Funder: NIHR Great Ormond Street Hospital Biomedical Research Centre NIHR Academic Clinical fellowshipFunder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/10000444

Behjati, Sam

Jackson, Thomas John

Jorgensen, Mette

Ogunbiyi, Olumide

Oliver, Thomas Richard William

Sebire, Neil

Slater, Olga

Apollo (Cambridge)

CORRESPONDENCEComment on: “Tumour-agnostic drugs in paediatric cancers”,Chisholm et al., BJC 2020British Journal of Cancer (2021) 124:524–526; https://doi.org/10.1038/s41416-020-01103-0We agree in principle with our colleagues’ endorsement in thisjournal of the use of the tropomyosin receptor kinase (TRK)inhibitor LOXO-101 (larotrectinib) in children.1 Our enthusiasmfor the accelerated deployment of LOXO-101 has beentempered by our experience of multi-TRK inhibitor resistancethough. Resistance mutations to LOXO-101 do occur but can beovercome by second- generation TRK inhibitors, such as LOXO-195 (selitrectinib).2 We, however, report the emergence ofresistance mutations to both first- and second-generation TRKwww.nature.com/bjcPhase 1IVA6 monthsPhase 2LOXO-1012 monthsPhase 3LOXO-1952.5 monthsDiagnosticbiopsyn=1Phase 4LOXO-195 > VIT2 monthsG623R+ F617LETV6-NTRK3WildtypeNTRK3G623RG623RF617LTumour readsNTRK3PD42749hPD42749eDeathPD42749dResectiontissuesn=2Resectiontissuesn=2Biopsytissuesn=2PD42749fPD42749iPD42749aPD42749g Biopsy IDTumourresponseabcClone sizea,g f,iedhSx SxBxBx< 1%–20%MainFig. 1 Evolution of multi-TRK resistance. a Clonal composition of tumour tissues over the course of illness. Coloured circles denote the clonalcomposition of tissues sequenced at a given time point. The scale of a clone’s contribution to these samples is relative to a circle’s size; largercircles indicate a greater contribution by that clone. Beneath this is a simplified overview of principal systemic therapies and the resultanttumour responses. IVA ifosfamide, vincristine, actinomycin D, VIT vincristine, irinotecan, temozolomide, LOXO-101 (larotrectinib) first-generation TRK inhibitor, LOXO-195 (selitrectinib) second-generation TRK inhibitor. Arrowheads tapering from left to right indicate partial/complete tumour response and vice versa for progression. b Sequence of somatic alterations of NTRK3. Black line: ETV6-NTRK3 fusion. Grey line:wild-type copy of NTRK3. Number of lines corresponds to copy number. Screen capture on the right shows the co-occurrence of bothresistance mutations on the same tumour sequencing reads. At the bottom are three coronal MRI images of the tumour (white arrow): one atdiagnosis (left) and two demonstrating the tumour’s best response to LOXO-101 (middle) and LOXO-195 (right). c Phylogenetic tree of tumourlineages. Solid lines: major branches where mapped mutations revealed the relationship of the clones identified. Labelled overlying colouredcircles represent the clones shown in panel a. Dashed lines: private mutations that did not inform tree building.Received: 8 June 2020 Revised: 24 July 2020 Accepted: 7 September 2020Published online: 1 October 2020© The Author(s) 2020 Published by Springer Nature on behalf of Cancer Research UKinhibitors in an NTRK-driven infantile fibrosarcoma (IFS). Ourcase questions the introduction of TRK inhibitors into clinicalpractice without the scrutiny of comparative clinical trials,especially in the context of NTRK-driven childhood tumours thatare rarely lethal. Our cautionary words are particularly pertinentin view of the recent approval to use LOXO-101 by the UK’sNational Institute for Health and Care Excellence.Our patient, a 10-month-old girl, suffered from an anteriormediastinal IFS extending into the neck that harboured acanonical IFS-associated ETV6-NTRK3 gene fusion. We treatedher over a period of 12.5 months with cytotoxic chemotherapy,first- and second-generation TRK inhibitors and two attempts atcomplete surgical resection (Fig. 1a, b). The tumour repeatedlyregrew and ultimately led to the child’s death. To understandthe development of treatment resistance, we reconstructed theevolution of the lethal clone from somatic mutations, obtainedby whole genome (fatal relapse) or exome sequences (seventissues obtained at diagnosis and after each recurrence).At diagnosis, the tumour contained single copies of wild-typeNTRK3 and the ETV6-NTRK3 fusion (Fig. 1b). Analysis of thefirst relapse revealed duplication of the ETV6-NTRK3 fusion.At second relapse, after 2 months of treatment with a first-generation TRK inhibitor (LOXO-101), we detected the NTRK3resistance mutation, G623R,3 along with loss of the wild-typeNTRK3 gene. Then, following 2.5 months of treatment with asecond-generation TRK inhibitor (LOXO-195), multidrug resis-tance emerged in the shape of two mutations, NTRK3 G623R andF617L.3 Both were present in the same cells of the dominantclone, as they were captured on the same reads (i.e. the sameDNA molecule) (Fig. 1b). Reconstructing the phylogeny oftumour lineages from substitutions and small indels revealeda complex clonal composition of the tumour, from which thelethal, double- mutant clone emerged (Fig. 1c). These analysesdelineate