Response to dacomitinib in advanced non-small-cell lung cancer harboring the rar

lNTRODUCTlON

Among non-small-cell lung cancer(NSCLC)patients with epidermal growth factor receptor(

)mutations,the most common mutations are exon 19 deletions and exon 21 L858R point mutations,accounting for 80%-90% of all

mutations[1].With the development of next-generation sequencing(NGS),more rare or atypical mutations,such as

exon 20 and exon 18,have been identified,but their responses to TKIs have been variable and less investigated.

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Mutations in

exon 18,including point mutations and deletion-insertion mutations,were observed in approximately 4% of patients with

mutations[2].DelE709_T710insD is a rare complex in-frame deletion mutation in exon 18 and accounts for only 0.11% of

mutations(33/31015)according to the Catalog of Somatic Mutations in Cancer(COSMIC)v.94 database[3].Evidence regarding its response to available

-TKIs is limited.

Here,we present a patient with advanced lung adenocarcinoma harboring the rare

delE709_T710insD mutation who responded well to the second-generation

TKI dacomitinib.

CASE PRESENTATlON

Chief complaints

A 56-year-old female patient presented with right chest discomfort for 3 mo.

History of present illness

Chest computed tomography(CT)revealed a 1.9 cm × 2.1 cm mass in the anterior segment of the right upper lobe and multiple nodules in the bilateral lungs,accompanied by right pleural effusion.Moreover,the right hilar,mediastinal,and paratracheal lymph nodes(LNs)were found to be enlarged.

History of past illness

The patient had no history of any other diseases.

Personal and family history

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Physical examination

The right supraclavicular painless lymph node was palpated in the size of a soybean.

Laboratory examinations

The laboratory test data revealed that the serum carcinoembryonic antigen level was 279.6 ng/mL.

Imaging examinations

A positron emission tomography(PET)scan showed increased fluorodeoxyglucose(FDG)uptake in the right upper lobe mass,multiple pulmonary and subpleural nodules,and right supraclavicular,mediastinal,and right hilar lymph nodes.PET also indicated hypermetabolic nodules with low density in segment 6 of the liver and anterolateral area of the liver capsule,along with multiple bone destruction changes and high FDG uptake in T7 and T8 vertebral bodies and appendages,L5 spinous processes,and bilateral iliac bones(Figure 1).Magnetic resonance imaging of the brain was negative.

The authors declare that they have no conflict of interest.

MULTlDlSClPLlNARY EXPERT CONSULTATlON

She subsequently underwent ultrasound-guided needle biopsy of the right supraclavicular lymph node and right closed thoracic drainage.Endobronchial ultrasound-transbronchial needle aspiration(EBUSTBNA)was performed on LN 7 and 11R.Cancer cells were found both in the pleural effusion and clavicular lymph nodes.Pathological results of LN 11R were identified pulmonary adenocarcinoma,with P40(-),CK7(+),TTF-1(+),Napsin A(+),CK5/6(-),ALK Ventana(-),ALK-Negative(-)through immunohistochemistry(IHC).Genetic testing was performed on cell block samples from pleural effusion by polymerase chain reaction(PCR).Routine molecular genetic testing,including mutation of

and

,and fusion of

and

,were all negative.Supplementary material listed all gene and mutation sites of the PCR diagnostic kits.

FlNAL DlAGNOSlS

Shen YH initiated the case report and supervised the entire study;Xu F collected patient data,performed a literature review and wrote the manuscript;Xia ML obtained and analyzed the next-generation sequencing results;Pan HY reviewed the histological pathological examination of the biopsy;Pan JW was involved in patient follow-up after discharge;all authors read and approved the final manuscript.

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TREATMENT

The patient then started chemotherapy with pemetrexed plus carboplatin and bevacizumab in September 2020.A CT scan after 2 cycles showed a reduction in the mass in the right upper lobe,but disease progression was observed in February 2021.The progression-free survival1(PFS1)is 5 mo,and the best response was reduced stable disease based on Response Evaluation Criteria in Solid Tumors(RECIST)criteria.To seek more effective and potential treatment,CT-guided transthoracic lung biopsy was taken from the right upper lobe as her family demanded.A 12-gene NGS panel(Shanghai Yikon Genomics Inc.China)for lung cancer revealed the

Del18(delE709_T710insD)mutation.However,there are no recommended targeted drugs for this rare mutation.Dacomitinib 30 mg/d was administered as the second-line treatment,starting in February 2021.

