Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study

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.