),and the positive rate of ALK detection in patients with first-line crizotinib treatment was higher than that of patients with second-/further-line crizotinib treatment(45.5%vs 32%).The echinoderm microtubule-associated protein-like 4(EML4)was the most common fusion partner of ALK rearrangements detected,and whether ALK fusion was detected by NGS in plasma had no significant effect on progression-free survival(PFS)of the whole population(10.5months vs 11.3months,P=0.251).TP53 mutation was the most frequently mutated gene in baseline plasma mutation profile,and concurrent TP53 mutation demonstrated shorter PFS compared with TP53 wild-type patients(10.1 months vs 12.9 months,P=0.265),though not in statistically significance.Additionally,two patients harbored ALK activating mutations(p.G1202R and p.S1206Y)upon progression on crizotinib treatment,and the dynamic changes of their frequency were consistant with treatment course.Conclusion:Plasma genotyping by NGS is an effective method for detecting and quantifying ALK fusions and other somatic mutations.TP53 mutation and various ALK fushion subtype may impact the efficacy of crizotinib treament,and whether the frequency of ALK fusion gene was associated with disease course still needs to be further investigated.