Background: The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments.
Methods: An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients' representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs.
Results: The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations.
Conclusions: ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.
Competing Interests: Disclosure HB reports non-remunerated activities as a principal investigator (PI) within grant for clinical research from the National Cancer Institute, and is a non-remunerated member of Board of Directors in the Alliance for Clinical Trials in Oncology; LC reports receipt of institutional research funding from AbbVie, Immunomedics, NanoString Technologies, Novartis, Seattle Genetics, Syndax, Veracyte, advisory role in Aptitude Health, AstraZeneca/Daiichi Sankyo, Exact Sciences, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, Novartis, and Sanofi; SD reports receipt of honoraria for participation in Advisory Board from AstraZeneca, Cellectis, Isis/Servier, Novartis, Orion, Pierre Fabre, Rappta, Sanofi, receipt of honoraria as invited speaker from AstraZeneca, Exact Sciences, Eli Lilly, Merck Sharp & Dohme (MSD), Pfizer, Seagen, institutional financial interest for research as a Steering Committee Member from AstraZeneca, Bristol Myers Squibb (BMS), Pfizer, Puma, Roche/Genentech, Sanofi, institutional research funding from GE, institutional financial interest for clinical research funding as a coordinating PI from Taiho, institutional financial interest as a local PI from Orion, and a non-remunerated member of Board of Directors of the Société Française de Sénologie et Pathologie Mammaire; NH reports receipt of honoraria for participation in Advisory Board from Aptitude Health, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz-Hexal, Seattle Genetics, receipt of honoraria as invited speaker from Art Tempi, AstraZeneca, Daiichi Sankyo, Eli Lilly, Medscape, MSD, Novartis, Onkowissen, Pierre Fabre, Roche, Seattle Genetics, receipt of honoraria from West German Study Group (WSG) (husband), ownership interest in West German Study Group, institutional research funding from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Odonate, Palleos, Pierre Fabre, Roche, Seattle Genetics, TRIO, WSG, a member of German AGO Breast Guideline Committee, a member of European School of Oncology/College of the European School of Oncology Breast Cancer Educational Programmes, Editor-in-Chief of Breast Care journal; DH reports receipt of honoraria for consulting in Advisory Board from Agendia, BioVeca, Cellworks, Cepheid, Epic Sciences, Freenome, L-Nutra, OncoCyte, Turnstone Biologics, owns stock shares in Inbiomotion SL, receipt of royalties from an institutional patent on which he is named investigator from Menarini Silicon Biosystems, institutional sponsored laboratory research as a coordinating PI from AstraZeneca, Pfizer, institutional sponsored laboratory and clinical research as a coordinating PI from Menarini Silicon Biosystems, non-remunerated activities as a past president and past member of Board of Directors of ASCO, non-remunerated Chair of Translational Research Advisory Committee in EORTC, and a non-remunerated member of the ESMO Working Group; KK reports receipt of honoraria for participation in Advisory Board from 4D Pharma, AstraZeneca, Cyclacel, Daiichi Sankyo, Eisai, Eli Lilly, Immunomedics, Merck, Novartis, OncoSec, Pfizer, Puma, Seattle Genetics, holding stocks/shares from Grail, spouse employment in Grail, no financial interest to institution as local PI from Acetylon, Amgen, Calithera, CytomX Therapeutics, Eli Lilly, Genentech, Immunomedics, Incyte, Novartis, Pfizer, Seattle Genetics, Zentalis, participation in Steering Committee of Ambrx, AstraZeneca, Genentech, Immunomedics, and support for attending meetings and/or travel from AstraZeneca, Eli Lilly, and Pfizer; LP reports receipt of honoraria for participation in Advisory Board and trial Steering Committee from AstraZeneca, Merck, honoraria for participation in Advisory Board from Novartis, Pfizer, Roche Genentech, no financial interest for clinical trial support to institution as local PI from AstraZeneca, Seagen, no financial interest for clinical trial support to institution as trial chair from Merck, Pfizer, research grant to institution from BMS, and no financial interest for advisory role in Breast Cancer Research Foundation, as a member of the scientific Advisory Board of Pfizer, for product samples, material transfer agreement; MR reports receipt of honoraria for participation in Advisory Board from BMS, Tolmar Pharmaceuticals, honoraria as invited speaker from WebMD, institutional financial interest for investigator-initiated clinical trials supported or drug supply from AstraZeneca, Roche, research grant to institution from Bayer, BMS, institutional financial interest for investigator-initiated clinical trials supported by Ipsen, Novartis, Pfizer, TerSera, and non-financial interest for advisory role from BMS; IS reports receipt of honoraria as invited speaker from Myriad Genetics and Nanostring Technologies; TS reports receipt of honoraria for participation in Advisory Board as a member of Patient Advisory Board from Pfizer and Roche; JS reports receipt of honoraria for participation in Advisory Board from Arvinas, AstraZeneca, Certara, Eisai, GlaxoSmithKline, honoraria as a Data and Safety Monitoring Board member from BMS, Novartis, Roche, and no financial interest to institution as coordinating PI from Merck, Olema, Radius Pharmaceuticals; GC reports receipt of honoraria for participation in Advisory Board from AstraZeneca, BMS, Daiichi Sankyo, Ellipsis, Exact Sciences, Lilly, Merck, Pfizer, Roche, Veracyte, receipt of honoraria as invited speaker from AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, receipt of honoraria for writing engagement from Pfizer, institutional research grant for investigator-initiated clinical trial from Merck, institutional funding for conduct of phase I studies from Astellas, AstraZeneca, Blueprint Medicine, BMS, Daiichi Sankyo, Kymab, Novartis, Philogen, Roche, Sanofi, non-remunerated activities as an officer of the Italian National Health Council, non-remunerated advisory role as a member of the Scientific Council of Europa Donna, non-remunerated advisory role in Fondazione Beretta, and non-remunerated member of Board of Directors of the Lega Italiana Lotta ai Tumori; FA reports receipt of institutional research grants from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche, and being a founder of Pegacsy. DT has been a past consultant for World Health Organization, noncommunicable diseases, cancer management team. All other authors have declared no conflicts of interest.
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