The patient was free of any known congenital disease.

OUTCOME AND FOLLOW-UP

A CT scan revealed that the primary lesion significantly decreased in size after 2 mo,and a partial response(PR)was achieved(Figure 2).There were no significant adverse effects of dacomitinib therapy.Nevertheless,recent CT showed that the mass of the right upper lobe grew larger,which met the RECIST criteria for progressive disease(PD)after 7.0 mo of dacomitinib treatment.

DlSCUSSlON

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

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Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Like afatinib,dacomitinib is a second-generation pan-

inhibitor that irreversibly binds to all three kinase-active members of the ErbB family(

),leading to more efficient

inhibition.The efficacy of dacomitinib on patients acquiring Ex18 G719A as later-line therapy has been reported by Morita A

[21].In addition,dacomitinib

has an IC

=29 nM for Ba/F3 cells expressing exon 18 delE709_T710insD[19],indicating the potential activity of this nonclassical mutation.The results of a phase 3 trial of dacomitinib(NCT01774721,ARCHER 1050)indicated that first-line dacomitinib significantly improved PFS and OS

gefitinib,and the adverse events were manageable[22].Based on these findings,dacomitinib seemed to be a promising candidate for

-positive advanced NSCLC,including less common mutations.However,limited clinical data have shown the effect of dacomitinib on rare mutations.

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CONCLUSlON

In our study,we reported that a patient with

delE709_T710insD achieved PR after the initiation of dacomitinib,with a PFS2 of 7 mo.To the best of our knowledge,this is the first report describing the clinical efficacy of dacomitinib for

delE709_T710insD.The efficacy of dacomitinib on rare mutations needs to be evaluated

by further studies.In addition,appropriate genetic diagnosis methodologies will provide patients with more opportunities for targeted therapy.Our report may help to provide new treatment options for NSCLC patients with nonclassical variants.

FOOTNOTES

Based on this,the patient was identified as "driver gene-negative" right lung adenocarcinoma,cT1cN3M1c(TNM 8th Edition),stage IVB.

Studies on the delE709_T710insD mutation and its response to

-TKIs,including gefitinib,erlotinib,and afatinib,have been reported sporadically in recent years(Table 1).Wu JY

[6]reported that the prevalence of delE709_T710insD is 0.16%(5/3146)in

mutations.Six gefitinib-treated patients harboring delE709_T710insD were nonresponders,with a median PFS of 2.65 mo[6-8].Erlotinib was administered in previous case reports[8-12],which also seemed to be a frustrated treatment for delE709_T710insD.One had a PR,5 had PD,and the response rate was only 25%(1/6).Afatinib was proven to be effective for such rare variants[13-18].Among the 6 patients receiving afatinib,one achieved a complete response(CR),and 5 achieved a PR.More significantly,1 patient with E709_T710delinsD mutations showed a survival benefit of afatinib after erlotinib treatment failed[19].The overall response rate of afatinib for delE709_T710insD was 100%(7/7).According to the analysis by Rubiera-Pebe R

[20],the median PFS comparison between first-generation TKIs and afatinib for patients with delE709_T710insD is 3.1 mo

7.0 mo,respectively.

,a study by Kobayashi Y

[19]investigated the sensitivities of exon 18 mutations to various

-TKIs and suggested that secondgeneration

i have broader inhibitory profiles than other TKIs for rare mutations.

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mutations are observed in up to 50% of Asian non-small-cell lung cancer(NSCLC)patients and approximately 10%-20% of non-Asian patients.

TKIs have become the standard first-line treatment for

sensitizing mutations(del18 and L858R)NSCLC based on Phase III trials

platinum-based doublet chemotherapy[4],which has revolutionized the management of

-mutated NSCLC.Uncommon mutations or less frequent alterations involving exons 18 and 20 in

account for 10-20% of all

mutations in NSCLC.Individuals with uncommon

mutations seem to be a heterogeneous group exhibiting differential sensitivity to

inhibitors,but clinical evidence is scarce[5].

