An investigator-initiated phase II study is the first to show that nivolumab has clinical activity with manageable toxicity in a statistically evaluable number of patients with carcinoma of unknown primary (CUP). Treatment with nivolumab showed an objective response rate (ORR) of 22.2% in previously treated patients as determined by blinded independent central review (BICR), which met the primary endpoint. The results demonstrate a definite clinical benefit of nivolumab in patients with CUP; benefits were more apparent in patients with known biomarkers for immune checkpoint inhibitors (ICIs), such as PD-L1 expression, TMB and MSI status, while some patients responded well regardless of such biomarker status, implying the need for further biomarker evaluation in this disease population. The results are published on 26 November 2021 by Dr Hidetoshi Hayashi of the Department of Medical Oncology, Kindai University Faculty of Medicine in Osaka, Japan and colleagues in the Annals of Oncology

CUP is a heterogeneous clinical entity. Most patients with CUP are categorised into an unfavourable subset and receive empirical chemotherapy. Recent immune profiling of CUP with the use of immunohistochemistry and analysis of gene expression suggested that patients with CUP might receive clinical benefit from ICI treatment because their immune profiles are similar to those of patients with ICI-responsive malignancies. However, limited data are available regarding the clinical efficacy of ICIs for patients with CUP.

Given the recent approval of ICIs for several cancer types, the study team performed a multicentre phase II study to assess the efficacy of nivolumab for patients with CUP (UMIN000030649). Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab 240 mg was administered every 2 weeks for up to 52 cycles. The primary endpoint was ORR in previously treated patients as determined by BICR according to RECIST v1.1.

In total, 56 patients with CUP were enrolled in the study. In 45 previously treated patients, the ORR was 22.2% (95% confidence interval [CI] 11.2–37.1%) with a median progression-free survival of 4.0 months (95% CI 1.9–5.8) and overall survival of 15.9 months (95% CI 8.4–21.5). Similar clinical benefits were also observed in 11 previously untreated patients.

Better clinical efficacy of nivolumab was apparent for tumours with a higher PD-L1 expression level, for those with a higher TMB, and for MSI–high tumours.

No differences in efficacy were found between tumour subgroups based on estimated tissue of origin.

Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed.

The authors concluded that their findings support the potential of nivolumab to become an additional therapeutic option for CUP, a disease with limited treatment options. They also wrote that a recent multicohort phase II study of pembrolizumab in advanced rare cancers included 22 patients with CUP. Among the 13 of these patients evaluable for objective response, the ORR according to immune-related RECIST was 23% (3 of 13 patients with a 95% CI of 5–54%). These results provide additional support for the use of ICIs in CUP treatment.

However, limitations of the current study include the lack of a comparator and the limited sample size. Another limitation is the difficulty associated with standardisation of CUP diagnosis. A lack of standardised applied definitions, classifications, and diagnostic work-up for CUP limits generalisation of the conclusions from a single study to the real world.

This study was funded by Ono Pharmaceutical Co. Ltd.


Tanizaki J, Yonemori K, Akiyoshi K, et al. Open-Label Phase II Study of the Efficacy of Nivolumab for Cancer of Unknown Primary. Annals of Oncology; Published online 26 November 2021. DOI: