Retrospective Analysis of the Experience With Larotrectinib in Patients With Solid Neoplasms With NTRK Fusion in Spain (SPAINTRK)
Conditions: Solid Neoplasms With NTRK Fusions
Sponsor: Grupo Espanol de Tumores Neuroendocrinos

‭Title:‬
‭Retrospective analysis of the experience with Larotrectinib in patients with solid‬
‭neoplasms with NTRK fusion in Spain (SPAINTRK)‬
‭Sponsor:‬
‭Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)‬
‭C. Balmes, 243. Escalera A 5º1ª‬
‭08006 Barcelona (España)‬
‭Protocol Code:‬
‭GETNE S2411 / SPAINTRK‬
‭Abbreviated title:‬
‭Experience with Larotrectinib in the Spanish population (SPAINTRK) prior to‬
‭reimbursement‬
‭Research Coordinators:‬
‭Dr. Jorge Hernando‬
‭Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron‬
‭Institute of Oncology, Barcelona‬
‭Protocol version and date:‬
‭1.1, January 13‬‭th‬‭, 2025‬

‭TABLE OF CONTENTS‬
‭SPONSOR’S SIGNATURE PAGE‬
‭4‬
‭ABBREVIATIONS‬
‭5‬
‭1. PROTOCOL SUMMARY‬
‭7‬
‭1.1.  Administrative Information‬
‭7‬
‭1.2.  Methodological Aspects‬
‭7‬
‭2. BACKGROUND‬
‭9‬
‭3. RATIONALE AND OBJECTIVES‬
‭14‬
‭3.1. Main Objective‬
‭14‬
‭3.2. Secondary Objectives‬
‭14‬
‭4. RESEARCH METHODS‬
‭15‬
‭4.1. Study design‬
‭15‬
‭4.2. Setting and study population‬
‭15‬
‭4.3. Inclusion Criteria‬
‭15‬
‭4.4. Exclusion Criteria‬
‭16‬
‭4.5. Study Size‬
‭16‬
‭4.6. Sampling and recruitment method‬
‭16‬
‭4.7. Case Definition‬
‭16‬
‭4.8. Data Logging‬
‭17‬
‭4.9. Study Calendar‬
‭17‬
‭5. ENDPOINTS AND VARIABLES‬
‭18‬
‭5.1. Endpoints‬
‭18‬
‭5.1.1. Primary Endpoints‬
‭18‬
‭5.1.2. Secondary Effectiveness Endpoints‬
‭18‬
‭5.1.3. Secondary Safety Endpoints‬
‭19‬
‭5.2. Study Variables‬
‭19‬
‭6. PROTECTION OF HUMAN SUBJECTS‬
‭22‬
‭6.1. Applicable Legislation‬
‭22‬
‭6.2. Oversight Clinical Research Ethics‬
‭22‬
‭6.3. Informed Consent‬
‭22‬
‭6.4. Confidentiality‬
‭23‬
‭6.5. Funding Source‬
‭25‬
‭6.6. Potential advantage and limitations of research methods‬
‭25‬
‭7. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE‬
‭REACTIONS‬
‭26‬
‭8. QUALITY ASSURANCE‬
‭27‬
‭8.1. Control of data consistency‬
‭27‬
‭8.2. On-site quality control‬
‭27‬
‭8.3. Audits‬
‭28‬
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‭9.  WORK PLAN (TASKS, MILESTONES AND STUDY CHRONOLOGY)‬
‭29‬
‭10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS‬
‭30‬
‭10.1. Commitment and Publication Rules‬
‭30‬
‭11. REFERENCES‬
‭31‬
‭APPENDIX 1. LIST OF STAND-ALONE DOCUMENTS‬
‭34‬
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‭SPONSOR’S SIGNATURE PAGE‬
‭Study‬‭title:‬‭Retrospective‬‭analysis‬‭of‬‭the‬‭experience‬‭with‬‭Larotrectinib‬‭in‬‭patients‬
‭with solid neoplasms with NTRK fusion in Spain (SPAINTRK)‬
‭Sponsor’s protocol number:‬‭GETNE S2411 / SPAINTRK‬
‭Protocol version and date: 1.1 from January 13‬‭th‬‭, 2025‬
‭SPONSOR REPRESENTATIVE:‬
‭Full Name‬
‭Tittle‬
‭Signature date‬
‭COORDINATING INVESTIGATORS‬
‭Full Name‬
‭Site‬
‭Coordinating Investigator‬
‭Signature date‬
‭PRINCIPAL INVESTIGATOR‬
‭Dr.‬
‭_______________________________________‬
‭Principal Investigator‬
‭Site:‬
‭_______________________________________‬
‭Signature date (dd/mm/yyyy)‬
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‭ABBREVIATIONS‬
‭ATP: adenosine triphosphate.‬
‭BDNF: brain-derived neurotrophic factor.‬
‭BSA: body surface area.‬
‭CR: complete response.‬
‭DoR: duration of the response.‬
‭DTC: differentiated thyroid carcinoma.‬
‭ECOG: eastern cooperative oncology group.‬
‭eCRF: electronic case report form.‬
‭EMA: European Medicines Agency.‬
‭EOM: estudio observacional con medicamentos.‬
‭ERK: extracellular signal-regulated kinase.‬
‭FDA: Food and Drug administration.‬
‭FISH: fluorescence in situ hybridization.‬
‭IHC: Immunohistochemistry.‬
‭MAPK: Mitogen activated protein kinase.‬
‭NGF: neurotrophins – nerve growth factor.‬
‭NGS: next-generation sequencing.‬
‭NT: neurotrophin.‬
‭NTRK: neurotrophic tyrosine receptor kinase.‬
‭ORR: objective response rate.‬
‭OS: overall survival.‬
‭PD: progression of the disease.‬
‭PFS: progression free survival.‬
‭PI3K: phosphatidylinositol 3-kinase.‬
‭PLCg: phospholipase C-g.‬
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‭PR: partial response.‬
‭PT: preferred term.‬
‭PTC: papillary thyroid carcinoma.‬
‭SOC: system organ class.‬
‭Trk: tropomyosin receptor kinase.‬
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‭1.‬
‭PROTOCOL SUMMARY‬
‭OBSERVATIONAL POST-AUTHORIZATION STUDY‬
‭1.1.‬
‭Administrative Information‬
‭Study title:‬
‭Retrospective‬ ‭analysis‬ ‭of‬ ‭the‬ ‭experience‬ ‭with‬ ‭Larotrectinib‬ ‭in‬ ‭patients‬ ‭with‬ ‭solid‬
‭neoplasms with NTRK fusion in Spain (SPAINTRK)‬
‭Abbreviation:‬
‭Experience‬ ‭with‬ ‭Larotrectinib‬ ‭in‬ ‭the‬ ‭Spanish‬ ‭population‬ ‭(SPAINTRK)‬ ‭prior‬ ‭to‬
‭reimbursement‬
‭Reason for developing the study:‬
‭Initiative of the sponsor‬
‭Sponsor:‬
‭Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)‬
‭Sponsor’s contact address:‬
‭C. Balmes, 243. Escalera A 5º1ª‬
‭08006 Barcelona (España)‬
‭Clinical monitor:‬
‭MFAR Clinical Research S.L.‬
‭Monitor contact address:‬
‭Sinfonía 28, 2-1, 28054, Madrid.‬
‭1.2.‬
‭Methodological Aspects‬
‭Medical product of interest‬
‭Larotrectinib‬
‭First Ethical Committee that evaluated the study:‬
‭Independent Ethics Committee (IEC) of Hospital Universitario Vall d´Hebron‬
‭Coordinating Investigators‬
‭Dr. Jorge Hernando‬
‭Coordinating Investigator Centers:‬
‭Medical‬ ‭Oncology‬ ‭Department,‬ ‭Vall‬ ‭d´Hebron‬ ‭University‬ ‭Hospital,‬ ‭Vall‬ ‭d´Hebron‬
‭Institute of Oncology, Barcelona.‬
‭Autonomous Community of the Coordinating Investigator‬
‭Catalonia‬
‭Territorial scope:‬
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‭Spain‬
‭Source of information:‬
‭Patient medical records‬
‭Type of study (according AEMPS classification):‬
‭Observational‬
‭Retrospective study:‬
‭Yes‬
‭Total number of patients expected to be included:‬
‭19‬
‭Planned study duration:‬
‭12 months‬
‭Study duration for each participant:‬
‭6 months‬
‭Objectives:‬
‭PRIMARY:‬
‭-Description‬ ‭of‬ ‭the‬ ‭effectiveness‬ ‭of‬ ‭Larotrectinib‬ ‭treatment‬ ‭in‬ ‭tumors‬ ‭with‬ ‭NTRK‬
‭fusion in Spanish patients as a clinical series.‬
‭SECONDARY:‬
‭-Description‬‭of‬‭treatment‬‭duration,‬‭including‬‭dose‬‭reductions‬‭and‬‭interruptions‬‭as‬‭well‬
‭as the reason to do so during the treatment with Larotrectinib‬
‭-Description‬ ‭of‬ ‭the‬ ‭effectiveness‬ ‭of‬ ‭Larotrectinib‬ ‭according‬‭to‬‭the‬‭previous‬‭lines‬‭of‬
‭therapy‬
‭-Line of treatment at which molecular testing for NTRK was performed.‬
‭-Exploration‬ ‭of‬ ‭clinical‬ ‭or‬ ‭histological‬ ‭variables‬ ‭related‬ ‭to‬ ‭the‬ ‭effectiveness‬ ‭and‬
‭tolerability of the treatment.‬
‭Main parameter for evaluation‬
‭Effectiveness‬
‭Number of investigators (expected):‬
‭A total of 14 investigators from 14 hospitals are expected to be included in‬
‭the study.‬
‭Field of application:‬
‭Solid neoplasms‬
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‭2.‬
‭BACKGROUND‬
‭2.1.‬ ‭Multi-omics‬ ‭approaches‬ ‭contribute‬ ‭to‬ ‭the‬‭development‬‭of‬‭new‬‭anti-cancer‬
‭therapies.‬
‭In‬ ‭the‬ ‭last‬ ‭decade,‬ ‭precision‬ ‭medicine,‬ ‭using‬ ‭integrative‬ ‭multi-omics‬ ‭approaches,‬
‭provided‬‭a‬‭new‬‭field‬‭of‬‭opportunities‬‭for‬‭developing‬‭new‬‭therapies‬‭to‬‭specifically‬‭treat‬
‭each‬‭tumor‬‭type‬‭and‬‭patient‬‭(1–3)‬‭.‬‭Particularly,‬‭treatment‬‭of‬‭solid‬‭tumors‬‭had‬‭a‬‭critical‬
‭change‬ ‭in‬ ‭recent‬ ‭years,‬ ‭thanks‬ ‭to‬ ‭the‬ ‭improvement‬ ‭and‬ ‭development‬ ‭of‬ ‭these‬
‭molecular‬ ‭diagnostic‬ ‭technologies‬ ‭that‬ ‭allowed‬ ‭to‬ ‭effectively‬ ‭identify‬ ‭oncogenic‬
‭mutations,‬‭such‬‭as‬‭gene‬‭activation‬‭point‬‭mutations,‬‭in-frame‬‭insertions/deletions‬‭and‬
