A challenging task – Identifying carcinoma of unknown primary (CUP) patients according to ESMO guidelines: The CUPISCO trial experience

Abstract

Background: The CUPISCO trial (NCT03498521) is an ongoing, phase II, randomised, multicentre study comparing molecularly-guided therapy with standard platinum-based chemotherapy in newly diagnosed poor-risk CUP patients. Methods: Eligible patients have poor-risk adeno- or undifferentiated CUP as defined by ESMO 2015 guidelines and tissue for molecular sequencing. Local sites initiate the screening process with potentially eligible patients. Patients then undergo central Eligibility Review (ER), a cooperative effort between a central pathology laboratory, external referent oncologists and each site's investigator and pathology laboratory to confirm the diagnosis. Patients with favourable prognostic subsets or with a strong suspicion of an existing primary site of origin based on immunohistochemistry (IHC) signature and clinical picture are excluded. Results: As of 19 March 2019, 157 patients had been screened, of whom 91 (58%) failed screening. Three patients were successfully re-screened. Of the 88 patients who permanently failed screening, 23 were due to technical reasons (e.g. insufficient quality/quantity of tissue for sequencing), 20 for failure to meet inclusion/exclusion criteria not directly related to CUP diagnosis, and 14 for other reasons (e.g. declining health status). A set of 31 patients were not enrolled because the CUP diagnosis could not be confirmed at the IHC level, 19 of those after ER review. Central IHC review results included pathological signatures more typical of specific primary tumours (e.g. prostate cancer or melanoma), or marker combinations typically positive in favourable CUP subsets or rare tumour entities. Conclusions: Experience with the CUPISCO study has highlighted challenges with standardised screening and diagnostic processes in an international clinical trial and the difficulties inherent in accurate diagnosis of poor-risk CUP. Confirming a CUP diagnosis for a clinical trial with multiple review checkpoints can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding and to improve diagnostic algorithms for CUP. Clinical trial identification: NCT03498521. Editorial acknowledgement: Medical writing assistance was provided by Ian Leighton, PhD, Nspm Ltd, Meggen, Switzerland, and supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Legal entity responsible for the study: F. Hoffmann-La Roche Ltd. Funding: F. Hoffmann-La Roche Ltd. Disclosure: C. Pauli: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. T. Bochtler: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. L. Mileshkin: Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Beigene. G. Baciarello: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas-Pharma; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Ipsen. F. Losa: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Servier. J.S. Ross: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine Inc. S. Yalcin: Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Amgen; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Merck Serono. A. Beringer: Full / Part-time employment: F. Hoffmann-La Roche Ltd. S. Foser: Full / Part-time employment: F. Hoffmann-La Roche Ltd. J. Scarato: Full / Part-time employment: F. Hoffmann-La Roche Ltd. M. Mueller-Ohldach: Full / Part-time employment: Hoffmann-La Roche Ltd. H. Moch: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. A. Krämer: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.