the development of a seemingly “supercharged” ETV6-NTRK3 resistance fusion, forged under the selective pressure ofTRK inhibitors.The key evidence justifying the use of LOXO-101 in childrenwith NTRK-driven tumours is a phase 1/2 study, which showedan impressive 93% objective response rate (ORR) amongst 15children.4 Two of these with locally advanced disease evenachieved R0 resections following treatment with TRK inhibitors.We note that one patient did develop the same NTRK3 G623Rresistance mutation as our patient although responded to asecond-generation inhibitor (selitrectinib). Recent work in amixed-age cohort across histologies suggests that a 45% ORRcan be achieved with LOXO-195 in patients with these NTRKkinase domain mutations.3On this basis, it would appear that TRK inhibition is anattractive, non-cytotoxic strategy for tumour shrinkage prior to, oreven in lieu of, surgery in childhood tumours of low metastaticpotential, such as IFS. Our challenge has been that the samemarked clinical responses to both TRK inhibitors were seen in ourpatient, yet were short lived and preceded the outgrowth of alethal tumour clone. Without access to long-term efficacy data orhead-to-head comparisons to best current practice, it is difficultto know how representative our experience is and so highlightsthe current challenge in identifying the most opportune momentto utilise TRK inhibitors in the management of IFS. Clearly, in thecontext of invariably lethal cancers, phase 1/2 studies mayprovide sufficient evidence for utilising tumour-agnostic drugs.However, in seldom lethal NTRK-driven childhood tumours, werequire comparative clinical trials beyond basket studies to learnwhen and how to deploy these drugs. Until such evidence isavailable, we would advocate a cautious use of TRK inhibitors inchildren.ACKNOWLEDGEMENTSWe thank Dr Grace Collord for her review of this letter. We are grateful to our patientand her family for participation in our investigation.AUTHOR CONTRIBUTIONST.R.W.O. analysed sequencing data. T.J.J. and O.O. contributed to experiments. N.S.provided pathological, and O.S., M.J. and S.B. oncological expertise. M.J. and S.B.co-directed this study.ADDITIONAL INFORMATIONEthics approval and consent to participate The child’s legal guardian providedinformed consent for participation in this REC-approved study (UK NHS NationalResearch Ethics Service reference 16/EE/0394). All patient information has beenanonymised for the purposes of this letter. The study was performed in accordancewith the Declaration of Helsinki.Consent to publish Express consent has been given to publish the details of thiscase by the child’s legal guardian.Data availability Raw sequencing data pertaining to this case are available in EGA.Competing interests Dr. Slater has advised Bayer on TRK inhibitors. The remainingauthors declare no competing interests.Funding information S.B. and T.R.W.O. are funded by Wellcome. All research at GreatOrmond Street Hospital NHS Foundation Trust and UCL Great Ormond StreetInstitute of Child Health is made possible by the NIHR Great Ormond Street HospitalBiomedical Research Centre. The views expressed are those of the author(s) and notnecessarily those of the NHS, the NIHR or the Department of Health and Social Care.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.Thomas Richard William Oliver 1,2, Thomas John Jackson3,4,Olumide Ogunbiyi3, Neil Sebire3,4, Olga Slater3,Mette Jorgensen3 and Sam Behjati1,2,51Wellcome Sanger Institute, Hinxton CB10 1SA, UK; 2CambridgeUniversity Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK;3Great Ormond Street Hospital for Children NHS Foundation Trust,London WC1N 3JH, UK; 4UCL Great Ormond Street Institute of ChildHealth, London WC1N 1EH, UK and 5Department of Paediatrics,University of Cambridge, Cambridge CB2 0QQ, UKCorrespondence: Mette Jorgensen (mette.jorgensen@gosh.nhs.uk) orSam Behjati (sb31@sanger.ac.uk)REFERENCES1. Chisholm, J. C., Carceller, F. & Marshall, L. V. Tumour-agnostic drugs in paediatriccancers. Br. J. Cancer 122, 1425–1427 (2020).2. Drilon, A., Nagasubramanian, R., Blake, J. F., Ku, N., Tuch, B. B., Ebata, K. et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinaseinhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 7,963–972 (2017).3. Drilon, A. TRK inhibitors in TRK fusion-positive cancers. Ann. Oncol. 30(Suppl 8),viii23–viii30 (2019).4. Laetsch, T. W., DuBois, S. G., Mascarenhas, L., Turpin, B., Federman, N., Albert, C. M.et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions:phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 19,705–714 (2018).Correspondence5251234567890();,:Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2020Correspondence526

Comment on: "Tumour-agnostic drugs in paediatric cancers", Chisholm et al., BJC 2020.

Comment on: “Tumour-agnostic drugs in paediatric cancers”, Chisholm et al., BJC 2020

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Comment on: "Tumour-agnostic drugs in paediatric cancers", Chisholm et al., BJC 2020.

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