‭amplification‬‭and‬‭gene‬‭re-arrangements.‬‭In‬‭addition,‬‭the‬‭identification‬‭of‬‭biomarkers‬‭by‬
‭these‬‭techniques,‬‭contributed‬‭to‬‭the‬‭prediction‬‭of‬‭treatment‬‭response‬‭in‬‭cancer‬‭patients‬
‭and‬‭contributed‬‭to‬‭the‬‭development‬‭of‬‭novel‬‭and‬‭effective‬‭anticancer‬‭agents,‬‭such‬‭as‬
‭those‬ ‭known‬ ‭as‬ ‭“histology-agnostic”‬ ‭medication‬ ‭(4)‬‭.‬ ‭Histology-agnostic‬ ‭drugs‬ ‭are‬
‭based‬‭on‬‭a‬‭molecular‬‭biomarker‬‭that‬‭defines‬‭the‬‭disease‬‭and‬‭not‬‭the‬‭organ‬‭(5)‬‭.‬‭This‬‭is‬
‭in‬‭contrast‬‭to‬‭other‬‭traditional‬‭drugs‬‭which‬‭are‬‭developed‬‭based‬‭on‬‭tumor‬‭type‬‭or‬‭those‬
‭that‬ ‭arise‬ ‭from‬ ‭a‬ ‭genomic‬ ‭approach‬ ‭based‬ ‭on‬ ‭the‬ ‭finding‬ ‭of‬ ‭a‬ ‭biomarker-defined‬
‭population‬‭within‬‭a‬‭tumor‬‭type.‬‭Indeed,‬‭since‬‭2017,‬‭the‬‭Food‬‭and‬‭Drug‬‭Administration‬
‭(FDA)‬ ‭approved‬ ‭few‬ ‭anticancer‬ ‭agents‬ ‭with‬ ‭histology-agnostic‬ ‭indication.‬ ‭Some‬ ‭of‬
‭those‬‭were‬‭related‬‭to‬‭the‬‭neurotrophic‬‭tyrosine‬‭receptor‬‭kinase‬‭(NTRK)‬‭gene‬‭fusions,‬
‭NTRK1,‬ ‭NTRK2‬ ‭and‬ ‭NTRK3,‬‭which‬‭are‬‭oncogenic‬‭drivers‬‭that‬‭can‬‭be‬‭targeted‬‭with‬
‭these histology-agnostic inhibitors and are present in solid tumors‬‭(6)‬‭.‬
‭Therefore,‬‭it‬‭seems‬‭essential‬‭the‬‭implementation‬‭of‬‭next-generation‬‭tumor‬‭sequencing‬
‭as‬ ‭regular‬ ‭clinical‬ ‭practice‬ ‭for‬ ‭cancer‬ ‭patients,‬ ‭to‬ ‭identify‬ ‭genetic‬ ‭variants‬ ‭that‬ ‭will‬
‭contribute‬‭to‬‭select‬‭the‬‭most‬‭effective‬‭treatment‬‭for‬‭the‬‭genetic‬‭alteration‬‭within‬‭each‬
‭tumor.‬ ‭However,‬ ‭there‬ ‭are‬ ‭several‬ ‭methods‬‭to‬‭identify‬‭NTRK‬‭gene‬‭fusions,‬‭such‬‭as‬
‭immunohistochemistry,‬
‭fluorescence‬ ‭in‬ ‭situ‬ ‭hybridization‬ ‭and‬ ‭next-generation‬
‭sequencing.‬ ‭Therefore,‬ ‭clinicians‬ ‭should‬ ‭select‬ ‭the‬ ‭testing‬ ‭method‬ ‭individualized‬ ‭to‬
‭each patient‬‭(7)‬‭.‬
‭2.2. NTRK fusions present in solid tumors.‬
‭More‬ ‭in‬ ‭detail,‬ ‭oncogenic‬ ‭alterations‬ ‭such‬ ‭as‬ ‭NTRK‬ ‭gene‬ ‭fusions,‬ ‭present‬ ‭in‬ ‭solid‬
‭tumors,‬‭constitute‬‭an‬‭excellent‬‭target‬‭for‬‭a‬‭precise‬‭therapy‬‭specifically‬‭for‬‭these‬‭tumors,‬
‭to‬‭halt‬‭its‬‭disease‬‭progression.‬‭NTRK‬‭fusions‬‭occur‬‭in‬‭the‬‭genes‬‭NTRK1,‬‭NTRK2‬‭and‬
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‭NTRK3‬ ‭that‬ ‭encode‬ ‭for‬ ‭the‬ ‭TrkA,‬ ‭TrkB‬ ‭and‬ ‭TrkC‬ ‭receptors,‬ ‭which‬ ‭are‬ ‭the‬ ‭3‬
‭transmembrane‬ ‭proteins‬ ‭with‬‭cytoplasmic‬‭tyrosine‬‭kinase‬‭domains,‬‭comprised‬‭in‬‭the‬
‭tropomyosin‬ ‭receptor‬ ‭kinase‬ ‭(Trk)‬ ‭family‬ ‭(7)‬‭.‬ ‭Trk‬ ‭signal‬ ‭transduction‬‭is‬‭mediated‬‭by‬
‭neurotrophins-nerve‬ ‭growth‬ ‭factor‬ ‭(NGF),‬ ‭brain-derived‬ ‭neurotrophic‬ ‭factor‬ ‭(BDNF),‬
‭and‬‭neurotrophins‬‭3‬‭and‬‭4‬‭(NT3‬‭and‬‭NT4).‬‭The‬‭role‬‭of‬‭neurotrophins‬‭through‬‭activation‬
‭of‬ ‭Trk‬ ‭receptors‬ ‭deals‬ ‭with‬ ‭regulation‬ ‭of‬ ‭cell‬ ‭survival,‬ ‭proliferation,‬ ‭fate‬ ‭of‬ ‭neural‬
‭precursors,‬ ‭axon‬ ‭growth,‬ ‭dendrite‬ ‭pruning‬ ‭and‬ ‭patterning‬ ‭of‬ ‭innervation‬ ‭and‬ ‭the‬
‭expression‬ ‭of‬ ‭proteins‬ ‭essential‬ ‭for‬ ‭an‬ ‭adequate‬ ‭neuronal‬ ‭functioning,‬ ‭such‬ ‭as‬ ‭ion‬
‭channels‬ ‭and‬ ‭neurotransmitter‬ ‭receptors‬ ‭(8)‬‭.‬ ‭Expression‬ ‭of‬ ‭Trk‬ ‭receptors‬ ‭after‬
‭embryogenesis,‬ ‭is‬ ‭primarily‬ ‭restrained‬‭to‬‭the‬‭nervous‬‭system,‬‭by‬‭exerting‬‭effects‬‭on‬
‭regulation of pain, proprioception, appetite and memory‬‭(9)‬‭.‬
‭As‬ ‭previously‬ ‭mentioned,‬ ‭fusions‬ ‭of‬ ‭the‬ ‭tropomyosin‬ ‭receptor‬ ‭kinase‬ ‭(Trk)‬ ‭can‬
‭constitute‬‭the‬‭primary‬‭oncogenic‬‭drivers‬‭in‬‭tumors‬‭that‬‭harbor‬‭them,‬‭in‬‭fact,‬‭it‬‭is‬‭very‬
‭uncommon‬‭the‬‭presence‬‭of‬‭other‬‭known‬‭oncogenic‬‭alterations‬‭within‬‭the‬‭same‬‭tumor‬
‭(10)‬‭.‬‭Besides,‬‭NTRK‬‭gene‬‭fusions‬‭are‬‭not‬‭common‬‭in‬‭the‬‭majority‬‭of‬‭cancers,‬‭they‬‭are‬
‭present‬ ‭in‬ ‭more‬ ‭than‬ ‭90%‬ ‭of‬ ‭some‬ ‭rare‬ ‭tumors‬ ‭(11,12)‬‭.‬ ‭Oncogenic‬ ‭fusions‬ ‭occur‬
‭between‬‭the‬‭kinase‬‭domain‬‭of‬ ‭NTRK1,‬‭NTRK2‬‭or‬‭NTRK3‬‭and‬‭a‬‭number‬‭of‬‭N-terminal‬
‭domains.‬‭These‬‭fusions‬‭consequently‬‭lead‬‭to‬‭overexpression‬‭of‬‭the‬‭chimeric‬‭protein,‬
‭which‬ ‭results‬ ‭in‬ ‭the‬ ‭constitutive‬ ‭activation‬ ‭of‬ ‭the‬ ‭ligand-independent‬ ‭downstream‬
‭signaling,‬‭that‬‭may‬‭end‬‭in‬‭an‬‭uncontrolled‬‭cell‬‭growth‬‭and‬‭proliferation,‬‭increasing‬‭the‬
‭chance‬‭of‬‭cancer‬‭development‬‭(12)‬‭.‬‭NTRK‬‭fusions‬‭were‬‭firstly‬‭identified‬‭in‬‭colorectal‬
‭and‬ ‭papillary‬ ‭thyroid‬ ‭carcinomas‬ ‭from‬ ‭both‬ ‭adults‬ ‭and‬ ‭pediatric‬ ‭patients‬ ‭(13–16)‬‭.‬
‭Frequency‬‭of‬‭these‬‭fusions‬‭varies‬‭from‬‭<1%‬‭in‬‭cancer‬‭types‬‭including‬‭lung,‬‭colorectal,‬
‭pancreatic,‬‭breast‬‭cancers‬‭melanoma‬‭and‬‭other‬‭solid‬‭or‬‭hematological‬‭cancers,‬‭up‬‭to‬
‭25%‬‭in‬‭thyroid,‬‭spitzoid‬‭and‬‭gastrointestinal‬‭stromal‬‭tumors‬‭and‬‭>90%‬‭in‬‭rare‬‭tumors‬
‭types,‬ ‭specifically‬ ‭secretory‬ ‭breast‬ ‭carcinoma,‬ ‭mammary‬ ‭analogue‬ ‭secretory‬
‭carcinoma,‬‭congenital‬‭infantile‬‭fibrosarcoma,‬‭and‬‭cellular‬‭or‬‭mix‬‭congenital‬‭mesoblastic‬
‭nephroma‬‭(12)‬‭.‬‭Interestingly,‬‭cancer‬‭types‬‭with‬‭high‬‭prevalence‬‭of‬‭NTRK‬‭fusion‬‭were‬
‭largely‬ ‭pediatric‬ ‭cancers,‬ ‭such‬ ‭as‬ ‭Trk‬ ‭fusion-positive‬ ‭thyroid‬ ‭carcinoma‬ ‭(17,18)‬‭,‬
‭differentiated‬ ‭(DTC)‬ ‭or‬ ‭papillary‬ ‭(PTC)‬‭(11.5-26.09%)‬‭(19)‬‭.‬‭The‬‭prevalence‬‭of‬‭NTRK‬
‭fusion‬‭has‬‭been‬‭reported‬‭to‬‭be‬‭found‬‭in‬‭1.2%‬‭of‬‭mostly‬‭non-metastatic‬‭thyroid‬‭cancers‬
‭(20)‬‭,‬‭in‬‭fact,‬‭papillary‬‭thyroid‬‭carcinoma,‬‭was‬‭one‬‭of‬‭the‬‭first‬‭tumor‬‭types‬‭in‬‭which‬‭the‬
‭NTRK1‬‭fusions‬‭were‬‭identified‬‭(12,21)‬‭.‬‭Approximately‬‭between‬‭5-25%‬‭of‬‭PTC‬‭cases‬‭in‬
‭pediatric‬ ‭patients‬‭harbor‬‭NTRK‬‭fusions‬‭while‬‭6%‬‭of‬‭adult‬‭PTCs‬‭have‬‭NTRK‬‭fusions.‬
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‭These‬‭thyroid‬‭carcinomas‬‭positive‬‭for‬‭TRK‬‭fusions‬‭seem‬‭to‬‭present‬‭a‬‭unique‬‭histology‬
‭pattern‬ ‭as‬ ‭a‬ ‭follicular‬ ‭growth,‬ ‭commonly‬ ‭associated‬ ‭with‬ ‭locoregional‬ ‭and‬ ‭distant‬
‭metastatic disease‬‭(18,22)‬‭.‬
‭2.3. Trk inhibitors for treatment of solid tumors harboring NTRK fusions.‬
‭Multiple‬‭studies‬‭reported‬‭a‬‭promising‬‭benefit‬‭of‬‭the‬‭use‬‭of‬‭Trk‬‭inhibitors‬‭for‬‭patients‬‭with‬
‭solid‬ ‭tumors‬‭that‬‭meet‬‭certain‬‭criteria,‬‭such‬‭as‬‭the‬‭tumor‬‭must‬‭have‬‭an‬‭NTRK‬‭gene‬
‭fusion‬ ‭and‬ ‭no‬ ‭documented‬ ‭resistance‬ ‭to‬ ‭the‬ ‭variant.‬ ‭Patient‬ ‭criteria‬ ‭also‬ ‭included‬
‭metastatic‬ ‭disease‬‭and‬‭significant‬‭morbidity‬‭in‬‭the‬‭event‬‭of‬‭surgical‬‭resection.‬‭There‬
‭must‬ ‭also‬ ‭be‬ ‭no‬ ‭adequate‬ ‭alternative‬ ‭treatment‬‭options‬‭or‬‭documented‬‭progression‬
‭after previous treatment‬‭(23)‬‭.‬
‭2.3.1 Larotrectinib as a Trk inhibitor.‬
‭Larotrectinib,‬‭is‬‭one‬‭of‬‭the‬‭histology-agnostic‬‭drugs‬‭previously‬‭mentioned,‬‭approved‬‭by‬
‭Food‬ ‭and‬ ‭Drug‬ ‭Administration‬ ‭(FDA)‬ ‭and‬ ‭European‬ ‭Medicines‬ ‭Agency‬ ‭(EMA)‬
‭(13,24,25)‬‭.‬ ‭In‬ ‭detail,‬ ‭Larotrectinib‬ ‭is‬ ‭a‬ ‭potent‬ ‭and‬ ‭highly‬ ‭selective‬ ‭small-molecule‬
‭inhibitor‬ ‭that‬ ‭binds‬ ‭to‬ ‭all‬ ‭three‬ ‭Trk‬ ‭(A,‬ ‭B‬ ‭and‬ ‭C)‬ ‭proteins,‬ ‭present‬ ‭in‬ ‭cancer‬ ‭cells,‬
‭consequently‬ ‭promoting‬ ‭a‬ ‭blockage‬ ‭in‬ ‭downstream‬ ‭signaling‬ ‭for‬‭cancer‬‭cell‬‭growth.‬
‭TrkA‬ ‭receptors‬ ‭interaction‬ ‭with‬ ‭NGF‬ ‭causes‬ ‭the‬ ‭activation‬ ‭of‬ ‭the‬ ‭RAS/Mitogen‬
‭activated‬ ‭protein‬ ‭kinase‬‭(MAPK)‬‭pathway,‬‭which‬‭leads‬‭to‬‭increased‬‭proliferation‬‭and‬
‭cellular‬ ‭growth‬ ‭through‬ ‭extracellular‬ ‭signal-regulated‬ ‭kinase‬ ‭(ERK)‬ ‭signaling.‬ ‭Other‬
‭pathways‬‭such‬‭as‬‭phospholipase‬‭C-g‬‭(PLCg)‬‭and‬‭Phosphatidylinositol‬‭3-kinase‬‭(PI3K)‬
‭are‬ ‭also‬ ‭activated.‬ ‭TrkC‬ ‭coupling‬ ‭with‬ ‭NT3‬ ‭causes‬ ‭preferential‬ ‭activation‬ ‭of‬ ‭the‬
‭PI3/AKT‬ ‭pathway‬ ‭preventing‬ ‭apoptosis‬ ‭and‬ ‭increasing‬ ‭cell‬ ‭survival,‬ ‭whereas‬ ‭TrkB‬
‭transduces‬ ‭the‬ ‭BDNF‬ ‭signal‬ ‭vial‬ ‭Ras-ERK,‬‭PI3K‬‭and‬‭PLC‬‭pathway,‬‭resulting‬‭in‬‭cell‬
‭differentiation‬‭and‬‭cell‬‭survival‬‭(25)‬‭.‬‭Therefore,‬‭Larotrectinib‬‭specifically‬‭blocks‬‭the‬‭ATP‬
‭binding site and demonstrates high potency against TrkA, TrkB and TrkC‬‭(26)‬‭.‬
‭Several‬‭clinical‬‭trials‬‭provided‬‭evidence‬‭that‬‭treatment‬‭with‬‭Larotrectinib‬‭in‬‭patients‬‭with‬
‭TRK‬‭fusion‬‭cancer‬‭across‬‭a‬‭diverse‬‭range‬‭of‬‭tumor‬‭types,‬‭irrespective‬‭of‬‭age,‬‭NTRK‬
‭gene,‬ ‭or‬ ‭fusion‬ ‭partner‬ ‭improved‬ ‭clinical‬ ‭outcomes‬ ‭in‬ ‭those‬ ‭patients‬ ‭(13,27–30)‬‭.‬
‭However,‬ ‭it‬ ‭should‬ ‭be‬ ‭noted‬ ‭that‬ ‭besides‬ ‭the‬ ‭probed‬ ‭efficacy‬ ‭and‬ ‭the‬ ‭safety‬ ‭data‬
‭collected‬‭in‬‭those‬‭trials,‬‭there‬‭is‬‭a‬‭need‬‭to‬‭monitor‬‭cognitive‬‭development‬‭in‬‭pediatric‬
‭patients‬‭undergoing‬‭long-term‬‭treatment,‬‭since‬‭TRK‬‭plays‬‭an‬‭essential‬‭role‬‭in‬‭neuronal‬
‭maturation and proliferation.‬
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‭All‬ ‭those‬ ‭trials‬ ‭emphasized‬ ‭the‬ ‭critical‬ ‭role‬ ‭of‬ ‭screening‬ ‭methods‬ ‭to‬ ‭detect‬ ‭NTRK‬
‭fusions,‬ ‭and‬ ‭recommended‬ ‭considering‬ ‭them‬ ‭as‬ ‭a‬ ‭priority‬ ‭at‬ ‭diagnosis‬ ‭in‬ ‭order‬ ‭to‬
‭identify those patients who can benefit from Larotrectinib therapy.‬
‭There‬‭is‬‭a‬‭risk‬‭acquiring‬‭on-target‬‭resistance‬‭to‬‭Trk‬‭inhibitors,‬‭patients‬‭with‬‭advanced‬
‭stage‬‭Trk‬‭fusion‬‭cancers‬‭and‬‭treated‬‭with‬‭Trk‬‭inhibitors‬‭may‬‭not‬‭be‬‭able‬‭to‬‭tolerate‬‭Trk‬
‭inhibitor‬ ‭therapy‬ ‭and‬ ‭progress.‬ ‭Mechanisms‬ ‭involved‬ ‭in‬ ‭development‬ ‭on-target‬
‭resistance‬ ‭can‬‭be‬‭related‬‭to‬‭amino‬‭acid‬‭substitutions‬‭in‬‭the‬‭solvent‬‭front,‬‭xDFG‬‭and‬
‭gatekeeper‬ ‭residues‬ ‭in‬ ‭the‬ ‭kinase‬ ‭domain‬ ‭of‬ ‭Trk‬ ‭fusion‬ ‭proteins,‬ ‭which‬ ‭sterically‬
‭interfere‬ ‭with‬ ‭Trk‬ ‭inhibitor‬ ‭binding.‬ ‭It‬ ‭may‬ ‭occur‬ ‭off-target‬ ‭or‬ ‭bypass‬ ‭resistance‬
‭mechanisms‬ ‭that‬ ‭enable‬ ‭tumors‬ ‭to‬ ‭develop‬ ‭by‬ ‭non-TRK‬ ‭signaling‬ ‭mechanisms.‬
‭However,‬ ‭an‬ ‭interesting‬ ‭observation‬ ‭is‬ ‭that‬ ‭Larotrectibnib‬ ‭can‬ ‭enhance‬ ‭radioactive‬
‭iodine‬‭uptake‬‭in‬‭advanced‬‭thyroid‬‭cancer.‬‭This‬‭is‬‭interesting‬‭since,‬‭it‬‭has‬‭been‬‭reported‬
‭that‬ ‭differentiated‬ ‭thyroid‬ ‭carcinoma‬ ‭may‬ ‭lose‬ ‭their‬ ‭capacity‬ ‭to‬ ‭take‬ ‭up‬ ‭iodine‬‭as‬‭a‬
‭consequence‬‭of‬‭oncogene‬‭activation‬‭through‬‭signaling‬‭pathways.‬‭This‬‭finding‬‭suggests‬
‭that‬ ‭treatment‬ ‭with‬ ‭radioactive‬ ‭iodine‬ ‭may‬ ‭be‬ ‭considered‬ ‭in‬ ‭patients‬ ‭who‬ ‭receive‬
‭Larotrectinib‬‭(31)‬‭.‬
‭2.3.2. Sequencing methods and Larotrectinib treatment implementation in Spain.‬
‭Therefore,‬‭approval‬‭of‬‭Larotrectinib‬‭by‬‭the‬‭FDA‬‭on‬‭26‬‭November‬‭2018,‬‭constituted‬‭an‬
‭important‬‭milestone‬‭in‬‭the‬‭context‬‭of‬‭oncology‬‭and‬‭particularly‬‭in‬‭the‬‭field‬‭of‬‭treating‬
‭solid‬‭neoplasm‬‭that‬‭harbors‬‭an‬‭NTRK‬‭gene‬‭fusion.‬‭Currently‬‭more‬‭and‬‭more‬‭centers‬
‭perform‬ ‭sequentiation‬ ‭methods‬ ‭(‬ ‭i.e,‬ ‭next-generation‬ ‭sequencing‬ ‭(NGS))‬ ‭on‬ ‭their‬
‭cancer‬‭patients,‬‭prioritizing‬‭certain‬‭pathologies‬‭such‬‭as‬‭thyroid‬‭or‬‭lung‬‭cancer.‬‭Spain‬‭is‬
‭starting‬‭but‬‭slowly‬‭implementing‬‭NGS‬‭as‬‭a‬‭general‬‭clinical‬‭option‬‭to‬‭characterize‬‭and‬
‭classify‬‭tumors‬‭in‬‭order‬‭to‬‭search‬‭for‬‭the‬‭best‬‭treatment.‬‭In‬‭fact,‬‭difficulties‬‭such‬‭as‬‭the‬
‭fragmentation‬ ‭of‬ ‭Spanish‬ ‭healthcare‬ ‭and‬ ‭the‬ ‭transfer‬ ‭of‬ ‭its‬ ‭management‬ ‭to‬ ‭every‬
‭region adds an additional difficulty.‬
‭In‬‭this‬‭scenario,‬‭the‬‭availability‬‭of‬‭data‬‭regarding‬‭safety‬‭and‬‭efficacy‬‭of‬‭treatment‬‭with‬
‭Larotrectinib in a population of different neoplasms in Spain would be of relevance.‬
‭Currently,‬‭around‬‭20‬‭patients‬‭have‬‭received‬‭this‬‭treatment‬‭in‬‭our‬‭country‬‭(12‬‭patients‬
‭have‬‭been‬‭treated‬‭more‬‭than‬‭one‬‭year),‬‭but‬‭there‬‭is‬‭no‬‭systematic‬‭collection‬‭of‬‭data‬‭on‬
‭outcomes.‬‭Therefore,‬‭this‬‭study‬‭will‬‭contribute‬‭to‬‭the‬‭understanding‬‭by‬‭clinicians‬‭and‬
‭authorities‬‭that‬‭selection‬‭of‬‭the‬‭best‬‭line‬‭of‬‭treatment‬‭can‬‭be‬‭achieved‬‭by‬‭performing‬
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‭NGS‬
‭on‬
‭patient‬
‭samples,‬
‭and‬
‭therefore‬
‭its‬
‭implementation‬
‭should‬
‭be‬
‭enhanced/reinforced‬ ‭in‬ ‭Spanish‬ ‭healthcare‬‭centers.‬‭The‬‭multidisciplinary‬‭oncological‬
‭cooperative‬ ‭group‬ ‭GETNE,‬ ‭the‬ ‭Spanish‬ ‭taskforce‬ ‭of‬ ‭neuroendocrine‬ ‭and‬‭endocrine‬
‭tumors,‬ ‭one‬ ‭of‬ ‭the‬ ‭populations‬ ‭especially‬ ‭enriched‬ ‭in‬ ‭NTRK‬ ‭fusions,‬ ‭propose‬ ‭the‬
‭SPAINTRK‬ ‭observational‬‭retrospective‬‭study‬‭to‬‭reunite‬‭data‬‭from‬‭all‬‭patients‬‭treated‬
‭with‬ ‭Larotrectinib‬ ‭for‬‭solid‬‭neoplasm‬‭in‬‭Spain.‬‭Therefore,‬‭GETNE‬‭will‬‭contribute‬‭and‬
‭shed‬ ‭light‬ ‭on‬ ‭the‬ ‭field‬ ‭of‬ ‭therapies‬ ‭for‬ ‭tumors‬ ‭harboring‬ ‭NTRK‬ ‭fusions,‬ ‭specifically‬
‭using Larotrectinib as main and an effective drug of treatment.‬
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‭3.‬
‭RATIONALE AND OBJECTIVES‬
‭SPAINTRK‬‭aims‬‭to‬‭be‬‭the‬‭first‬‭trial‬‭in‬‭Spain‬‭to‬‭systematically‬‭collect‬‭data‬‭on‬‭outcomes‬
‭of‬ ‭Spanish‬ ‭patients‬ ‭with‬ ‭solid‬ ‭neoplasms‬ ‭treated‬ ‭with‬ ‭Larotrectinib‬ ‭through‬ ‭the‬
‭compassionate‬ ‭drug‬ ‭use‬ ‭program,‬ ‭during‬ ‭the‬ ‭time‬ ‭elapsed‬ ‭between‬ ‭the‬ ‭indication‬
‭approval‬‭and‬‭the‬‭drug‬‭commercialization.‬‭This‬‭will‬‭contribute‬‭to‬‭selection‬‭of‬‭the‬‭best‬
‭treatment‬ ‭for‬ ‭cancer‬ ‭patients‬ ‭with‬ ‭NTRK‬ ‭fusions,‬ ‭such‬ ‭as‬ ‭Trk‬ ‭inhibitors‬ ‭like‬
‭Larotrectinib.‬ ‭Since‬ ‭the‬ ‭FDA‬ ‭and‬ ‭the‬ ‭EMA‬ ‭approved‬ ‭the‬ ‭use‬ ‭of‬ ‭Trk‬ ‭inhibitors,‬ ‭like‬
‭Larotrectinib,‬‭there‬‭is‬‭a‬‭new‬‭and‬‭effective‬‭option‬‭of‬‭treatment‬‭for‬‭patients‬‭with‬‭NTRK‬
‭fusions‬‭in‬‭solid‬‭neoplasms.‬‭This‬‭observational‬‭retrospective‬‭study‬‭will‬‭allow‬‭to‬‭analyze‬
‭data‬ ‭of‬ ‭patients‬ ‭treated‬ ‭with‬ ‭Larotrectinib‬ ‭across‬ ‭the‬ ‭country‬ ‭and‬ ‭increase‬ ‭the‬
‭knowledge on response to rare and different cancers‬
‭3.1.‬
‭Main Objective‬
‭●‬ ‭Description‬‭of‬‭the‬‭effectiveness‬‭of‬‭Larotrectinib‬‭treatment‬‭in‬‭tumors‬‭with‬‭NTRK‬
‭fusion in Spanish patients as a clinical series.‬
‭3.2.‬
‭Secondary Objectives‬
‭●‬ ‭Describe‬ ‭treatment‬ ‭duration,‬ ‭including‬ ‭dose‬ ‭reductions‬ ‭and‬ ‭interruptions‬
‭occurred‬‭along‬‭the‬‭treatment‬‭with‬‭Larotrebtinib,‬‭as‬‭well‬‭as‬‭to‬‭study‬‭the‬‭reasons‬
‭behind those decisions.‬
‭●‬ ‭Study the effectiveness of Larotrebtinib and previous lines of therapy.‬
‭●‬ ‭Identified‬ ‭the‬ ‭line‬ ‭of‬ ‭treatment‬ ‭at‬ ‭which‬ ‭molecular‬ ‭testing‬ ‭for‬ ‭NTRK‬ ‭was‬
‭performed.‬
‭●‬ ‭Exploration‬‭of‬‭clinical‬‭and/or‬‭histological‬‭variables‬‭related‬‭to‬‭the‬‭effectiveness‬
‭and tolerability of Larotrectinib treatment.‬
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‭4.‬
‭RESEARCH METHODS‬
‭4.1.‬
‭Study design‬
‭This‬‭is‬‭an‬‭observational‬‭retrospective‬‭study‬‭including‬‭thyroid‬‭cancer‬‭patients‬‭with‬‭solid‬
‭neoplasms with NTRK fusions.‬
‭The‬‭study‬‭will‬‭use‬‭secondary‬‭data‬‭retrieved‬‭from‬‭medical‬‭records‬‭from‬‭each‬‭patient.‬
‭The‬ ‭medical‬ ‭records‬‭include‬‭all‬‭the‬‭clinical‬‭variables‬‭defined‬‭in‬‭order‬‭to‬‭perform‬‭the‬
‭analysis and it is not necessary to access additional sources.‬
‭The‬ ‭assignment‬ ‭of‬ ‭a‬ ‭patient‬ ‭to‬ ‭a‬ ‭specific‬ ‭therapeutic‬ ‭strategy‬ ‭has‬ ‭been‬ ‭already‬
‭decided‬‭in‬‭advance‬‭by‬‭the‬‭usual‬‭clinical‬‭practice‬‭of‬‭medicine;‬‭the‬‭decision‬‭to‬‭prescribe‬
‭a‬‭specific‬‭treatment‬‭was‬‭clearly‬‭dissociated‬‭from‬‭the‬‭decision‬‭to‬‭include‬‭a‬‭patient‬‭in‬‭the‬
