Fig. 1. High TMB is predictive of clinical outcome after combined administration of nivolumab and ipilimumab in patients with recurrent or refractory unfavorable CUP.
a CheCUP trial design. Patients with recurrent or refractory unfavorable CUP provided tumor samples to specify TMB by comprehensive genomic profiling and underwent baseline CT scan of the neck, chest and abdomen. Patients enrolled in the CheCUP trial had at least one measurable lesion according to RECIST v1.1. All patients who met study criteria received nivolumab (240 mg) every two weeks and ipilimumab (1 mg/kg) every six weeks until disease progression. Response to ICI treatment was evaluated by the trial radiologists according to RECIST v1.1 at follow-up visits every second treatment cycle. If patients consented to translational research, liquid biopsy samples (serum, whole blood for PBMNCs and plasma isolation) suitable for ctDNA analyses were collected in parallel with radiological assessment. b Schematic outlining of patient enrollment and specimens involved in this study. The CheCUP trial cohort (blue) was stratified as either TMBhigh or TMBlow based on a TMB cut-off of 12 mutations/Mb following comprehensive genomic profiling of tumor tissue. The translational research cohort (red) provided liquid biopsy samples for on-treatment ctDNA analyses. Kaplan-Meier estimates of (c) PFS and (d) OS, stratified according to patient’s TMB status: TMBhigh (n = 5) and TMBlow (n = 26). Crosses denote censored observations, and for each time interval the number of patients at risk are indicated below the plots. Comparisons were made using a two-sided log-rank test, Cox proportional hazard regression modeling was used to calculate hazard ratio. The horizontal dashed lines mark the median values, the vertical dashed lines the one-year values. 95% CI, 95% confidence interval; HR, hazard ratio. Source data are provided as a Source Data file.