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Background: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis., Methods: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing., Findings: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy., Interpretation: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests All authors received research funding in the form of third-party medical writing assistance from F Hoffmann-La Roche. AK reports research funding for a clinical trial in CUP from Bristol Myers Squibb; research funding for a clinical trial in CUP from Molecular Health; and consulting fees, support for attending meetings or travel, or both, participation in a data safety monitoring board or advisory board from F Hoffmann-La Roche. TB was study oncologist for the CUPISCO trial for F Hoffman-La Roche and received remuneration for this work for the benefit of employer, and support for attending meetings or travel, or both. CP reports travel, accommodation, or expenses and additional costs linked to the study (paid to institution), and investigator fees from F Hoffmann-La Roche. K-KS reports grants or contracts (paid to institution for running trials) from Merck Sharp & Dohme, Roche, AstraZeneca, and Merck; consulting fees (personal) from Nouscom; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (personal) from Merck Sharp & Dohme, Bristol Myers Squibb, Merck, Servier, Seagen, and Nouscom; support for attending meetings or travel (personal), or both, from Merck Sharp & Dohme, Bristol Myers Squibb, Roche, and Merck; and an advisory board (personal) for Mirati Therapeutics. NCo reports honoraria, advisory board membership, support for attending meetings or travel, or both, from F Hoffman-La Roche; a patent pending, application number GB2317261.2; an advisory or leadership role for CUP Foundation (Jo's Friends; unpaid); and research support to team from AstraZeneca, Orion, F Hoffmann-La Roche, Taiho, GSK, Novartis, Starpharma, Bayer, Eisai, UCB, Redx Pharmaceuticals, Stemline Therapeutics, Boehringer Ingelheim, Merck, AstraZeneca, Cancer Research UK, Orion, and LOXO-Oncology. JJdM reports support for attending meetings or travel, or both, from Bristol Myers Squibb. RAP-C reports medical writing and processing fees from Astellas, Ipsen, Roche, BeiGene, and Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eisai, Bristol Myers Squibb, Astellas, Roche, Amgen, and Eli Lilly; payment for expert testimony from AstraZeneca, Eli Lilly, and Bristol Myers Squibb; support for attending meetings or travel, or both, from Roche, Lilly, Astellas, and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board for AstraZeneca, Roche, and Ipsen. FL reports grants or contracts from Lilly and Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, Merck, Sanofi, and Roche; and support for attending meetings or travel, or both from Lilly, Merck, and Merck Sharp & Dohme. DGJR reports consulting fees from Merck, Pfizer, and Astellas; payment for honoraria, lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Merck Sharp & Dohme; and participation on a data safety monitoring board or advisory board for Janssen and AstraZeneca. JT reports consulting fees from Servier and Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Merck Sharp & Dohme, Servier, Bayer, and Ipsen; and reports support for attending meetings or travel, or both (American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2022), from Zentiva and Roche. CA reports research grants from Roche, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Nektar, Johnson & Johnson, Lilly, Amgen, Incyte, and Bayer; advisory boards for Novartis, Merck, AstraZeneca, Johnson & Johnson, Lilly, Teva, Astellas, and Bristol Myers Squibb; and peakers bureaus for Bristol Myers Squibb, Johnson & Johnson, Lilly, Teva, Amgen, and Bayer. MÖ reports an advisory board, honoraria, and travel support from Janssen; additional costs linked to the study (paid to institution), investigator fees, and honoraria from F Hoffmann-La Roche; an advisory board and honoraria from Sanofi; an advisory board and honoraria for Astellas; honoraria from Novartis; travel support from Bristol Myers Squibb; and travel support and speaker support from AstraZeneca. MS reports honoraria for lectures F Hoffmann-La Roche. FB reports additional costs linked to the study and investigator fees from F Hoffmann-La Roche; an advisory board for AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb; speakers bureaus for AstraZeneca and Bristol Myers Squibb; and travel support or accommodation from Takeda, Merck Sharp & Dohme. SYK reports research funding (paid to institution; principal investigator since 2019) from F Hoffmann-La Roche; honorarium for lecture (May, 2023) from LG Chem; honorarium for lecture (August, 2023) from Merck Sharp & Dohme Korea; an advisory board (December, 2021) for Ono Korea; and an advisory board (December, 2022) for Guardant Health. YN reports research funding (paid to institution) from AbbVie, Ono, Daiichi Sankyo, Taiho, Pfizer, Boehringer Ingelheim, Eli Lilly, Eisai, AstraZeneca, Chugai, and Bayer; payment for honoraria, lectures, presentations, speakers’ bureaus, manuscript writing, or educational events (personal) from AstraZeneca, Eisai, Ono, Gardant, Takeda, Eli Lilly, Novartis, Pfizer, Chugai, PDR pharma, Nihon Kayaku, Taiho, Bristol Myers Squibb, Bayer, Daiichi Sankyo, and Merck Sharp & Dohme. AI reports additional costs linked to the study, investigator fees, advisory role, honoraria, and research funding from F Hoffmann-La Roche; an advisory role and honoraria