‭study.‬‭No‬‭intervention‬‭will‬‭be‬‭applied‬‭to‬‭patients,‬‭either‬‭diagnostic‬‭or‬‭follow-up,‬‭other‬
‭than‬‭the‬‭usual‬‭clinical‬‭practice.‬‭Epidemiological‬‭methods‬‭will‬‭be‬‭used‬‭to‬‭analyze‬‭the‬
‭data collected.‬
‭4.2.‬
‭Setting and study population‬
‭In‬‭total,‬‭19‬‭patients‬‭diagnosed‬‭with‬‭solid‬‭neoplasms‬‭that‬‭have‬‭been‬‭confirmed‬‭to‬‭bear‬
‭NTRK‬ ‭fusions‬ ‭in‬ ‭their‬ ‭tumors‬ ‭will‬ ‭be‬ ‭included‬ ‭in‬ ‭the‬ ‭study.‬ ‭It‬ ‭is‬ ‭known‬ ‭that‬ ‭these‬
‭patients‬‭have‬‭received‬‭the‬‭treatment‬‭with‬‭Larotrectinib‬‭in‬‭14‬‭centers‬‭in‬‭Spain,‬‭prior‬‭to‬
‭treatment reimbursement in Spain.‬
‭4.3.‬
‭Inclusion Criteria‬
‭1.‬ ‭Infant and adult patients (all ages).‬
‭2.‬ ‭Patients with confirmed diagnosis of solid neoplasms.‬
‭3.‬ ‭Patients‬‭must‬‭have‬‭detected‬‭NTRK‬‭fusions‬‭by‬‭the‬‭following‬‭diagnostic‬‭methods‬
‭NGS,‬ ‭fluorescence‬ ‭in‬ ‭situ‬ ‭hybridization‬ ‭(FISH)‬ ‭and/or‬ ‭Immunohistochemistry‬
‭(IHC).‬
‭4.‬ ‭Patients‬ ‭must‬ ‭be‬ ‭treated‬ ‭with‬ ‭Larotrectinib‬ ‭under‬ ‭the‬ ‭compassionate‬ ‭use‬
‭program (before the commercialization) in order to be included in the study.‬
‭5.‬ ‭Data‬ ‭should‬ ‭be‬ ‭available‬ ‭in‬ ‭order‬ ‭to‬ ‭evaluate‬ ‭effectiveness‬ ‭and‬ ‭consequent‬
‭follow up.‬
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‭4.4.‬
‭Exclusion Criteria‬
‭●‬ ‭Patients‬‭with‬‭solid‬‭neoplasms‬‭treated‬‭with‬‭Larotrectinib‬‭in‬‭clinical‬‭trials‬‭or‬‭other‬
‭settings different from clinical practice.‬
‭●‬ ‭Patients‬ ‭that‬ ‭initiated‬ ‭treatment‬ ‭with‬ ‭Larotrectinib‬ ‭after‬ ‭the‬ ‭obtention‬ ‭of‬
‭prize-reimbursement  and commercialization.‬
‭4.5.‬
‭Study Size‬
‭The‬ ‭sample‬ ‭size‬ ‭calculation‬‭is‬‭based‬‭on‬‭the‬‭actual‬‭number‬‭of‬‭patients‬‭known‬‭to‬‭be‬
‭treated‬ ‭in‬ ‭Spain‬ ‭with‬ ‭Larotrectinib.‬ ‭At‬ ‭the‬ ‭moment‬ ‭19‬ ‭patients‬ ‭from‬ ‭14‬ ‭different‬
‭healthcare‬‭centers‬‭have‬‭been‬‭localized‬‭that‬‭were‬‭treated‬‭in‬‭the‬‭Spanish‬‭territory‬‭with‬
‭Larotrectinib. We expect to include and collect data from all of them.‬
‭4.6.‬
‭Sampling and recruitment method‬
‭Patients‬‭will‬‭be‬‭consecutively‬‭included,‬‭in‬‭compliance‬‭with‬‭the‬‭previously‬‭established‬
‭inclusion criteria.‬
‭According‬‭to‬‭the‬‭definition‬‭of‬‭study‬‭population‬‭and‬‭disease‬‭established‬‭in‬‭this‬
‭scientific‬‭report,‬‭patients‬‭will‬‭be‬‭selected‬‭from‬‭cases‬‭diagnosed‬‭with‬‭solid‬‭neoplasms‬
‭bearing‬‭NTRK‬‭fusions‬‭detected‬‭by‬‭any‬‭of‬‭these‬‭methods,‬‭NGS,‬‭FISH‬‭and/or‬‭IHC,‬‭and‬
‭treated‬ ‭with‬ ‭Larotrectinib.‬ ‭The‬ ‭19‬ ‭patients‬ ‭treated‬ ‭with‬ ‭Larotrectinib‬ ‭in‬ ‭the‬ ‭Spanish‬
‭territory are localized and belong to 14 different sites/healthcare centers.‬
‭To‬ ‭prevent‬ ‭two‬ ‭or‬ ‭more‬ ‭reporting‬ ‭physicians‬ ‭from‬ ‭logging‬ ‭the‬ ‭same‬‭case,‬‭a‬
‭coordinator,‬‭who‬‭controls‬‭the‬‭cases‬‭included‬‭in‬‭his‬‭or‬‭her‬‭center,‬‭is‬‭appointed‬‭in‬‭health‬
‭centers‬‭with‬‭several‬‭reporting‬‭physicians,‬‭and‬‭preventive‬‭measures‬‭are‬‭implemented‬‭in‬
‭the‬ ‭tool‬ ‭controlling‬ ‭duplications‬ ‭in‬ ‭variables‬ ‭(such‬ ‭as‬ ‭birth‬ ‭date,‬ ‭gender,‬ ‭center‬ ‭or‬
‭diagnosis).‬
‭4.7.‬
‭Case Definition‬
‭A‬‭‘case’‬‭is‬‭defined‬‭as‬‭any‬‭patient,‬‭diagnosed,‬‭treated,‬‭or‬‭followed‬‭in‬‭the‬‭different‬‭health‬
‭centers‬‭where‬‭reporting‬‭physicians‬‭authorized‬‭by‬‭the‬‭sponsor,‬‭who‬‭meets‬‭the‬‭inclusion‬
‭criteria.‬‭A‬‭key‬‭point‬‭is‬‭that‬‭the‬‭patient‬‭was‬‭diagnosed‬‭with‬‭solid‬‭neoplasms‬‭that‬‭harbors‬
‭a‬ ‭NTRK‬ ‭fusion‬ ‭and‬ ‭he/she‬ ‭was‬ ‭receiving‬ ‭treatment‬ ‭with‬ ‭Larotrectinib.‬ ‭Data‬ ‭from‬
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‭patient’s treatment should have been recorded and be available at the centers.‬
‭4.8.‬
‭Data Logging‬
‭Once‬‭the‬‭patient‬‭is‬‭compliant‬‭with‬‭inclusion/exclusion‬‭criteria‬‭information‬‭on‬‭the‬
‭clinical‬ ‭history‬ ‭will‬ ‭be‬ ‭collected‬ ‭to‬ ‭gather‬ ‭the‬ ‭necessary‬ ‭data‬ ‭and‬ ‭to‬ ‭complete‬ ‭the‬
‭electronic‬ ‭forms‬ ‭of‬ ‭the‬ ‭study‬ ‭designed‬ ‭for‬ ‭this‬ ‭purpose.‬ ‭All‬ ‭data‬ ‭collected‬ ‭during‬
‭treatment,‬‭as‬‭well‬‭as‬‭demographic‬‭data,‬‭will‬‭be‬‭provided‬‭for‬‭the‬‭purpose‬‭of‬‭this‬‭study‬
‭and completed at the electronic Case Report Form (eCRF) to proceed to its analysis.‬
‭4.9.‬
‭Study Calendar‬
‭Start‬‭date‬‭of‬‭data‬‭collection‬‭(First‬‭Patient‬‭First‬‭Visit‬‭of‬‭Data‬‭Extraction‬‭Start)‬‭:‬‭January‬
‭2025 (expected).‬
‭End‬ ‭of‬ ‭data‬ ‭collection‬ ‭(Last‬ ‭patient‬ ‭Last‬ ‭visit‬ ‭or‬ ‭data‬ ‭extraction‬ ‭completion)‬‭:‬‭May‬
‭2025  (expected)‬
‭Completion of Study Report:‬‭4Q 2025  (expected)‬
‭Primary publication date:‬‭1Q 2026  (expected)‬
‭Figure 1.‬‭Study calendar scheme and milestones.‬
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‭5.‬
‭ENDPOINTS AND VARIABLES‬
‭5.1.‬
‭Endpoints‬
‭5.1.1.‬ ‭Primary Endpoints‬
‭●‬ ‭Duration‬ ‭of‬ ‭response‬ ‭(DoR):‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬ ‭first‬ ‭confirmed‬
‭response‬ ‭(complete‬ ‭(CR)‬ ‭or‬ ‭partial‬ ‭(PR)‬ ‭response),‬ ‭according‬ ‭to‬ ‭Objective‬
‭response‬‭rate‬‭(ORR)‬‭defined‬‭below,‬‭to‬‭the‬‭date‬‭of‬‭the‬‭documented‬‭progression‬
‭of‬‭the‬‭disease‬‭(PD)‬‭as‬‭determined‬‭using‬‭RECIST‬‭V1.1‬‭criteria‬‭or‬‭death‬‭due‬‭to‬
‭any‬‭cause,‬‭whichever‬‭occurs‬‭first.‬‭Those‬‭patients‬‭with‬‭response‬‭and‬‭without‬‭PD‬
‭or death event will be censored on the date of their last tumor assessment.‬
‭Results‬‭will‬‭be‬‭presented‬‭as‬‭individual‬‭cases,‬‭not‬‭compiled‬‭as‬‭the‬‭patients‬‭have‬
‭different pathologies which may differ in prognosis.‬
‭5.1.2.‬ ‭Secondary Effectiveness Endpoints‬
‭●‬ ‭Objective‬ ‭response‬ ‭rate‬ ‭(ORR):‬ ‭is‬ ‭assessed‬ ‭by‬ ‭the‬ ‭investigator‬ ‭analysis‬ ‭of‬
‭tumor‬ ‭growth‬ ‭through‬ ‭imaging‬ ‭follow-up‬ ‭(CT‬ ‭scan/MRI),‬ ‭using‬ ‭a‬ ‭method‬ ‭to‬
‭evaluate‬‭it‬‭as‬‭RECIST‬‭V1.1.‬‭This‬‭will‬‭be‬‭considered‬‭as‬‭the‬‭number‬‭of‬‭patients‬
‭with‬‭confirmed‬‭complete‬‭response‬‭(CR)‬‭or‬‭partial‬‭response‬‭(PR)‬‭as‬‭their‬‭overall‬
‭best‬ ‭response‬ ‭throughout‬ ‭the‬ ‭period‬ ‭of‬ ‭treatment‬ ‭with‬ ‭Larotrectinib.‬ ‭Tumor‬
‭measurements‬‭that‬‭were‬‭assessed‬‭locally‬‭by‬‭the‬‭clinician‬‭according‬‭to‬‭RECIST,‬
‭V1.1,‬ ‭should‬ ‭be‬ ‭recorded‬ ‭and‬ ‭indicate‬ ‭the‬ ‭change‬ ‭in‬ ‭size‬ ‭of‬ ‭tumors‬ ‭as‬
‭compared with baseline, at the first dose of study treatment.‬
‭●‬ ‭Progression‬ ‭free‬ ‭survival‬ ‭(PFS):‬ ‭Time‬ ‭from‬ ‭first‬ ‭dosing‬ ‭date‬ ‭to‬ ‭the‬ ‭date‬ ‭of‬
‭confirmed‬‭PD‬‭according‬‭to‬‭RECIST‬‭1.1.‬‭Patients‬‭alive‬‭and‬‭free‬‭of‬‭events‬‭at‬‭the‬
‭date‬ ‭of‬ ‭the‬ ‭analysis‬ ‭will‬ ‭be‬ ‭censored‬ ‭at‬ ‭their‬ ‭last‬‭known‬‭tumor‬‭assessment.‬
‭Patients‬‭who‬‭start‬‭a‬‭new‬‭treatment‬‭line‬‭without‬‭progression‬‭will‬‭be‬‭censored‬‭on‬
‭the date of first dose of the subsequent anticancer treatment.‬
‭●‬ ‭Overall‬‭survival‬‭(OS):‬‭defined‬‭as‬‭the‬‭time‬‭elapsed‬‭from‬‭the‬‭first‬‭dose‬‭of‬‭study‬
‭treatment‬‭until‬‭death‬‭from‬‭any‬‭cause.‬‭Patients‬‭alive‬‭and‬‭free‬‭of‬‭events‬‭at‬‭the‬
‭date‬‭of‬‭the‬‭analysis‬‭will‬‭be‬‭censored‬‭at‬‭their‬‭last‬‭known‬‭contact.‬‭Survival‬‭will‬‭be‬
‭assessed by recording patients' status at each visit.‬
‭Results‬‭will‬‭be‬‭presented‬‭as‬‭individual‬‭cases,‬‭not‬‭compiled‬‭as‬‭the‬‭patients‬‭have‬
‭different pathologies which may differ in prognosis.‬
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‭5.1.3.‬ ‭Secondary Safety Endpoints‬
‭●‬ ‭Safety:‬‭All‬‭safety‬‭information‬‭will‬‭be‬‭collected‬‭retrospectively‬‭according‬‭to‬‭data‬
‭available‬‭in‬‭the‬‭chart‬‭review.‬‭A‬‭descriptive‬‭analysis‬‭of‬‭adverse‬‭events‬‭collected‬
‭in medical charts will be done taking into account:‬
‭○‬ ‭The‬‭frequency‬‭of‬‭AEs‬‭will‬‭be‬‭reported‬‭per‬‭patient‬‭by‬‭MedDRA‬‭System‬
‭Organ Class (SOC) and Preferred Term (PT);‬
‭○‬ ‭The maximum CTCAE grade will be reported per patient;‬
‭○‬ ‭The‬‭causal‬‭relationship‬‭with‬‭the‬‭study‬‭drug‬‭will‬‭be‬‭assessed‬‭locally‬‭by‬
‭the investigator‬
‭●‬ ‭Larotrectinib‬ ‭interruptions‬ ‭/‬‭Delays:‬‭number‬‭of‬‭interruptions‬‭and‬‭delays‬‭of‬‭EB‬
‭treatment‬ ‭reported‬ ‭per‬ ‭patient‬ ‭(frequency)‬ ‭and‬ ‭reason‬‭for‬‭dose‬‭interruption‬‭/‬
‭delay.‬
‭●‬ ‭Larotrectinib‬ ‭dose‬ ‭reductions‬ ‭or‬ ‭modifications:‬ ‭Number‬ ‭of‬ ‭reductions‬ ‭or‬
‭modifications‬‭of‬‭EB‬‭doses‬‭reported‬‭per‬‭patient‬‭(frequency)‬‭and‬‭reason‬‭for‬‭dose‬
‭reduction / modification.‬
‭●‬ ‭Larotrectinib‬ ‭treatment‬ ‭duration:‬ ‭Time‬ ‭elapsed‬ ‭between‬ ‭first‬ ‭dose‬ ‭and‬
‭permanent discontinuation of the study treatment.‬
‭5.2.‬
‭Study Variables‬
‭Investigators will provide information of each of the following variables:‬
‭●‬ ‭Variables for Demography:‬
‭○‬ ‭Age at enrollment.‬
‭○‬ ‭Sex (male, female).‬
‭○‬ ‭Race (white, black, Asian, other)‬
‭○‬ ‭Height (cm).‬
‭○‬ ‭Weight (kg).‬
‭○‬ ‭Body mass index.‬
‭○‬ ‭Body‬ ‭surface‬ ‭area‬ ‭(BSA)‬ ‭-‬ ‭calculated‬ ‭from‬ ‭the‬ ‭reported‬ ‭height‬ ‭and‬
‭weight using Mostseller’s formula:‬
‭■‬ ‭BSA (m2)= (height (cm) x weight (kg) / 3600) 1/2‬
‭○‬ ‭Performance‬ ‭status.will‬ ‭be‬ ‭presented‬ ‭using‬ ‭the‬ ‭Eastern‬ ‭Cooperative‬
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‭Oncology Group (ECOG) scale.‬
‭●‬ ‭Cancer history:‬
‭○‬ ‭Primary cancer diagnosis.‬
‭○‬ ‭Primary tumor type, histology and location‬
‭○‬ ‭Stage of disease at initial diagnosis(I-IV).‬
‭○‬ ‭Time since initial diagnosis.‬
‭○‬ ‭Extent‬ ‭of‬ ‭disease‬ ‭at‬ ‭enrollment‬‭(metastatic,‬‭locally‬‭advanced,‬‭sites‬‭of‬
‭disease,‬ ‭presence‬ ‭of‬ ‭at‬ ‭least‬ ‭one‬ ‭measurable‬ ‭lesion).‬ ‭Stage‬ ‭of‬ ‭the‬
‭disease at inclusion‬
‭○‬ ‭Time since diagnosis of metastatic or locally advanced disease (years).‬
‭●‬ ‭Prior anticancer treatments:‬
‭○‬ ‭Prior systemic treatments type, start and end dates.‬
‭○‬ ‭Number of prior systemic regimens or treatment courses.‬
‭○‬ ‭Best‬ ‭overall‬ ‭response‬ ‭to‬ ‭the‬ ‭most‬ ‭recent‬ ‭prior‬ ‭systemic‬ ‭regimen‬ ‭or‬
‭treatment‬ ‭course‬ ‭(CR,‬ ‭PR,‬ ‭stable‬ ‭disease,‬ ‭progressive‬ ‭disease,‬
‭unknown or inevaluable or not applicable).‬
‭○‬ ‭Prior radiotherapy.‬
‭○‬ ‭Prior cancer-related surgery.‬
‭●‬ ‭NTRK fusions:‬
‭○‬ ‭NTRK fusion gene: NTRK1, NTRK2, NTRK3.‬
‭○‬ ‭NTRK fusion isoform (i.e ETV6-NTRK3).‬
‭○‬ ‭Method of detection: NGS, FISH or IHC and dates of the determinations.‬
‭○‬ ‭Other oncogenic alterations present.‬
‭●‬ ‭Treatment with Larotrectinib:‬
‭○‬ ‭Dose of Larotrectinib.‬
‭○‬ ‭Larotrectinib start and end date. Reasons for end of treatment‬
‭○‬ ‭Data records of dose reductions and/or interruptions and their reason.‬
‭○‬ ‭Best response and best response date‬
‭○‬ ‭Progression date.‬
‭○‬ ‭Frequency‬‭of‬‭AEs‬‭reported‬‭per‬‭patient‬‭by‬‭MedDRA‬‭System‬‭Organ‬‭Class‬
‭(SOC)‬ ‭and‬ ‭Preferred‬ ‭Term‬ ‭(PT);‬ ‭the‬ ‭maximum‬ ‭CTCAE‬ ‭grade‬ ‭will‬ ‭be‬
‭reported‬‭per‬‭patient.‬‭Causal‬‭relationship‬‭with‬‭the‬‭study‬‭treatment‬‭will‬‭be‬
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‭reported for all events.‬
‭●‬ ‭Survival:‬
‭○‬ ‭Patient status (alive, death, lost to follow-up)‬
‭○‬ ‭Reasons of death (if applicable)‬
‭○‬ ‭Subsequent‬ ‭anticancer‬ ‭treatments‬ ‭(type,‬ ‭start‬ ‭and‬ ‭end‬ ‭dates,‬ ‭best‬
‭response, progression dates)‬
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‭6.‬
‭PROTECTION OF HUMAN SUBJECTS‬
‭6.1.‬
‭Applicable Legislation‬
‭This‬‭is‬‭an‬‭observational,‬‭descriptive,‬‭non-interventional‬‭study‬‭with‬‭the‬‭main‬‭objective‬‭of‬
‭collecting‬ ‭information‬ ‭on‬‭Larotrectinib-treated‬‭solid‬‭neoplasms‬‭patients‬‭with‬‭detected‬
‭NTRK‬ ‭fusions,‬ ‭under‬ ‭clinical‬ ‭attention‬ ‭and‬ ‭follow-up‬ ‭in‬ ‭oncology‬ ‭departments‬ ‭of‬
‭centers distributed across national level.‬
‭The‬‭study‬‭design‬‭includes‬‭retrospective‬‭data‬‭collection.‬‭Therefore,‬‭in‬‭accordance‬‭with‬
‭the‬‭Royal‬‭Decree‬‭957/2020‬‭which‬‭regulates‬‭the‬‭observational‬‭studies‬‭with‬‭medicines‬
‭for‬‭human‬‭use,‬‭this‬‭is‬‭considered‬‭a‬‭retrospective‬‭observational‬‭study‬‭with‬‭medicines‬
‭(Estudio‬ ‭observacional‬ ‭con‬ ‭medicamentos‬ ‭[EOM]).‬ ‭In‬ ‭compliance‬ ‭with‬ ‭the‬ ‭same‬
‭legislation,‬‭the‬‭participation‬‭of‬‭any‬‭center‬‭will‬‭be‬‭conditional‬‭upon‬‭approval‬‭of‬‭a‬‭Clinical‬
‭Research Ethics Committee and/or authorization through the institution conformity.‬
‭Participating‬‭in‬‭this‬‭study‬‭does‬‭not‬‭pose‬‭any‬‭additional‬‭risk‬‭to‬‭patients‬‭because‬‭this‬‭is‬‭a‬
‭study‬ ‭developed‬ ‭from‬ ‭information‬ ‭retrieved‬ ‭from‬ ‭the‬ ‭clinical‬ ‭histories‬ ‭and‬ ‭clinical‬
‭assessment‬‭of‬‭patients,‬‭all‬‭in‬‭the‬‭context‬‭of‬‭the‬‭usual‬‭clinical‬‭practice‬‭and‬‭without‬‭the‬
‭involvement‬ ‭of‬ ‭patients‬ ‭in‬ ‭any‬‭type‬‭of‬‭intervention‬‭or‬‭without‬‭the‬‭modification‬‭of‬‭the‬
‭treatment that they would receive had they not participated in the study.‬
‭The‬‭present‬‭protocol‬‭will‬‭be‬‭conducted‬‭in‬‭accordance‬‭with‬‭the‬‭principles‬‭adopted‬‭by‬
‭the‬‭18‬‭th‬ ‭World‬‭Medical‬‭Assembly‬‭(Helsinki,‬‭1964)‬‭and‬‭their‬‭subsequent‬‭amendments‬
‭(Fortaleza, 2013), following the rules of good clinical practice and deontological code.‬
‭6.2.‬
‭Oversight Clinical Research Ethics‬
‭The‬ ‭study‬ ‭will‬ ‭be‬ ‭initially‬ ‭submitted‬ ‭for‬ ‭evaluation‬ ‭by‬ ‭the‬ ‭Clinical‬ ‭Research‬ ‭Ethics‬
‭Committee‬‭of‬‭the‬‭Hospital‬‭Vall‬‭d’‬‭Hebron‬‭(Barcelona).‬‭As‬‭detailed‬‭in‬‭section‬‭6.1,‬‭the‬
‭study‬‭will‬‭also‬‭have‬‭the‬‭corresponding‬‭and‬‭applicable‬‭authorisations‬‭according‬‭to‬‭the‬
‭local‬ ‭regulations‬ ‭of‬ ‭each‬ ‭center‬ ‭and‬ ‭the‬ ‭guidelines‬ ‭of‬ ‭the‬ ‭Royal‬ ‭Decree‬ ‭957/2020‬
‭which regulates the observational studies with medicines for human use.‬
‭6.3.‬
‭Informed Consent‬
‭Patients‬‭will‬‭not‬‭be‬‭asked‬‭for‬‭informed‬‭consent‬‭to‬‭be‬‭registered‬‭as‬‭a‬‭case‬‭in‬‭this‬‭study.‬
‭This‬ ‭study‬ ‭is‬ ‭considered‬ ‭to‬ ‭meet‬ ‭all‬ ‭the‬ ‭requirements‬ ‭for‬ ‭exemption‬ ‭from‬ ‭consent‬
‭according‬‭to‬‭the‬‭“International‬‭Ethical‬‭Guidelines‬‭for‬‭Health-related‬‭Research‬‭Involving‬
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‭Humans” (CIOMS-OMS 2016):‬
‭●‬ ‭This‬ ‭is‬ ‭a‬ ‭study‬ ‭of‬ ‭general‬ ‭public‬ ‭interest‬ ‭and‬ ‭social‬ ‭value,‬ ‭in‬ ‭the‬ ‭field‬ ‭of‬
‭biomedical research.‬
‭●‬ ‭It‬‭is‬‭a‬‭case‬‭registry‬‭in‬‭which‬‭the‬‭retrospective‬‭collection‬‭of‬‭personal‬‭and‬‭health‬
‭data‬ ‭of‬ ‭the‬ ‭patient‬ ‭is‬ ‭minimized‬ ‭to‬ ‭the‬ ‭maximum,‬ ‭which‬ ‭is‬ ‭kept‬ ‭in‬‭a‬‭secure‬
‭system‬‭with‬‭access‬‭restricted‬‭exclusively‬‭to‬‭the‬‭researchers‬‭of‬‭the‬‭participating‬
‭hospital and the coordinators of the study.‬
‭●‬ ‭Obtaining‬‭informed‬‭consent‬‭for‬‭this‬‭registry‬‭may‬‭be‬‭impractical‬‭in‬‭many‬‭cases,‬
‭due‬‭to‬‭the‬‭acute‬‭or‬‭serious‬‭condition‬‭of‬‭the‬‭patient‬‭and‬‭the‬‭moment‬‭in‬‭which‬‭the‬
‭oncologist‬‭becomes‬‭aware‬‭of‬‭the‬‭case.‬‭Additionally,‬‭obtaining‬‭consent‬‭would‬‭be‬
‭a‬‭limitation‬‭for‬‭the‬‭correct‬‭execution‬‭of‬‭the‬‭project,‬‭which‬‭requires‬‭an‬‭exhaustive‬
‭registry of all cases of which there is knowledge.‬
‭●‬ ‭Finally,‬ ‭it‬ ‭is‬ ‭considered‬ ‭that‬ ‭the‬ ‭collection‬ ‭of‬ ‭cases‬ ‭with‬ ‭the‬ ‭established‬
‭confidentiality guarantees does not pose any risk to patients.‬
‭The‬‭patient's‬‭participation‬‭in‬‭the‬‭study‬‭must‬‭be‬‭recorded‬‭in‬‭the‬‭patient's‬‭medical‬‭history,‬
‭making explicit reference to the study SPAINTRK / GETNE S2411.‬
‭The‬ ‭sponsor's‬ ‭objective‬ ‭is‬ ‭to‬ ‭avoid‬ ‭serious‬ ‭problems‬ ‭of‬ ‭scientific‬ ‭validity‬‭that‬‭could‬
