Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
Bibliographical noteFunding Information:
J.H. is the owner of Slide Score. B.V. L.V., M.v.S., I.N., M.d.M., J.v.d.B., K.K.v.d.V., K.S., S.A., S.D., G.V., S.S.B., S.M., W.F.S., C.S., S.M.H., C.D., S.L., G.P., M.C.U.C., Z.K., and H.M.H. have nothing to disclose. T.O.N. has consulted for Nanostring and received compensation and has intellectual property rights/ownership interests from Bioclassifier LLC, not related to the subject material under consideration and received funding support from the Canadian Cancer Society. D.L.R. reports research funding from AstraZeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, and Ultivue; instrument support from Ventana, Akoya/PerkinElmer, and NanoString; advisory board of Amgen, AstraZeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, NanoString, PerkinElmer, Ventana, and Ultivue; consultancy for Biocept; honorarium and travel support from BMS; royalties from Rarecyte and is a founder and equity holder of PixelGear. Sh.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, and Eli Lilly, acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech and acted as consultant (paid to her institution) to Aduro Biotech. J.M.S.B. reports research funding from ThermoFisher, Genoptix, Agendia, NanoString Technologies, Stratifyer GmbH, and Biotheranostics and advisory roles for Insight Genetics, BioNTech AG, Biotheranostics, Pfizer, RNA Diagnostics, and OncoXchange. J.M.S.B. reports the following patents: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility (January 2017; 15/ 325,472; EPO – 15822898.1; Canada – not yet assigned), Systems, Devices and Methods for Constructing and Using a Biomarker, US utility (January 2017; 15/ 328,108; EPO – 15824751.0; Canada – not yet assigned), Histone gene module predicts anthracycline benefit (October 2016; PCT/CA2016/000247), 95‐Gene Signature of Residual Risk Following Endocrine Treatment (December 2016; PCT/ CA2016/000304), Immune Gene Signature Predicts Anthracycline Benefit (December 2016; PCT/CA2016/000305). D.A.D. is on the advisory board and consults for Oncology Analytics Inc., and has consulted for and received travel funds from Novartis for work unrelated to the current manuscript. A.T. reports benefits from ICR’s Inventors Scheme associated with patents for one of PARP inhibitors in BRCA1/2-associated cancers. A.T. also reports Honoraria from Pfizer, Vertex, Prime Oncology, and Artios, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics, and Merck Serono. J.A.H. is the director and owner of Vivactiv Ltd. R.S. reports research funding from Roche, Puma, and Merck; advisory board and consultancy for BMS; travel funding from Roche, Merck, and AstraZeneca, outside the scope of this work. M.K. reports funding to the institute from BMS, Roche and an advisory role for BMS, outside the submitted work.
The Department of Pathology of the Netherlands Cancer Institute is thanked for the support of this study and ensuring the rapid turnaround times. The Breast Cancer Research Foundation and Bristol-Myers-Squibb (BMS) are thanked for financial support. We also thank the BMS-International Immuno-Oncology Network (BMS/II-ON) and the Dutch Cancer Society (NKI2015-7710) for funding the clinical trial costs and this feasibility study (NKI2016-10510). S.L., R.S., and M.K. are supported by a grant from the Breast Cancer Research Foundation (BCRF, NY, US). The following is a list of current members of the International Immuno-Oncology Working Group (TILs Working Group). A member is defined as a person willing to be involved, informed and be part of the activities of the TILs Working Group. The authors alone are responsible for the views expressed in the work of the TIL Working Group and they do not necessarily represent the decisions, policy, or views of their employer.
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