Effective response to crizotinib of concurrent KIF5B-MET and METCDR2-rearranged

INTRODUCTION

The mesenchymal-epithelial transition()gene,located on chromosome 7q21-31,encodes a receptor tyrosine kinase and is activated by its ligand,hepatocyte growth factor[1,2].The MET signaling pathway is often upregulated in various human malignancies,including non-small cell lung cancer(NSCLC)[2].The most commongene aberrations are gene amplifications and exon 14 splice variants foundin approximately 2% to 10% of lung cancer patients[3].Chromosomal rearrangements resulting in gene fusions involvingare generally rare but could account fordriven oncogenesis[4].Currently,a total of fivefusion partner genes have been reported in NSCLC,including[5,6],[5],[7,8],[9],and ATXN7L1[10](Table 1)Crizotinib,an FDA-approved tyrosine kinase inhibitor for-rearranged and-rearranged NSCLC,has been originally designed to targetamplifications and mutations[11].Several cases and clinical studies have reported the efficacy of crizotinib and cabozantinib in targetingamplification[12,13],exon 14 skipping[14],and certain rearrangements[5-7,10]in NSCLC patients.A recent metaanalysis analyzed six clinical trials(cohort size range: 8-69)on-altered NSCLC revealed an objective response rate of 40.6%(95%CI: 28.3%–53.0%)and disease control rate of 78.9%(95%CI: 70.3%–87.4%)for crizotinib,with a median progression-free survival and overall survival of 5.2 and 12.7 mo,respectively[15].Most of these studies enrolled fewfusion-positive patients,because they are exceedingly rare.Current knowledge regardingfusions is mostly derived from two cohort studies in Chinese lung cancer patients,which identified one(0.04%,1/2410)fusion[16]and fifteen(0.26%,15/5695)fusions involving the MET kinase domain[17],respectively.

Herein,we report the clinical efficacy of crizotinib in a patient with poorly differentiated NSCLC withand a concurrent novelfusion.

CASE PRESENTATION

Chief complaints

In November 2018,a 46-year-old female never-smoker presented in our clinic with a complaint of persistent dry cough.

History of present illness

The cough had been lasted for over a week.

History of past illness

Past medical history was not remarkable for this patient.

Computed tomography(CT)and magnetic resonance imaging revealed a tumor in the lower lobe of the right lung,right hilar and mediastinal lymph node involvement,and multi-organ metastasis including the left pleura,liver,pericardium,and bone.

Laboratory examinations

Histopathological analysis of tissue biopsy samples collected from the right lung revealed poorly differentiated NSCLC(Figure 1)with the immunohistochemistry results of AE1/AE3(+),SMACA4 BRG1(+),CK18(+),INI-1(+),CD56(-),chromogranin A(-),synaptophysin(-),CK7(-),ERG(-),GATA3(-),CD34(-),CDX2(-),P40(-),SALL4(-),TTF-1(-),Desmin(-),and S-100(-).In addition,PD-L1 expression analysis revealed a tumor proportion score of 80%.Molecular analysis of the biopsies detected no driver alterations in EGFR,ALK,or ROS1.

Imaging examinations

But her apartment was empty. Somehow in the hours overnight, she had packed by herself and moved by herself. The rooms were now impersonal14; their cold stillness could not respond when he fell to the floor and sobbed15.

FINAL DIAGNOSIS

The final diagnosis of the patient was NSCLC stage IV(T4N3M1).

TREATMENT

Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images.

The case was reported in accordance with the CARE reporting checklist(2016).

And she remembered that his head had rested on her bosom64, and how heartily65 she had kissed him; but he knew nothing of all this, and could not even dream of her

OUTCOME AND FOLLOW-UP

Lizaso A and Lin J were employees of Burning Rock Biotech during the conduct of the study.All other authors declare no competing interests.

After crizotinib failure,we chose nivolumab(a human IgG4 PD-1 antibody)as a salvage therapy because of the high PD-L1 expression.However,the patient did not benefit from nivolumab and her condition was declining significantly.She was hospitalized for worsening respiratory function and died shortly thereafter with an overall survival(OS)of 7 mo from diagnosis.

DISCUSSION

Gene alterations inare emerging as clinically relevant biomarker for predicting the response to MET inhibitors[2].However,due to the rarity offusions,treatment responses have only been clinically evaluated foramplification and exon 14 skipping[12-14]and only a few case reports have reported the efficacy of crizotinib in patients withfusions with various partners[5-7].In our report,we describe the detection ofco-occurring with a novel gene fusion involvingandand provided the clinical evidence of the efficacy of crizotinib in aand-rearranged poorly differentiated NSCLC patient.K24:M15 has been reported in 0.5%(1/206)of adenocarcinoma and 4%(2/28)of sarcomatoid lung cancer patients in a recent study in Taiwanese patients[19].andstudies consistently demonstrated the oncogenic potential offusion and sensitivity to crizotinib[19].Consistently,several case reports have observed clinical efficacy of crizotinib in K24:M14[6]and K24:M15[5]-rearranged NSCLC[5,6].The dramatic response to crizotinib observed in our patient highly suggests that the fusions acting either solely or in synergy served as oncogenic driver/s in the patient’s tumor which confers sensitivity to crizotinib.The oncogenic potential and sensitivity to crizotinib or other MET inhibitors of the novel gene fusionas well as the presence of two concurrentfusions require further investigations.

The negative results for histopathologic markers TTF-1,CK7,P40,and CDX2 and classic driver mutations in,,andprovided neither clear indication of the cell differentiation nor any therapeutic targets.With a poor response to the first-line chemotherapy regimen,our patient had a very poor prognosis.Comprehensive genomic profiling allowed us to understand the mutation landscape of the tumor and explore alternative therapeutic targets that provided benefit to our patient.The detection of the potentially targetablefusions in our patient with poorly differentiated NSCLC highlights the importance of comprehensive genomic profiling regardless of tumor histology,particularly in patients with no known driver mutations to guide therapeutic decisions.

China

Attention should be paid to managing toxicities associated with crizotinib monotherapy.In a study of 2028 Japanese-rearranged patients receiving crizotinib,adverse drug reactions occurred in 91.6% of patients,the most common(incidence ≥ 15%)of which were nausea(32.2%),diarrhea(24.3%),photopsia(18.9%),vomiting(17.5%),and dysgeusia(16.8%).A considerable proportion of patients(623,30.7%)discontinued treatment within 12 wk after therapy initiation due to adverse events.Only 68.2% of patients remained on crizotinib after 3 mo,55.2% after 6 mo,and 36.1% after 12 mo,with a median duration of 7.9 mo[10].Therefore,it is advised to monitor patients for these adverse reactions during the clinical use of crizotinib.

CONCLUSION

The efficacy of crizotinib in an advanced poorly differentiated NSCLC patient with concurrentandgene fusions suggests that crizotinib can serve as a therapeutic option in patients withfusions.Further clinical studies are required to confirm the clinical value of crizotinib or other MET inhibitors in patients withfusion.

She represented to him what a powerful enchanter Grumedan was, and how, if he were provoked, he might avenge30 himself upon the Princess, since he was the most unjust and churlish of all the enchanters, and had often before had to be punished by the Fairy Queen for some of his ill-deeds

ACKNOWLEDGEMENTS

The authors thank the patient and her family.We also thank the investigators,study coordinators,operation staff,and the whole project team who worked on this case.We are grateful to Xiao Zou and Lei Lei at Burning Rock Biotech for technical assistance.

FOOTNOTES

Liu LF and Deng JY contributed to the study concept and design and performed the statistical analysis;Liu LF,Deng JY,and Lin J contributed to the acquisition,analysis,and interpretation of the data;Liu L,Deng J,and Lizaso A contributed to the drafting of the manuscript;Sun S contributed to the critical revision of the manuscript for important intellectual content.

the National Key R&D Program of China,No.2017YFC0907900 and 2017YFC0907904.

Based on the findings presented above,the patient was then treated with two cycles of gemcitabine(1.0 g/mon days 1 and 8)plus cisplatin(75 mg/mon day 1)with no clinical benefit.

In January 2019,an abdominal CT scan revealed the enlargement of the lung primary and liver metastases.To explore potentially actionable mutations,tumor biopsy samples were submitted for capture-based targeted sequencing using a panel with 520 cancer-related genes(OncoScreen Plus,Burning Rock,China).As shown in Figure 2,the analysis revealed the detection of two concurrentfusions with respective partner genes(K24:M15)and(M15:C3).No other classic lung cancer driver mutations were detected apart fromC277X.Due to economic and insurance conditions and out of concern over evidence suggesting reduced efficacy of immunotherapy in nonsmall cell lung cancer patients carrying oncogenic driver alterations[18],crizotinib(250 mg,p.o.bid)was started as the second line treatment in February 2019.After 4 wk of therapy,review of chest CT revealed a dramatic reduction of the lesions in the left and right lobes of the lungs with no new lesions,which was evaluated as partial response with Response Evaluation Criteria in Solid Tumors v.1.1(RECIST 1.1)(Figure 3A and B).At approximately 3 mo from the start of targeted therapy,the patient continued to benefit from crizotinib without side effects.However,the disease progressed afterwards in May,2019 as per RECIST 1.1.Specifically,compared with the previous evaluation(Figure 3B),new lesions emerged mostly in the right lung,accompanied by growth of the previously reduced tumor(Figure 3C and D).

It is not the same thing. In this chair, I can move by myself; I can go anywhere I need to go. That boat traps me so I can t do anything ?nbsp;I couldn t even save myself if something happened and I fell out.

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After the failure of crizotinib,we chose an immune checkpoint inhibitor(ICI)as a salvage therapy.Although with high PD-L1 expression,the patient did not benefit from the ICI.This is similar with the finding of previous studies that ICIs are less effective in NSCLC withmutation orfusion[18,20].

Sadly, I never saw Erma again. My parents sat me down after school one day to say a letter had arrived from the chaplain at the hospital on Long Island. Erma had been rushed to the hospital after being found lying in the snow near her home. She had lingered for several days before she succumbed16 to pneumonia17. Before she died, she had written a letter in front of the chaplain addressed to My best friend, Anne. The chaplain knew my parents and of my association with Erma and had forwarded the letter to us. It said simply: Thank you for being my friend. I love you. Take my driftwood and make others happy. Love Erma. It took me weeks before I could talk to my parents about Erma s death. She was the first person I knew who had died. I found it hard to relate to the fact that I would never see her again. I dreamed about her, the ocean behind her smiling face, the beauty of her driftwood.

Lian-Fang Liu 0000-0001-5450-0711;Jia-Ying Deng 0000-0002-1744-1203;Analyn Lizaso 0000-0002-4175-7398;Jing Lin 0000-0001-5789-0970;Si Sun 0000-0001-8849-6343.

Scarcely had he left the town behind him when he came to a broad river which no man might pass, for he was standing at the end of the world, and this was the river which flowed round it

Then little Gerda wept hot tears, which fell on his breast, and penetrated7 into his heart, and thawed8 the lump of ice, and washed away the little piece of glass which had stuck there. Then he looked at her, and she sang—

Zhang H

He dismounted, and moved towards them; but his companions hurried after and begged him first to let them go and announce him to the king, and said that then, when they had put their possessions in a place of security, they would enter into the all important matter of the princess

Wang TQ

Zhang H