‭mean‬‭that‬‭a‬‭relevant‬‭proportion‬‭of‬‭patients‬‭are‬‭lost,‬‭for‬‭example‬‭those‬‭with‬‭fatal‬‭events‬
‭or‬ ‭loss‬ ‭of‬ ‭follow-up,‬ ‭and‬ ‭that‬ ‭due‬ ‭to‬ ‭a‬ ‭lack‬ ‭of‬ ‭representativeness‬‭of‬‭the‬‭population‬
‭affected by the disease, the results obtained may present some type of bias.‬
‭For‬‭all‬‭patients,‬‭the‬‭data‬‭are‬‭included‬‭in‬‭the‬‭study‬‭in‬‭an‬‭anonymized‬‭and‬‭dissociated‬
‭form,‬ ‭guaranteeing‬ ‭that‬ ‭they‬ ‭cannot‬ ‭be‬ ‭associated‬ ‭with‬‭any‬‭identified‬‭or‬‭identifiable‬
‭person.‬‭The‬‭use‬‭of‬‭patient‬‭data‬‭will‬‭be‬‭subject‬‭to‬‭a‬‭commitment‬‭of‬‭confidentiality‬‭by‬‭all‬
‭personnel‬‭participating‬‭in‬‭the‬‭study,‬‭including‬‭the‬‭researcher‬‭and‬‭his‬‭collaborators,‬‭data‬
‭managers,‬‭data‬‭analysts,‬‭and‬‭monitors;‬‭this‬‭must‬‭be‬‭correctly‬‭recorded‬‭in‬‭the‬‭patient's‬
‭medical history, with specific reference to the study SPAINTRK / GETNE S2411.‬
‭6.4.‬
‭Confidentiality‬
‭Pursuant‬‭to‬‭the‬‭Statutory‬‭Law‬‭on‬‭Personal‬‭Data‬‭Protection‬‭(‬‭Ley‬‭Orgánica‬‭3/2018,‬‭de‬‭5‬
‭de‬‭diciembre,‬‭de‬‭Protección‬‭de‬‭Datos‬‭de‬‭Carácter‬‭Personal‬‭y‬‭garantía‬‭de‬‭los‬‭derechos‬
‭digitales‬ ‭–‬ ‭LOPD),‬ ‭the‬ ‭sponsor‬ ‭guarantees‬ ‭the‬ ‭adoption‬ ‭of‬ ‭necessary‬ ‭measures‬ ‭to‬
‭ensure the confidential treatment of personal data.‬
‭Only‬ ‭reporting‬ ‭physicians‬ ‭will‬ ‭know‬ ‭the‬ ‭full‬ ‭name‬ ‭of‬ ‭their‬ ‭patients.‬ ‭No‬ ‭sensitive‬
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‭information unnecessary for the intended purposes of the study is collected.‬
‭An‬‭electronic‬‭platform‬‭will‬‭be‬‭used‬‭to‬‭log‬‭data‬‭in‬‭the‬‭eCRF.‬‭To‬‭access‬‭the‬‭application,‬
‭users‬‭must‬‭identify‬‭themselves‬‭with‬‭a‬‭username‬‭and‬‭a‬‭password‬‭strictly‬‭for‬‭personal‬
‭use.‬ ‭Each‬ ‭reporting‬ ‭physician‬‭will‬‭only‬‭access‬‭the‬‭data‬‭he‬‭or‬‭she‬‭introduced‬‭that‬‭is‬
‭strictly‬‭necessary‬‭for‬‭the‬‭job.‬‭Any‬‭document‬‭containing‬‭identifying‬‭data‬‭of‬‭the‬‭principal‬
‭investigator,‬‭hospital,‬‭contact‬‭person,‬‭and‬‭telephone‬‭number‬‭will‬‭remain‬‭in‬‭the‬‭center‬‭at‬
‭all times, without being included in the database.‬
‭Data‬‭will‬‭be‬‭collected‬‭in‬‭a‬‭research‬‭file‬‭under‬‭the‬‭responsibility‬‭of‬‭the‬‭sponsor‬‭and‬‭will‬
‭be‬ ‭treated‬ ‭in‬ ‭the‬ ‭framework‬ ‭of‬ ‭the‬ ‭study,‬ ‭guaranteeing‬ ‭that‬ ‭the‬ ‭sponsor‬ ‭will‬ ‭adopt‬
‭pertinent‬‭measures‬‭to‬‭ensure‬‭compliance‬‭with‬‭the‬‭current‬‭legislation‬‭on‬‭data‬‭protection‬
‭in‬‭all‬‭cases.‬‭The‬‭coded‬‭data‬‭can‬‭be‬‭transmitted‬‭to‬‭third‬‭parties‬‭and‬‭to‬‭other‬‭countries‬
‭but‬‭in‬‭no‬‭case‬‭they‬‭will‬‭contain‬‭information‬‭that‬‭can‬‭directly‬‭identify‬‭any‬‭patient,‬‭such‬
‭as‬‭name‬‭and‬‭surnames,‬‭initials,‬‭address,‬‭or‬‭social‬‭security‬‭number,‬‭among‬‭others.‬‭If‬
‭this‬‭transfer‬‭occurs,‬‭it‬‭will‬‭be‬‭for‬‭the‬‭same‬‭study‬‭purposes‬‭as‬‭those‬‭described‬‭above‬‭or‬
‭for‬‭scientific‬‭publications‬‭only,‬‭but‬‭always‬‭maintaining‬‭patient‬‭confidentiality‬‭according‬
‭to current legislation.‬
‭The‬ ‭database‬ ‭will‬ ‭be‬ ‭examined‬‭exclusively‬‭by‬‭the‬‭scientific‬‭and‬‭medical‬‭staff‬‭of‬‭the‬
‭sponsor.‬‭No‬‭personal‬‭data‬‭or‬‭any‬‭information‬‭that‬‭may‬‭be‬‭related‬‭to‬‭patients‬‭will‬‭be‬
‭included‬‭in‬‭this‬‭database.‬‭The‬‭database‬‭administrator,‬‭treatment‬‭manager,‬‭and‬‭monitor‬
‭(if applicable) will have access to all data that are not linked to any identifiable person.‬
‭In‬‭data‬‭explorations‬‭by‬‭researchers‬‭authorized‬‭by‬‭the‬‭Scientific‬‭Committee‬‭and‬
‭in‬‭international‬‭data‬‭transfers‬‭to‬‭International‬‭Registries,‬‭if‬‭applicable,‬‭patients‬‭will‬‭be‬
‭identified‬‭by‬‭a‬‭numerical‬‭code‬‭automatically‬‭and‬‭randomly‬‭assigned‬‭by‬‭the‬‭computer‬
‭application‬ ‭at‬ ‭the‬ ‭start‬ ‭of‬ ‭logging‬ ‭of‬ ‭each‬ ‭case‬ ‭to‬ ‭maintain‬ ‭the‬ ‭confidentiality‬ ‭of‬
‭personal‬ ‭patient‬ ‭data,‬ ‭as‬ ‭established‬ ‭in‬ ‭the‬ ‭European‬ ‭Union‬ ‭(EU)‬ ‭Parliament‬ ‭and‬
‭Council‬‭General‬‭Data‬‭Protection‬‭Regulation‬‭2016/679‬‭on‬‭April‬‭27,‬‭2016.‬‭This‬‭type‬‭of‬
‭coding‬ ‭is‬ ‭used‬ ‭because‬ ‭it‬ ‭guarantees‬ ‭patient‬ ‭confidentiality‬ ‭while‬ ‭respecting‬ ‭the‬
‭exercise of their access, revocation, consultation, and opposition rights.‬
‭Access‬ ‭to‬ ‭personal‬ ‭information‬ ‭of‬ ‭the‬ ‭study‬ ‭subjects‬ ‭will‬ ‭be‬ ‭restricted‬ ‭to‬ ‭the‬ ‭study‬
‭physician/collaborators,‬ ‭health‬ ‭authorities‬ ‭(Spanish‬ ‭Medicines‬ ‭Agency),‬ ‭Clinical‬
‭Research‬‭Ethics‬‭Committee,‬‭and‬‭staff‬‭authorized‬‭by‬‭the‬‭sponsor,‬‭when‬‭they‬‭need‬‭to‬
‭assess‬ ‭study‬ ‭data‬ ‭and‬ ‭procedures,‬ ‭but‬ ‭always‬ ‭maintaining‬ ‭patient‬ ‭confidentiality‬ ‭in‬
‭compliance with the current legislation.‬
‭This‬ ‭assessment‬ ‭will‬ ‭be‬ ‭performed‬ ‭in‬ ‭the‬ ‭presence‬ ‭of‬ ‭the‬ ‭principal‬ ‭investigator‬ ‭or‬
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‭collaborators,‬ ‭responsible‬ ‭for‬ ‭guaranteeing‬ ‭the‬ ‭data‬ ‭confidentiality‬ ‭on‬ ‭the‬ ‭clinical‬
‭histories‬‭of‬‭the‬‭study‬‭subjects.‬‭Only‬‭data‬‭collected‬‭for‬‭the‬‭study‬‭will‬‭be‬‭transmitted‬‭to‬
‭third‬‭parties,‬‭which‬‭in‬‭no‬‭case‬‭will‬‭contain‬‭information‬‭that‬‭can‬‭directly‬‭identify‬‭the‬‭study‬
‭subjects,‬ ‭such‬ ‭as‬ ‭name‬ ‭and‬ ‭surnames,‬ ‭initials,‬ ‭address,‬ ‭or‬ ‭social‬ ‭security‬ ‭number,‬
‭among‬‭others.‬‭If‬‭this‬‭transfer‬‭occurs,‬‭it‬‭will‬‭be‬‭for‬‭the‬‭same‬‭study‬‭purposes‬‭as‬‭those‬
‭described‬ ‭here‬ ‭and‬ ‭maintaining‬ ‭patient‬ ‭confidentiality,‬ ‭at‬ ‭least‬ ‭with‬ ‭the‬ ‭level‬ ‭of‬
‭protection‬ ‭of‬ ‭the‬ ‭current‬ ‭legislation,‬ ‭including‬ ‭data‬ ‭transfer‬ ‭outside‬ ‭the‬ ‭area‬ ‭of‬
‭application of the reference legislation.‬
‭6.5.‬
‭Funding Source‬
‭The‬‭study‬‭sponsor,‬‭GETNE‬‭through‬‭collaboration‬‭with‬‭Bayer‬‭Hispania‬‭S.L.U,‬‭funds‬‭the‬
‭study‬‭according‬‭to‬‭the‬‭guidelines‬‭of‬‭the‬‭present‬‭protocol.‬‭This‬‭funding‬‭covers‬‭the‬‭cost‬
‭of‬‭registration‬‭and‬‭control‬‭processes‬‭in‬‭Ethics‬‭Committees‬‭and‬‭health‬‭authorities;‬‭the‬
‭design,‬ ‭maintenance,‬ ‭and‬ ‭management‬ ‭of‬ ‭the‬ ‭database;‬ ‭eventual‬ ‭statistical‬
‭consultations,‬‭if‬‭necessary;‬‭and‬‭publishing‬‭and‬‭reporting‬‭costs.‬‭The‬‭funding‬‭will‬‭be,‬‭in‬
‭any case, independent of the results of the study.‬
‭The‬ ‭sponsor‬ ‭guarantees‬ ‭non-interference‬ ‭in‬ ‭the‬ ‭processes‬ ‭of‬ ‭case‬ ‭selection,‬ ‭data‬
‭analysis,‬ ‭or‬ ‭in‬ ‭any‬ ‭other‬ ‭process‬ ‭that‬ ‭may‬ ‭affect‬ ‭the‬ ‭study‬ ‭results‬ ‭involving‬ ‭data‬
‭exploration and presentation.‬
‭6.6.‬
‭Potential advantage and limitations of research methods‬
‭The‬‭observational‬‭approach‬‭of‬‭this‬‭study‬‭offers‬‭the‬‭advantage‬‭of‬‭generating‬‭scientific‬
‭data‬‭to‬‭demonstrate‬‭that‬‭detection‬‭of‬‭NTRK‬‭fusion‬‭in‬‭patients‬‭with‬‭solid‬‭neoplasms‬‭by‬
‭using‬ ‭detections‬ ‭methods‬ ‭such‬ ‭as‬ ‭NGS,‬ ‭FISH‬ ‭or‬ ‭IHC‬ ‭in‬ ‭the‬ ‭real‬ ‭world‬ ‭and‬ ‭give‬
‭external‬‭validity‬‭to‬‭the‬‭clinical‬‭trials‬‭that‬‭led‬‭to‬‭its‬‭commercialization.‬‭Accordingly,‬‭this‬
‭study‬‭will‬‭assess‬‭whether‬‭treatment‬‭with‬‭Larotrectinib‬‭supposes‬‭an‬‭effective‬‭benefit‬‭on‬
‭these patients.‬
‭Inherent‬‭limitations‬‭of‬‭non-interventional,‬‭observational‬‭studies‬‭in‬‭general‬‭are‬‭the‬‭risk‬
‭of‬ ‭selection/ascertainment‬ ‭bias,‬ ‭the‬ ‭inclusion‬ ‭of‬ ‭non-standardized‬ ‭assessments‬ ‭and‬
‭evaluations,‬ ‭the‬ ‭non-standardization‬‭of‬‭time-points,‬‭and‬‭the‬‭lack‬‭of‬‭a‬‭parallel‬‭control‬
‭group,‬ ‭which‬ ‭complicate‬ ‭the‬ ‭interpretation‬ ‭of‬ ‭the‬ ‭causality‬ ‭between‬ ‭treatments‬ ‭and‬
‭outcomes.‬‭Furthermore,‬‭as‬‭with‬‭any‬‭"as‬‭observed"‬‭analysis,‬‭there‬‭is‬‭a‬‭potential‬‭risk‬‭of‬
‭bias‬ ‭due‬ ‭to‬ ‭missing‬ ‭outcome‬ ‭data;‬ ‭this‬ ‭specific‬ ‭risk‬ ‭increases‬ ‭with‬ ‭the‬ ‭number‬ ‭of‬
‭missing outcome data.‬
