Hatswell, AJ

Sullivan, WG

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UCL Discovery

CORRESPONDENCELetter re: ‘Intrapatient comparisons of efficacy ina single-arm trial of entrectinib in tumour-agnostic indications’We read with interest the article by Krebs et al.1 To conveythe clinical value of entrectinib across its tumour-agnosticlicensed indication, the authors report and interpretwithin-patient and within-cohort comparisons with priorline of therapy using their pivotal phase II trial (clinicaltrials.gov identifier: NCT02568267) in lieu of randomised,controlled trial data.We commend the extent of data reported in an open-access forum and see strength in this application in thelevel of prior therapy data available, although quality issueswith prior-line data collection in NCT02568267 is a limita-tion, as recognised by the authors. However, we would liketo draw attention to further issues which we feel are vitalfor interpretation of the results, but only partly captured inthe authors’ Discussion.Although useful in the absence of more robust compar-ator data, any comparison with previous line of therapy isintractably confounded by sample selection, an essentialconsideration for interpretation. As we covered in ourgeneral exploration of comparisons with previous line oftreatment,2 those patients who have prior line of therapydata available upon entry into NCT02568267 were bothprognostically favourable enough to survive with sufficienthealth to meet clinical trial entry requirements, andsimultaneously prognostically unfavourable enough to becandidates for as-yet-unlicensed treatment. When consid-ered as a proxy for current care, prior-line datasets aregenerally limited in that they exclude both the most andleast favourable of the target group, with bidirectional im-plications for bias that cannot be adjusted for and must beassessed carefully case by case.Further, there is issue in the authors’ assertion that ‘byusing patients as their own control, intrapatient analysesalso eliminate between-patient variability’. A patient’sprognostic profile is definitively different across treatmentlinesdage, number of prior therapies, last therapy receivedand response to last therapy are a few typical prognosticfactors that definitively vary with treatment line. In tumour-agnostic medicine, the implications of the biases highlightedhere are complicated further, as they are influenced by thenatural history of each disease in question.We briefly note two additional issues with the approachand interpretation that we feel are important for inference,without the space to explicitly critique each issue here: thecomparison of current progression-free survival with priorVolume 6 - Issue 6 - 2021time to discontinuation (TTD), when current TTD versusprior TTD has clear internal consistency advantages; theauthors’ interpretation of the likely bias in their censoringpoints, and between their entrectinib intrapatient compar-ison and the elsewhere published intrapatient comparisonfor larotrectinib.3Again, we are grateful for the contribution of Krebs et al.;however, in lieu of a ‘like for like’ comparison of endpoints,and a more balanced and comprehensive assessment ofpotential biases, we do not share the authors’ convictionthat results presented ‘show the value and feasibility ofusing an intrapatient analysis to assess comparative effec-tiveness of tumour-agnostic MTAs in a heterogeneous pa-tient population.’ To achieve this we feel further analysesand information are required.W. G. Sullivan1* & A. J. Hatswell2,31129 Machon Bank Road, Sheffield;2Delta Hat Limited,1 Lamorna Court 43 Wollaton Road Beeston, Nottingham;3Department of Statistical Science,University College London Standard Institution, London, UK(*E-mail: willgsullivan@outlook.com).Available online 28 October 2021© 2021 The Author(s). Published by Elsevier Ltd on behalfof European Society for Medical Oncology. This is an openaccess article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.esmoop.2021.100282DOI of original article: https://doi.org/10.1016/j.esmoop.2021.100072FUNDINGNone declared.DISCLOSUREThe authors have declared no conflicts of interest.REFERENCES1. Krebs MG, Blay JY, Le Tourneau C, et al. Intrapatient comparisons ofefficacy in a single-arm trial of entrectinib in tumour-agnostic in-dications. ESMO Open. 2021;6(2):100072.2. Hatswell AJ, Sullivan WG. Creating historical controls using data from aprevious line of treatment e two non-standard approaches. StatMethods Med Res. 2020;29:1563-1572.3. Italiano A, Nanda S, Briggs A, et al. Larotrectinib versus prior therapies intropomyosin receptor kinase fusion cancer: an intra-patient compara-tive analysis. Cancers. 2020;12(11):3246.1

Letter re: 'Intrapatient comparisons of efficacy in a single-arm trial of entrectinib in tumour-agnostic indications'

http://dx.doi.org/10.1016/j.esmoop.2021.100282

Letter re: 'Intrapatient comparisons of efficacy in a single-arm trial of entrectinib in tumour-agnostic indications'

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