LBA100 - CUP-ONE trial: A prospective double-blind validation of molecular classifiers in the diagnosis of cancer of unknown primary and clinical outcomes

Background

Cancer of unknown primary remains a major challenge with poor prognoses, protracted pathways and limitations of site-determination by immunohistochemistry. Gene expression signatures (GEP) show promise as molecular cancer classifiers, but their utility in diagnosis and prognosis warrants study. The CUP-ONE Trial prospectively compared a 92-gene assay GEP versus centralized IHC (C-IHC; 10 markers).

Methods

641 consented patients (36 UK sites; 54 mths) had local pathology & MDT outputs classified as a Reference diagnosis (RD). Tissue was allocated, double-blind, randomized to 3 arms (N): C-IHC (329); CTID (418) CancerTYPE ID, Biotheranostics & Healthscope (418; became unviable). Outputs mandated classification to 14 cancer types. The Intention to diagnose (ITD N=392) set had at least 1 available classifier output. Primary Endpoint was %match of a classifier to RD-site of origin (ratio: total number Match results and total number in ITD dataset with a confirmed or suspected RD (C/S; N=131)). Secondary endpoints included overall classifier accuracy in evaluables with a C/S site of origin, concordance of classifiers & a pre-specified diagnostic score.

Results

Investigators final classifications (N) were CUP (451), ‘Suspected’ (72) and revised 118 to ‘known’ sites. In the ITD set: median 67yrs, 50% male, 92% stage IV. 418 (65%) samples were sufficient for 1 classifier output. Sample inadequacy (C-IHC 7.3%; CTID 13.4%) lead to 306 C-IHC & 362 CTID classifications. In Pair-wise comparisons CTID correctly classified 17.2% [1.9%-29.6%; p=0.0243] more than C-IHC; Agreement of 2 classifiers was 97%. Secondary analysis comparisons showed point estimates favouring CTID but not all statistically significant. Both classified Lung, Colorectal, Breast and Ovary well but CTID did particularly well with Cholangiocarcinoma /gall bladder (60% accuracy) but not in pancreas (9.1%) versus C-HIC (27.2%). Median OS (mths) was poor across all 3 groups CUP: 5.3 (4.6-6.4); Suspected: 9.0 (8.3-11.9); Confirmed: 7.8 (5-13).

Conclusions

CUP-ONE assessed accuracy of CTID Vs C-IHC with comparable outcomes but a higher assignment of Cholangiocarcinoma in CUP. Survival was better in the C/S subset but remains poor overall.

Clinical trial identification

ISRCTN17282276, EudraCT: 2008-000657-35.

Editorial acknowledgement

None

Legal entity responsible for the study

NHS Greater Glasgow & Clyde and University of Glasgow.

Funding

Cancer Research UK (Grant Ref C18607/A7967 and Grant Ref C18607/A7742).

Disclosure

H. Soifer: Financial Interests, Personal, Full or part-time Employment: Biotheranostics. K. Treuner: Financial Interests, Personal, Full or part-time Employment, Employment bu Biotheranostics, a hologic company and stock ownership with company (Hologic): Biotheranostics, A Hologic. Y. Zhang: Financial Interests, Personal, Full or part-time Employment, Employment by Biotheranostics, a Hologic Company and stock ownership with the company (Hologic): Biotheranostics, Hologic. C. Schnabel: Financial Interests, Personal, Full or part-time Employment: Biotheranostics. T.R.J. Evans: Financial Interests, Institutional, Advisory Board, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board, Advisory Boards - GI cancers, melanoma: Roche / Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche / Genentech; Financial Interests, Institutional, Advisory Board, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board, advisory board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board, Advisory board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board, advisory board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol-Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Roche, Basilea, Celgene, GSK, Immunocore, Medivir, Starpharma, Novartis, Sapience Therapeutics, MiNa Therapeutics, CytomX, Lilly, Bicycle Therapeutics, Sierra, BeiGene, Pfizer, Johnson & Johnson, UCB, Avacta, Codiak, Nurix, T3P; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, Sanofi, iOnctura; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca): Institut National du Cancer (France). K.A. Oien: Non-Financial Interests, Institutional, Other, Research collaborations with partners incl. BioTheranostics, Illumina, Leica, OracleBio & BioClavis with funding incl. from Cancer Research UK, Innovate UK & Medical Research Council: University of Glasgow. All other authors have declared no conflicts of interest.