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‭7.‬
‭MANAGEMENT‬ ‭AND‬ ‭REPORTING‬ ‭OF‬ ‭ADVERSE‬ ‭EVENTS/ADVERSE‬
‭REACTIONS‬
‭As‬‭stipulated‬‭in‬‭the‬‭Royal‬‭Decree‬‭957/2020‬‭which‬‭regulates‬‭the‬‭observational‬‭studies‬
‭with‬ ‭medicines‬ ‭for‬ ‭human‬ ‭use,‬ ‭for‬ ‭those‬ ‭studies‬ ‭in‬ ‭which‬ ‭detection‬ ‭of‬ ‭suspected‬
‭serious‬ ‭adverse‬ ‭reactions‬ ‭during‬ ‭the‬ ‭study‬ ‭is‬ ‭not‬ ‭possible‬ ‭or‬ ‭where‬ ‭the‬ ‭individual‬
‭evaluation‬ ‭or‬ ‭causality‬ ‭of‬ ‭a‬ ‭clinical‬ ‭event‬ ‭within‬ ‭an‬ ‭specific‬ ‭drug‬ ‭is‬ ‭not‬ ‭appropriate‬
‭(such‬‭as‬‭those‬‭retrospective),‬‭expedite‬‭notification‬‭of‬‭suspected‬‭adverse‬‭reactions‬‭will‬
‭not be mandatory.‬
‭Accumulated‬‭data‬‭on‬‭safety‬‭aspects‬‭(serious‬‭adverse‬‭events‬‭and‬‭adverse‬‭drug‬
‭reactions)‬‭related‬‭to‬‭medical‬‭products‬‭subject‬‭of‬‭study‬‭will‬‭be‬‭recorded‬‭by‬‭sites‬‭in‬‭the‬
‭eCRF‬‭and‬‭included‬‭in‬‭the‬‭clinical‬‭study‬‭report‬‭by‬‭the‬‭sponsor,‬‭as‬‭this‬‭study‬‭is‬‭based‬‭on‬
‭secondary use of data, no expedite reporting to the Sponsor is required.‬
‭In‬‭addition‬‭to‬‭the‬‭details‬‭specified‬‭in‬‭the‬‭previous‬‭paragraph,‬‭any‬‭relevant‬‭safety‬‭finding‬
‭detected‬‭during‬‭the‬‭study‬‭will‬‭be‬‭brought‬‭to‬‭the‬‭attention‬‭of‬‭the‬‭AEMPS‬‭and‬‭competent‬
‭bodies of Autonomous Communities involved, regardless of the study design or type.‬
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‭8.‬
‭QUALITY ASSURANCE‬
‭8.1.‬
‭Control of data consistency‬
‭The‬ ‭investigator‬ ‭or‬ ‭qualified‬ ‭designee‬ ‭is‬ ‭responsible‬ ‭for‬ ‭recording‬ ‭and‬‭verifying‬‭the‬
‭accuracy of subject data.‬
‭●‬ ‭The‬‭study‬‭will‬‭use‬‭eCRFs.‬‭A‬‭designated‬‭CRO‬‭staff‬‭will‬‭review‬‭the‬‭data‬‭entered‬
‭by‬‭investigational‬‭staff‬‭for‬‭completeness‬‭and‬‭accuracy.‬‭Electronic‬‭data‬‭queries‬
‭stating‬‭the‬‭nature‬‭of‬‭the‬‭findings‬‭and‬‭requesting‬‭clarification‬‭will‬‭be‬‭created‬‭for‬
‭discrepancies‬ ‭and‬ ‭missing‬ ‭values‬ ‭and‬ ‭sent‬ ‭to‬‭the‬‭investigational‬‭site‬‭via‬‭the‬
‭EDC‬‭system.‬‭Designated‬‭investigator‬‭site‬‭staff‬‭is‬‭required‬‭to‬‭respond‬‭promptly‬
‭to queries and to make any necessary changes to the data.‬
‭●‬ ‭Concomitant‬ ‭treatments‬ ‭and‬ ‭all‬ ‭information‬ ‭on‬ ‭medications‬ ‭entered‬ ‭into‬ ‭the‬
‭database‬‭will‬‭be‬‭coded‬‭using‬‭the‬‭WHO‬‭Drug‬‭Reference‬‭List,‬‭which‬‭employs‬‭the‬
‭Anatomical Therapeutic Chemical classification system.‬
‭●‬ ‭Medical‬ ‭history/current‬ ‭medical‬ ‭conditions‬ ‭and‬ ‭adverse‬ ‭events‬ ‭will‬‭be‬‭coded‬
‭using the Medical dictionary for regulatory activities (MedDRA) terminology.‬
‭●‬ ‭The‬‭site‬‭staff‬‭designated‬‭by‬‭the‬‭investigator‬‭will‬‭enter‬‭the‬‭information‬‭required‬
‭by‬ ‭the‬ ‭protocol‬ ‭onto‬ ‭the‬ ‭eCRFs‬ ‭as‬ ‭well‬ ‭as‬ ‭onto‬ ‭the‬ ‭designated‬ ‭CRO’s‬
‭requisition form.‬
‭8.2.‬
‭On-site quality control‬
‭●‬ ‭Before‬ ‭study‬ ‭initiation,‬ ‭the‬ ‭protocol‬ ‭and‬ ‭eCRFs‬ ‭will‬ ‭be‬ ‭reviewed‬ ‭with‬ ‭the‬
‭investigators and their staff through a telephonic site initiation visit.‬
‭●‬ ‭During‬ ‭the‬ ‭study,‬ ‭a‬ ‭monitor‬ ‭will‬ ‭contact‬ ‭the‬ ‭selected‬ ‭sites‬ ‭through‬ ‭remote‬
‭monitoring‬‭visits‬‭to‬‭check‬‭the‬‭completeness‬‭of‬‭patient‬‭records,‬‭the‬‭accuracy‬‭of‬
‭entries‬‭on‬‭the‬‭eCRFs.‬‭Key‬‭study‬‭personnel‬‭must‬‭be‬‭available‬‭to‬‭assist‬‭the‬‭field‬
‭monitor during these visits.‬
‭●‬ ‭The‬‭investigator‬‭must‬‭maintain‬‭source‬‭documents‬‭for‬‭each‬‭patient‬‭in‬‭the‬‭study,‬
‭consisting‬‭of‬‭case‬‭and‬‭visit‬‭notes‬‭(hospital‬‭or‬‭clinic‬‭medical‬‭records)‬‭containing‬
‭demographic‬‭and‬‭medical‬‭information,‬‭laboratory‬‭data,‬‭electrocardiograms,‬‭and‬
‭the results of any other tests or assessments.‬
‭●‬ ‭All‬‭information‬‭recorded‬‭on‬‭eCRFs‬‭must‬‭be‬‭traceable‬‭to‬‭source‬‭documents‬‭in‬
‭the patient's file.‬
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‭●‬ ‭The‬‭investigator‬‭must‬‭give‬‭the‬‭monitor‬‭access‬‭to‬‭all‬‭relevant‬‭source‬‭documents‬
‭to confirm their consistency with the eCRF entries.‬
‭8.3.‬
‭Audits‬
‭●‬ ‭To‬‭ensure‬‭quality‬‭of‬‭data,‬‭study‬‭integrity,‬‭and‬‭compliance‬‭with‬‭the‬‭protocol‬‭and‬
‭the‬‭various‬‭applicable‬‭regulations‬‭and‬‭guidelines,‬‭the‬‭“Sponsor”‬‭may‬‭conduct‬
‭site visits to institutions participating in protocols.‬
‭●‬ ‭The‬ ‭investigator,‬ ‭by‬ ‭accepting‬ ‭to‬ ‭participate‬ ‭to‬ ‭this‬ ‭protocol,‬ ‭agrees‬ ‭to‬
‭cooperate‬ ‭fully‬ ‭with‬ ‭any‬ ‭quality‬ ‭assurance‬ ‭visit‬ ‭undertaken‬ ‭by‬ ‭third‬ ‭parties,‬
‭including‬‭representatives‬‭from‬‭the‬‭“Sponsor”,‬‭national‬‭and/or‬‭foreign‬‭regulatory‬
‭authorities‬‭or‬‭company‬‭supplying‬‭the‬‭product‬‭under‬‭investigation,‬‭as‬‭well‬‭as‬‭to‬
‭allow‬ ‭direct‬ ‭access‬ ‭to‬ ‭documentation‬ ‭pertaining‬ ‭to‬ ‭the‬‭clinical‬‭trial‬‭(including‬
‭CRFs,‬‭source‬‭documents,‬‭hospital‬‭patient‬‭charts‬‭and‬‭other‬‭study‬‭files)‬‭to‬‭these‬
‭authorized individuals.‬
‭●‬ ‭The‬ ‭investigator‬ ‭must‬ ‭inform‬ ‭the‬ ‭“Sponsor”‬ ‭immediately‬‭in‬‭case‬‭a‬‭regulatory‬
‭authority inspection would be scheduled.‬
‭●‬ ‭The‬‭source‬‭documents‬‭should‬‭be‬‭stored‬‭for‬‭5‬‭years‬‭and‬‭be‬‭available‬‭for‬‭audits‬
‭and inspections if applicable.‬
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‭9.‬
‭WORK PLAN (TASKS, MILESTONES AND STUDY CHRONOLOGY)‬
‭2024 (Month)‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭7‬
‭8‬
‭9‬
‭10‬
‭11‬
‭12‬
‭Study activation‬
‭Recruitment period‬
‭Data‬ ‭and‬ ‭endpoint‬
‭capture‬
‭2025 (Month)‬
‭1‬
‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭7‬
‭8‬
‭9‬
‭10‬
‭11‬
‭12‬
‭Recruitment period‬
‭Data‬ ‭and‬ ‭endpoint‬
‭capture‬
‭Analysis of results‬
‭Management‬
‭and‬
‭presentation‬ ‭of‬ ‭data‬
‭for publication‬
‭Figure 2. Working plan and calendar, GANTT chart‬
‭Please refer to section 4 for further detail on the study calendar.‬
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‭10.‬
‭PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS‬
‭The‬ ‭study‬ ‭sponsor‬ ‭holds‬ ‭the‬ ‭rights‬ ‭of‬ ‭exploring‬ ‭the‬ ‭data‬ ‭collected,‬ ‭stores‬ ‭and‬
‭safeguards‬‭them,‬‭and‬‭acts‬‭as‬‭a‬‭Scientific‬‭Committee‬‭for‬‭the‬‭approval‬‭of‬‭proposals‬‭for‬
‭data exploration and publication of results made by researchers.‬
‭The‬ ‭objective‬ ‭of‬ ‭the‬ ‭study,‬ ‭openly‬ ‭epidemiological,‬ ‭is‬ ‭to‬ ‭collect‬ ‭information‬ ‭on‬ ‭the‬
‭management‬ ‭of‬ ‭the‬ ‭study‬ ‭disease‬ ‭in‬ ‭different‬ ‭participating‬ ‭hospitals‬ ‭to‬ ‭establish‬ ‭a‬
‭framework‬ ‭for‬ ‭action‬ ‭(usual‬ ‭practice)‬ ‭and,‬ ‭therefore,‬ ‭study‬ ‭options‬ ‭for‬ ‭disease‬
‭management beneficial for the patients.‬
‭10.1.‬ ‭Commitment and Publication Rules‬
‭The‬ ‭Coordinating‬ ‭Investigators‬ ‭and‬ ‭the‬ ‭Sponsor‬ ‭are‬ ‭responsible‬ ‭for‬ ‭the‬ ‭periodic‬
‭preparation‬ ‭of‬ ‭monographs‬ ‭or‬ ‭manuscripts‬ ‭summarizing‬ ‭the‬ ‭logged‬ ‭data‬ ‭for‬
‭publication.‬ ‭The‬ ‭global‬ ‭data‬ ‭will‬ ‭be‬ ‭used‬ ‭in‬ ‭papers‬ ‭submitted‬ ‭for‬ ‭publication‬ ‭to‬
‭congresses and to medical journals, mentioning the study and the sponsor.‬
‭The‬‭authors‬‭of‬‭the‬‭scientific‬‭communications‬‭will‬‭be‬‭all‬‭investigators‬‭contributing‬‭to‬‭the‬
‭study.‬
‭The‬‭manuscript‬‭containing‬‭the‬‭main‬‭data‬‭of‬‭this‬‭study‬‭will‬‭be‬‭submitted‬‭to‬‭a‬‭scientific,‬
‭indexed,‬‭peer-reviewed‬‭journal‬‭for‬‭publication‬‭approximately‬‭12‬‭months‬‭after‬‭the‬‭study‬
‭initiation‬ ‭(estimated‬ ‭4Q2025).‬ ‭We‬ ‭expect‬ ‭to‬ ‭have‬ ‭the‬ ‭results‬ ‭published‬ ‭by‬ ‭1Q2026‬
‭(estimated).‬
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‭11.‬
‭REFERENCES‬
‭1.‬ ‭FDA‬ ‭Approves‬ ‭Entrectinib‬ ‭for‬ ‭Tumors‬ ‭with‬‭NTRK‬‭Fusions‬‭-‬‭NCI‬‭[Internet].‬‭2019‬
‭[cited‬
‭2024‬
‭Sep‬
‭9].‬
‭Available‬
‭from:‬