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

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China

Fei Xu 0000-0003-4200-1485;Meng-Ling Xia 0000-0002-0182-7400;Hui-Yun Pan 0000-0002-2536-5773;Jiong-Wei Pan 0000-0002-4077-2561;Yi-Hong Shen 0000-0002-7815-9973.

Wang LL

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A

Wang LL

1 Han B,Tjulandin S,Hagiwara K,Normanno N,Wulandari L,Laktionov K,Hudoyo A,He Y,Zhang YP,Wang MZ,Liu CY,Ratcliffe M,McCormack R,Reck M.

mutation prevalence in Asia-Pacific and Russian patients with advanced NSCLC of adenocarcinoma and non-adenocarcinoma histology: The IGNITE study.

2017;113: 37-44[PMID: 29110846 DOI: 10.1016/j.lungcan.2017.08.021]

2 Cheng C,Wang R,Li Y,Pan Y,Zhang Y,Li H,Zheng D,Zheng S,Shen X,Sun Y,Chen H.

Exon 18 Mutations in East Asian Patients with Lung Adenocarcinomas: A Comprehensive Investigation of Prevalence,Clinicopathologic Characteristics and Prognosis.

2015;5: 13959[PMID: 26354324 DOI: 10.1038/srep13959]

3 Atalogue of Somatic Mutations in Cancer,release version 94.[cited 20 January 2022].Available from: https://cancer.sanger.ac.uk/cosmic

4 Hsu WH,Yang JC,Mok TS,Loong HH.Overview of current systemic management of

-mutant NSCLC.

2018;29: i3-i9[PMID: 29462253 DOI: 10.1093/annonc/mdx702]

5 Russo A,Franchina T,Ricciardi G,Battaglia A,Picciotto M,Adamo V.Heterogeneous Responses to Epidermal Growth Factor Receptor(

)Tyrosine Kinase Inhibitors(TKIs)in Patients with Uncommon

Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario.

2019;20[PMID: 30901844 DOI: 10.3390/ijms20061431]

6 Wu JY,Shih JY.Effectiveness of tyrosine kinase inhibitors on uncommon E709X epidermal growth factor receptor mutations in non-small-cell lung cancer.

2016;9: 6137-6145[PMID: 27785061 DOI: 10.2147/OTT.S118071]

7 Wu JY,Yu CJ,Chang YC,Yang CH,Shih JY,Yang PC.Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer.

2011;17: 3812-3821[PMID: 21531810 DOI: 10.1158/1078-0432.CCR-10-3408]

8 Sousa AC,Silveira C,Janeiro A,Malveiro S,Oliveira AR,Felizardo M,Nogueira F,Teixeira E,Martins J,Carmo-Fonseca M.Detection of rare and novel

mutations in NSCLC patients: Implications for treatment-decision.

2020;139: 35-40[PMID: 31715539 DOI: 10.1016/j.lungcan.2019.10.030]

9 Ackerman A,Goldstein MA,Kobayashi S,Costa DB.

delE709_T710insD: a rare but potentially

inhibitor responsive mutation in non-small-cell lung cancer.

2012;7: e19-e20[PMID: 22982663 DOI: 10.1097/JTO.0b013e3182635ab4]

10 Klughammer B,Brugger W,Cappuzzo F,Ciuleanu T,Mok T,Reck M,Tan EH,Delmar P,Klingelschmitt G,Yin AY,Spleiss O,Wu L,Shames DS.Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer Whose Tumors Harbor Uncommon

Mutations.

2016;11: 545-555[PMID: 26773740 DOI: 10.1016/j.jtho.2015.12.107]

11 Martin J,Lehmann A,Klauschen F,Hummel M,Lenze D,Grohé C,Tessmer A,Gottschalk J,Schmidt B,Pau HW,Witt C,Moegling S,Kromminga R,Jöhrens K.Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non-Small-Cell Lung Cancer.

