CUPISCO is the first randomised study of molecularly-guided therapy for newly diagnosed unfavourable subset of patients with cancer of unknown primary (CUP). The results from this phase II, prospective, randomised, open-label, active-controlled, multicentre study show that, compared with standard platinum-based chemotherapy, molecularly-guided therapy conferred a significant and clinically meaningful improvement in progression-free survival (PFS) to patients with previously untreated, unfavourable, non-squamous CUP who reached disease control during an induction period with three platinum-based chemotherapy cycles.
Effects were generally consistent across subgroups, with a greater benefit observed in patients who had an actual actionable molecular target for molecularly-guided therapy, and in patients treated with molecularly-guided therapy who reached a complete response with chemotherapy during the induction period. The findings from the primary analysis of the study are reported by Prof. Alwin Krämer of the Clinical Cooperation Unit Molecular Hematology–Oncology, German Cancer Research Center (DKFZ) in Heidelberg, Germany, and colleagues on 31 July 2024 in The Lancet.
CUP accounts for 2-5% of all malignancies, with 80-85% being of an unfavourable subset. There has been little progress in improving outcomes for patients with CUP. The unfavourable subset has a poor prognosis, with a median overall survival (OS) of less than 1 year when treated with the current standard-of-care, platinum-based chemotherapy.
Studies have shown that gene expression-profiling-based tissue-of-origin identification with subsequent primary site-directed therapy did not improve PFS or OS compared with platinum-based chemotherapy in patients with newly diagnosed CUP. The authors wrote in the background that unfavourable CUP might therefore be viewed as a model disease for the development of tumour-agnostic treatment strategies. Up to one-third of patients with CUP harbour targetable genomic alterations, with a broad range of prevalence.
The CUPISCO study was designed to test the concept of using comprehensive genomic profiling at diagnosis to inform a molecularly-guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable CUP. The aim was to compare the efficacy and safety of molecularly-guided therapy versus standard platinum-based chemotherapy, to establish whether the inclusion of comprehensive genomic profiling in the initial diagnostic work-up leads to improved outcomes over the current standard-of-care.
The study was done at 159 sites in 34 countries. Patients with central eligibility review-confirmed CUP (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by comprehensive genomic profiling, 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 molecularly-guided therapy versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed PFS in the intention-to-treat (ITT) population. Follow-up is ongoing.
From 10 July 2018 to 9 December 2022, a total of 636 of 1505 screened patients (42%) 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 molecularly-guided therapy group and 110 (25%) to the chemotherapy group. Median PFS in the ITT population was 6.1 months (95% confidence interval [CI] 4.7–6.5) in the molecularly-guided therapy 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).
Although OS data were immature at the time of writing, preliminary analyses suggest that molecularly-guided treatment might also result in an OS benefit. The best confirmed overall response rate was in favour of molecularly-guided treatment versus chemotherapy. The study team did not find evidence of an effect of molecularly-guided treatment on duration of response or disease control rate.
Due to differing exposure times between cohorts, adverse events were adjusted for patient-years at risk. Related adverse event rates per 100-patient-years at risk were generally similar or lower with molecularly-guided therapy versus chemotherapy. No evidence was seen of a different time to deterioration of quality-of-life in patients in the molecularly-guided therapy group compared with those in the chemotherapy group, as measured by the patient-reported outcomes scores.
The authors wrote that future analyses will aim to identify, by DNA methylation profiling, tissue-of-origin from CUPISCO participants from whom leftover tumour biopsy material is available, as part of the trial’s translational analysis plan, and correlate tissue-of-origin with mutational profiles and response to the respective treatment. As research into CUP diagnosis, molecular characterisation, and therapy has gained momentum, additional studies are necessary to establish the best therapy for each patient.
In an invited comment, Drs. Elie Rassy of the Gustave Roussy and Université Paris-Saclay in Villejuif, France, F Anthony Greco of the Sarah Cannon Cancer Center, Tennessee Oncology in Nashville, TN, USA and Nicholas Pavlidis of the University of Ioannina in Ioannina, Greece wrote that notably, the benefit of the molecularly-guided therapy was affected by the response to the induction chemotherapy, with patients achieving complete response having the largest benefit (23.2 months versus 6.5 months), whereas the differences in the other patients were less pronounced. However, this observation is limited by the small sample size but warrants further evaluation. More importantly, the forthcoming analysis of the group of patients with progressive disease holds significant promise for the potential role of precision medicine in CUP.
The CUPISCO study had additional pragmatic implications in the management of CUP. It required central review for diagnostic confirmation to ensure the inclusion of a homogeneous population and encountered 39% ineligibility on screening. This finding, which has led to a revision of the ESMO guidelines, advocates for comprehensive algorithm-based clinical assessments in routine clinical practice.
The investigators opted for the use of liquid biopsy alongside tissue samples, which allows a more practical approach in clinical practice, as does the incorporation of novel therapies that are now widely available. The CUPISCO study confirms the beneficial role of a biomarker-driven approach in selected patients with CUP following standard chemotherapy and marks a significant stride towards better outcomes. Therapies based on the molecular evaluation of tissue or blood biopsies represent a practice-changing step forward in the management of patients with CUP, although additional clinical research is necessary and agnostic approvals are warranted to move further forward according to the commentators.
The study was funded by F Hoffmann-La Roche. The authors acknowledged the Roche–Genentech team, the Foundation Medicine, the USZ laboratory, and Cytel. Incyte and Servier provided medical support and supplied pemigatinib and ivosidenib. The research was supported by Deutsche Krebshilfe Priority Program Translational Oncology grant, the UK National Institute for Health and Care Research Manchester Clinical Research Facility and the Manchester Experimental Cancer Medicine Centre award.
References
- Krämer A, Bochtler T, Pauli C, et al. Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study. The Lancet; Published online 31 July 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00814-6
- Rassy E, Greco FA, Pavlidis N. Molecular guided therapies: a practice-changing step forward in cancer of unknown primary management. The Lancet; Published online 31 July 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00975-9