Abstract
Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. 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/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
Highlights
Cancer of unknown primary (CUP) is defined as histologically confirmed metastatic cancer for which identification of the primary site is not possible after an appropriate diagnostic approach.[1]
Key exclusion criteria included concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease; a history of immune checkpoint inhibitors (ICIs) [anti-PD-1, anti-programmed death-ligand 1, or anti-cytotoxic T-lymphocyte antigen 4] therapy or treatment with any T cell-stimulatory antibody; and CUP of the favorable subset, including extragonadal germ cell syndrome, neuroendocrine carcinoma, adenocarcinoma restricted to axillary lymph nodes, peritoneal carcinomatosis, or squamous carcinoma limited to cervical, supraclavicular, or inguinal lymph nodes
We evaluated the clinical efficacy of nivolumab according to tumor characteristics, including histology, gene alterations and predicted tissue of origin based on nextgeneration sequencing (NGS) results,[14] metastatic pattern, as well as known biomarkers for ICIs such as PD-L1 expression, Microsatellite instability (MSI), and tumor mutation burden (TMB) (Figure 2 and Supplementary Figure S8, available at https://doi.org/10. 1016/j.annonc.2021.11.009)
Summary
Cancer of unknown primary (CUP) is defined as histologically confirmed metastatic cancer for which identification of the primary site is not possible after an appropriate diagnostic approach.[1]. Cancer immunotherapy including the administration of immune checkpoint inhibitors (ICIs) has markedly changed the treatment paradigm for many types of cancer, including malignant melanoma, non-small-cell lung cancer, gastroesophageal cancer, genitourinary cancer, and head and neck cancer.[9] Our recent immune profiling of CUP with the use of immunohistochemistry (IHC) and analysis of gene expression suggested that individuals with CUP might receive clinical benefit from ICI treatment because their immune. Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors.
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