from Daiichi Sankyo; an advisory role for Immune Design; an advisory role and honoraria from Epizyme; an advisory role and honoraria from Bayer and Lilly; patents, royalties, or intellectual property from Bristol Myers Squibb; honoraria from Novartis and Ipsen; and research funding from AstraZeneca–MedImmune, PharmaMar, Merck Sharp & Dohme Oncology, and Merck Serono. NCh reports being an employee and holding stocks or shares at F Hoffmann-La Roche. GD-P reports being an employee and holding stocks or shares at F Hoffmann-La Roche. CM reports being an employee of F Hoffmann-La Roche. JS reports being an employee and holding stocks or shares at F Hoffmann-La Roche. MT reports being an employee and holding stocks or shares at F Hoffmann-La Roche, and patents planned, issued, or pending (antibodies against human CSF-1R and uses thereof; modulators for HER2 signalling in HER2 expressing patients with gastric cancer) from F Hoffmann-La Roche. JSR reports being an employee of Foundation Medicine; and holding stocks or shares at Roche Holdings. HM reports research funding (paid to institution), consulting fees, and participation on a data safety monitoring board or advisory board for F Hoffmann-La Roche; and an advisory role and honoraria for lectures from Amgen, Astellas, Bayer, AstraZeneca, Merck, Stemline Therapeutics. LM reports additional costs linked to the CUPISCO trial (paid to institution), support for the presentation of the CUPISCO trial results and associated publication; and travel and accommodation expenses to attend the 2023 European Society for Medical Oncology meeting and present the CUPISCO trial results from F Hoffmann-La Roche., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer of unknown primary (CUP) is defined as a primary metastatic malignancy, in which the primary tumor remains elusive in spite of a comprehensive diagnostic workup. The frequency and prognostic value of circulating tumor cells (CTCs), which are considered to be the source of metastasis, has not yet been systematically evaluated in CUP., Methods: A total of 110 patients with a confirmed diagnosis of CUP according to the European Society for Medical Oncology (ESMO) guidelines, who presented to our clinic between July 2021 and May 2023, provided blood samples for CTC quantification using CellSearch methodology. CTC counts were correlated with demographic, clinical, and molecular data generated by comprehensive genomic profiling of tumor tissue., Results: CTCs were detected in 26% of all patients at initial presentation to our department. The highest CTC frequency was observed among patients with unfavorable CUP (35.5%), while patients with single-site/oligometastatic CUP harbored the lowest CTC frequency (11.4%). No statistically significant association between CTC positivity and the number of affected organs (P = 0.478) or disease burden (P = 0.120) was found. High CTC levels (≥5 CTCs/7.5 mL; 12/95 analyzed patients) predicted for adverse overall survival compared to negative or low CTC counts (6-months overall survival rate 90% vs 32%, log-rank P < 0.001; HR 5.43; 95% CI 2.23-13.2). CTC dynamics were also prognostic for overall survival by landmark analysis (log-rank P < 0.001, HR 10.2, 95% CI 1.95-52.9)., Conclusions: CTC frequency is a strong, independent predictor of survival in patients with CUP. CTC quantification provides a useful prognostic tool in the management of these patients., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMB high vs. TMB low stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMB low and TMB high , respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response., (© 2023. Springer Nature Limited.)

Introduction: About 20% of all cancer of unknown primary (CUP) cases can be classified into favorable subgroups, which are defined by either obvious analogies to certain cancers with a known primary or amenability to local ablative treatment. In the updated European Society for Medical Oncology (ESMO) guidelines for diagnosis and treatment of CUP, the definition of favorable subgroups has been revised according to the latest scientific findings. In particular, the definition and treatment of oligometastatic CUP have undergone considerable changes in recent years. Thus, we delineate the current diagnostic and therapeutic standards for the two favorable CUP subtypes single-site/oligometastatic and head/neck CUP., Methods: The classification, diagnostic workup, and treatment of single-site and oligometastatic CUP are summarized based on the current ESMO and American Society of Clinical Oncology (ASCO) guidelines together with a literature review., Conclusions: Single-site and oligometastatic CUP is defined by the presence of a maximum of five metastases that are amenable to local ablative treatment. Median overall survival is favorable and exceeds 4 years after local ablation of all detectable metastases. Lymph node metastases in the head and neck region represent a frequent scenario of single-site CUP. They usually originate from human papillomavirus (HPV)-associated squamous cell carcinoma in the oropharynx. Diagnostic workup comprises computed tomography (CT), magnetic resonance imaging (MRI) if necessary, and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), followed by panendoscopy and biopsies of suspicious mucosal sites. Neck dissection, potentially followed by adjuvant radiotherapy, and definitive radiotherapy represent equally effective oncological treatment options with respect to a favorable prognosis., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)