‭https://www.cancer.gov/news-events/cancer-currents-blog/2019/fda-entrectinib-ntrk‬
‭-fusion‬
‭2.‬ ‭Committee‬‭on‬‭the‬‭Review‬‭of‬‭Omics-Based‬‭Tests‬‭for‬‭Predicting‬‭Patient‬‭Outcomes‬
‭in‬‭Clinical‬‭Trials,‬‭Board‬‭on‬‭Health‬‭Care‬‭Services,‬‭Board‬‭on‬‭Health‬‭Sciences‬‭Policy,‬
‭Institute‬‭of‬‭Medicine.‬‭Evolution‬‭of‬‭Translational‬‭Omics:‬‭Lessons‬‭Learned‬‭and‬‭the‬
‭Path‬ ‭Forward‬ ‭[Internet].‬ ‭Micheel‬ ‭CM,‬‭Nass‬‭SJ,‬‭Omenn‬‭GS,‬‭editors.‬‭Washington‬
‭(DC):‬ ‭National‬ ‭Academies‬ ‭Press‬ ‭(US);‬ ‭2012‬‭[cited‬‭2024‬‭Sep‬‭9].‬‭Available‬‭from:‬
‭http://www.ncbi.nlm.nih.gov/books/NBK202168/‬
‭3.‬ ‭Heo‬‭YJ,‬‭Hwa‬‭C,‬‭Lee‬‭GH,‬‭Park‬‭JM,‬‭An‬‭JY.‬‭Integrative‬‭Multi-Omics‬‭Approaches‬‭in‬
‭Cancer‬‭Research:‬‭From‬‭Biological‬‭Networks‬‭to‬‭Clinical‬‭Subtypes.‬‭Mol‬‭Cells.‬‭2021‬
‭Jul 31;44(7):433–43.‬
‭4.‬ ‭Tarantino‬ ‭P,‬ ‭Mazzarella‬ ‭L,‬ ‭Marra‬ ‭A,‬ ‭Trapani‬ ‭D,‬ ‭Curigliano‬ ‭G.‬ ‭The‬ ‭evolving‬
‭paradigm‬ ‭of‬ ‭biomarker‬ ‭actionability:‬ ‭Histology-agnosticism‬‭as‬‭a‬‭spectrum,‬‭rather‬
‭than a binary quality. Cancer Treat Rev. 2021 Mar;94:102169.‬
‭5.‬ ‭Hierro‬ ‭C,‬ ‭Matos‬ ‭I,‬ ‭Martin-Liberal‬ ‭J,‬ ‭Ochoa‬ ‭de‬ ‭Olza‬ ‭M,‬ ‭Garralda‬ ‭E.‬
‭Agnostic-Histology‬ ‭Approval‬ ‭of‬‭New‬‭Drugs‬‭in‬‭Oncology:‬‭Are‬‭We‬‭Already‬‭There?‬
‭Clin Cancer Res Off J Am Assoc Cancer Res. 2019 Jun 1;25(11):3210–9.‬
‭6.‬ ‭Koopman‬‭B,‬‭Kuijpers‬‭CCHJ,‬‭Groen‬‭HJM,‬‭Timens‬‭W,‬‭Schuuring‬‭E,‬‭Willems‬‭SM,‬‭et‬
‭al.‬‭Detection‬‭of‬‭NTRK‬‭Fusions‬‭and‬‭TRK‬‭Expression‬‭and‬‭Performance‬‭of‬‭pan-TRK‬
‭Immunohistochemistry‬ ‭in‬ ‭Routine‬ ‭Diagnostics:‬ ‭Results‬ ‭from‬ ‭a‬ ‭Nationwide‬
‭Community-Based Cohort. Diagn Basel Switz. 2022 Mar 9;12(3):668.‬
‭7.‬ ‭Solomon‬‭JP,‬‭Benayed‬‭R,‬‭Hechtman‬‭JF,‬‭Ladanyi‬‭M.‬‭Identifying‬‭patients‬‭with‬‭NTRK‬
‭fusion‬
‭cancer.‬
‭Ann‬
‭Oncol‬
‭Off‬
‭J‬
‭Eur‬
‭Soc‬
‭Med‬
‭Oncol.‬
‭2019‬
‭Nov‬
‭1;30(Suppl_8):viii16–22.‬
‭8.‬ ‭Huang‬‭EJ,‬‭Reichardt‬‭LF.‬‭Trk‬‭receptors:‬‭roles‬‭in‬‭neuronal‬‭signal‬‭transduction.‬‭Annu‬
‭Rev Biochem. 2003;72:609–42.‬
‭9.‬ ‭Chao‬ ‭MV.‬ ‭Neurotrophins‬ ‭and‬ ‭their‬ ‭receptors:‬ ‭A‬ ‭convergence‬ ‭point‬ ‭for‬ ‭many‬
‭signalling pathways. Nat Rev Neurosci. 2003 Apr;4(4):299–309.‬
‭10.‬‭Bazhenova‬‭L,‬‭Lokker‬‭A,‬‭Snider‬‭J,‬‭Castellanos‬‭E,‬‭Fisher‬‭V,‬‭Fellous‬‭M,‬‭et‬‭al.‬‭TRK‬
‭Fusion‬ ‭Cancer:‬ ‭Patient‬ ‭Characteristics‬ ‭and‬ ‭Survival‬ ‭Analysis‬ ‭in‬ ‭the‬ ‭Real-World‬
‭Setting. Target Oncol. 2021 May;16(3):389–99.‬
‭11.‬ ‭Okamura‬‭R,‬‭Boichard‬‭A,‬‭Kato‬‭S,‬‭Sicklick‬‭JK,‬‭Bazhenova‬‭L,‬‭Kurzrock‬‭R.‬‭Analysis‬‭of‬
‭NTRK‬‭Alterations‬‭in‬‭Pan-Cancer‬‭Adult‬‭and‬‭Pediatric‬‭Malignancies:‬‭Implications‬‭for‬
‭NTRK-Targeted Therapeutics. JCO Precis Oncol. 2018;2018:PO.18.00183.‬
‭12.‬‭Cocco‬ ‭E,‬ ‭Scaltriti‬ ‭M,‬ ‭Drilon‬ ‭A.‬ ‭NTRK‬ ‭fusion-positive‬ ‭cancers‬ ‭and‬ ‭TRK‬ ‭inhibitor‬
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‭therapy. Nat Rev Clin Oncol. 2018 Dec;15(12):731–47.‬
‭13.‬‭Drilon‬ ‭A,‬ ‭Laetsch‬ ‭TW,‬ ‭Kummar‬ ‭S,‬ ‭DuBois‬ ‭SG,‬ ‭Lassen‬ ‭UN,‬ ‭Demetri‬ ‭GD,‬ ‭et‬ ‭al.‬
‭Efficacy‬‭of‬‭Larotrectinib‬‭in‬‭TRK‬‭Fusion–Positive‬‭Cancers‬‭in‬‭Adults‬‭and‬‭Children.‬‭N‬
‭Engl J Med. 2018 Feb 22;378(8):731–9.‬
‭14.‬‭Vaishnavi‬‭A,‬‭Le‬‭AT,‬‭Doebele‬‭RC.‬‭TRKing‬‭down‬‭an‬‭old‬‭oncogene‬‭in‬‭a‬‭new‬‭era‬‭of‬
‭targeted therapy. Cancer Discov. 2015 Jan;5(1):25–34.‬
‭15.‬‭Amatu‬ ‭A,‬ ‭Sartore-Bianchi‬ ‭A,‬ ‭Siena‬ ‭S.‬ ‭NTRK‬ ‭gene‬ ‭fusions‬ ‭as‬ ‭novel‬ ‭targets‬ ‭of‬
‭cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023.‬
‭16.‬‭Harada‬ ‭G,‬ ‭Drilon‬ ‭A.‬ ‭TRK‬ ‭inhibitor‬ ‭activity‬ ‭and‬‭resistance‬‭in‬‭TRK‬‭fusion-positive‬
‭cancers in adults. Cancer Genet. 2022 Jun;264–265:33–9.‬
‭17.‬‭Pekova‬‭B,‬‭Sykorova‬‭V,‬‭Mastnikova‬‭K,‬‭Vaclavikova‬‭E,‬‭Moravcova‬‭J,‬‭Vlcek‬‭P,‬‭et‬‭al.‬
‭NTRK‬ ‭Fusion‬ ‭Genes‬ ‭in‬ ‭Thyroid‬ ‭Carcinomas:‬ ‭Clinicopathological‬ ‭Characteristics‬
‭and Their Impacts on Prognosis. Cancers. 2021 Apr 16;13(8):1932.‬
‭18.‬‭Chu‬ ‭YH,‬ ‭Wirth‬ ‭LJ,‬ ‭Farahani‬ ‭AA,‬ ‭Nosé‬ ‭V,‬ ‭Faquin‬ ‭WC,‬ ‭Dias-Santagata‬ ‭D,‬‭et‬‭al.‬
‭Clinicopathologic‬ ‭features‬ ‭of‬ ‭kinase‬ ‭fusion-related‬ ‭thyroid‬ ‭carcinomas:‬ ‭an‬
‭integrative‬ ‭analysis‬ ‭with‬ ‭molecular‬ ‭characterization.‬ ‭Mod‬ ‭Pathol‬ ‭Off‬ ‭J‬ ‭U‬ ‭S‬ ‭Can‬
‭Acad Pathol Inc. 2020 Dec;33(12):2458–72.‬
‭19.‬‭O’Haire‬‭S,‬‭Franchini‬‭F,‬‭Kang‬‭YJ,‬‭Steinberg‬‭J,‬‭Canfell‬‭K,‬‭Desai‬‭J,‬‭et‬‭al.‬‭Systematic‬
‭review‬‭of‬‭NTRK‬‭1/2/3‬‭fusion‬‭prevalence‬‭pan-cancer‬‭and‬‭across‬‭solid‬‭tumours.‬‭Sci‬
‭Rep. 2023 Mar 13;13(1):4116.‬
‭20.‬‭Cancer‬‭Genome‬‭Atlas‬‭Research‬‭Network.‬‭Integrated‬‭genomic‬‭characterization‬‭of‬
‭papillary thyroid carcinoma. Cell. 2014 Oct 23;159(3):676–90.‬
‭21.‬‭Pierotti‬‭MA,‬‭Bongarzone‬‭I,‬‭Borello‬‭MG,‬‭Greco‬‭A,‬‭Pilotti‬‭S,‬‭Sozzi‬‭G.‬‭Cytogenetics‬
‭and‬‭molecular‬‭genetics‬‭of‬‭carcinomas‬‭arising‬‭from‬‭thyroid‬‭epithelial‬‭follicular‬‭cells.‬
‭Genes Chromosomes Cancer. 1996 May;16(1):1–14.‬
‭22.‬‭Pekova‬‭B,‬‭Sykorova‬‭V,‬‭Dvorakova‬‭S,‬‭Vaclavikova‬‭E,‬‭Moravcova‬‭J,‬‭Katra‬‭R,‬‭et‬‭al.‬
‭RET,‬‭NTRK,‬‭ALK,‬‭BRAF,‬‭and‬‭MET‬‭Fusions‬‭in‬‭a‬‭Large‬‭Cohort‬‭of‬‭Pediatric‬‭Papillary‬
‭Thyroid Carcinomas. Thyroid Off J Am Thyroid Assoc. 2020 Dec;30(12):1771–80.‬
‭23.‬‭Iannantuono‬‭GM,‬‭Riondino‬‭S,‬‭Sganga‬‭S,‬‭Rosenfeld‬‭R,‬‭Guerriero‬‭S,‬‭Carlucci‬‭M,‬‭et‬
‭al.‬‭NTRK‬‭Gene‬‭Fusions‬‭in‬‭Solid‬‭Tumors‬‭and‬‭TRK‬‭Inhibitors:‬‭A‬‭Systematic‬‭Review‬
‭of Case Reports and Case Series. J Pers Med. 2022 Nov 2;12(11):1819.‬
‭24.‬‭Mota-George‬ ‭G,‬ ‭Schneider‬ ‭SM.‬ ‭Larotrectinib:‬ ‭A‬ ‭Targeted‬ ‭Therapy‬ ‭for‬ ‭Solid‬
‭Tumors. Clin J Oncol Nurs. 2021 Apr 1;25(2):181–7.‬
‭25.‬‭Federman‬‭N,‬‭McDermott‬‭R.‬‭Larotrectinib,‬‭a‬‭highly‬‭selective‬‭tropomyosin‬‭receptor‬
‭kinase‬ ‭(TRK)‬ ‭inhibitor‬ ‭for‬ ‭the‬ ‭treatment‬ ‭of‬ ‭TRK‬ ‭fusion‬ ‭cancer.‬ ‭Expert‬ ‭Rev‬ ‭Clin‬
‭Pharmacol. 2019 Oct;12(10):931–9.‬
‭26.‬‭Kummar‬‭S,‬‭Lassen‬‭UN.‬‭TRK‬‭Inhibition:‬‭A‬‭New‬‭Tumor-Agnostic‬‭Treatment‬‭Strategy.‬
‭Target Oncol. 2018 Oct;13(5):545–56.‬
‭27.‬‭Laetsch‬‭TW,‬‭DuBois‬‭SG,‬‭Mascarenhas‬‭L,‬‭Turpin‬‭B,‬‭Federman‬‭N,‬‭Albert‬‭CM,‬‭et‬‭al.‬
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‭Larotrectinib‬‭for‬‭paediatric‬‭solid‬‭tumours‬‭harbouring‬‭NTRK‬‭gene‬‭fusions:‬‭phase‬‭1‬
‭results‬ ‭from‬ ‭a‬ ‭multicentre,‬ ‭open-label,‬ ‭phase‬ ‭1/2‬ ‭study.‬ ‭Lancet‬ ‭Oncol.‬ ‭2018‬
‭May;19(5):705–14.‬
‭28.‬‭Hong‬‭DS,‬‭Bauer‬‭TM,‬‭Lee‬‭JJ,‬‭Dowlati‬‭A,‬‭Brose‬‭MS,‬‭Farago‬‭AF,‬‭et‬‭al.‬‭Larotrectinib‬
‭in‬ ‭adult‬ ‭patients‬ ‭with‬ ‭solid‬ ‭tumours:‬ ‭a‬ ‭multi-centre,‬ ‭open-label,‬ ‭phase‬ ‭I‬
‭dose-escalation‬ ‭study.‬ ‭Ann‬ ‭Oncol‬ ‭Off‬ ‭J‬ ‭Eur‬ ‭Soc‬ ‭Med‬ ‭Oncol.‬ ‭2019‬ ‭Feb‬
‭1;30(2):325–31.‬
‭29.‬‭Lassen‬‭UN,‬‭Albert‬‭CM,‬‭Kummar‬‭S,‬‭Tilburg‬‭CM‬‭van,‬‭Dubois‬‭SG,‬‭Geoerger‬‭B,‬‭et‬‭al.‬
‭Larotrectinib‬‭efficacy‬‭and‬‭safety‬‭in‬‭TRK‬‭fusion‬‭cancer:‬‭An‬‭expanded‬‭clinical‬‭dataset‬
‭showing‬‭consistency‬‭in‬‭an‬‭age‬‭and‬‭tumor‬‭agnostic‬‭approach.‬‭Ann‬‭Oncol.‬‭2018‬‭Oct‬
‭1;29:viii133.‬
‭30.‬‭Hong‬ ‭DS,‬ ‭Kummar‬ ‭S,‬ ‭Farago‬ ‭AF,‬ ‭Lassen‬ ‭UN,‬ ‭Berlin‬ ‭J,‬ ‭Schilder‬ ‭RJ,‬ ‭et‬ ‭al.‬
‭Larotrectinib‬‭efficacy‬‭and‬‭safety‬‭in‬‭adult‬‭TRK‬‭fusion‬‭cancer‬‭patients.‬‭J‬‭Clin‬‭Oncol.‬
‭2019 May 20;37(15_suppl):3122–3122.‬
‭31.‬‭Groussin‬‭L,‬‭Clerc‬‭J,‬‭Huillard‬‭O.‬‭Larotrectinib-Enhanced‬‭Radioactive‬‭Iodine‬‭Uptake‬
‭in Advanced Thyroid Cancer. N Engl J Med. 2020 Oct 22;383(17):1686–7.‬
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‭APPENDIX 1.‬‭LIST OF STAND-ALONE DOCUMENTS‬
‭Number‬
‭Document‬ ‭reference‬
‭number‬
‭Date‬
‭Title‬
‭1‬
‭1.0‬
‭15 OCT 2024‬
‭List of all participating‬
‭sites and physicians‬
‭1‬
‭1.0‬
‭15 OCT 2024‬
‭eCRF Template‬
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