2019;20: 350-362.e4[PMID: 31175009 DOI: 10.1016/j.cllc.2019.04.012]

12 Isaksson S,Hazem B,Jönsson M,Reuterswärd C,Karlsson A,Griph H,Engleson J,Oskarsdottir G,Öhman R,Holm K,Rosengren F,Annersten K,Jönsson G,Borg Å,Edsjö A,Levéen P,Brunnström H,Lindquist KE,Staaf J,Planck M.Clinical Utility of Targeted Sequencing in Lung Cancer: Experience From an Autonomous Swedish Health Care Center.

2020;1: 100013[PMID: 34589915 DOI: 10.1016/j.jtocrr.2020.100013]

13 Ibrahim U,Saqib A,Atallah JP.

exon 18 delE709_T710insD mutated stage IV lung adenocarcinoma with response to afatinib.

2017;108: 45-47[PMID: 28625646 DOI: 10.1016/j.lungcan.2017.02.023]

14 An N,Wang H,Zhu H,Yan W,Jing W,Kong L,Zhang Y,Yu J.Great efficacy of afatinib on a patient with lung adenocarcinoma harboring uncommon

delE709_T710insD mutations: a case report.

2019;12: 7399-7404[PMID: 31686847 DOI: 10.2147/OTT.S221638]

15 Iwamoto Y,Ichihara E,Hara N,Nakasuka T,Ando C,Umeno T,Hirabae A,Maeda Y,Kiura K.Efficacy of afatinib treatment for lung adenocarcinoma harboring exon 18 delE709_T710insD mutation.

2019;49: 786-788[PMID: 31187861 DOI: 10.1093/jjco/hyz086]

16 D'Haene N,Le Mercier M,Salmon I,Mekinda Z,Remmelink M,Berghmans T.SMAD4 Mutation in Small Cell Transformation of Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma.

2019;24: 9-13[PMID: 30413663 DOI: 10.1634/theoncologist.2018-0016]

17 Wei Y,Cui Y,Guo Y,Li L,Zeng L.A Lung Adenocarcinoma Patient With a Rare

E709_T710delinsD Mutation Showed a Good Response to Afatinib Treatment:A Case Report and Literature Review.

2021;11: 700345[PMID: 34178699 DOI: 10.3389/fonc.2021.700345]

18 Jelli B,Taton O,D'Haene N,Remmelink M,Mekinda Z.Complete Response to Afatinib of an

Exon 18 delE709_T710insD-Mutated Stage IV Lung Adenocarcinoma.

2021;8: 002749[PMID: 34527619 DOI: 10.12890/2021_002749]

19 Kobayashi Y,Togashi Y,Yatabe Y,Mizuuchi H,Jangchul P,Kondo C,Shimoji M,Sato K,Suda K,Tomizawa K,Takemoto T,Hida T,Nishio K,Mitsudomi T.

Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.

2015;21: 5305-5313[PMID: 26206867 DOI: 10.1158/1078-0432.ccr-15-1046]

20 Rubiera-Pebe R,Hicks JK,Tanvetyanon T.Efficacy of tyrosine kinase inhibitors against lung cancer with

exon 18 deletion: Case report and pooled analysis.

2021;28: 100407[PMID: 34090219 DOI: 10.1016/j.ctarc.2021.100407]

21 Morita A,Hosokawa S,Yamada K,Umeno T,Kano H,Kayatani H,Shiojiri M,Sakugawa M,Bessho A.Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon

mutation.

2021;12: 1248-1251[PMID: 33651475 DOI: 10.1111/1759-7714.13897]

22 Wu YL,Cheng Y,Zhou X,Lee KH,Nakagawa K,Niho S,Tsuji F,Linke R,Rosell R,Corral J,Migliorino MR,Pluzanski A,Sbar EI,Wang T,White JL,Nadanaciva S,Sandin R,Mok TS.Dacomitinib

gefitinib as first-line treatment for patients with

-mutation-positive non-small-cell lung cancer(ARCHER 1050): a randomised,open-label,phase 3 trial.

2017;18: 1454-1466[PMID: 28958502 DOI: 10.1016/S1470-2045]