Discussion
toxicity, toxicities, tumor, multiple cancer
NON-SMALL CELL LUNG CANCER, TUMOR, MULTIPLE CANCER, DISEASE, RECRUITMENT, REMISSION, ANEUPLOIDY
This investigator-initiated phase II trial assessed combined immunotherapy with nivolumab and ipilimumab in patients with unfavorable CUP relapsed after or refractory to platinum-based chemotherapy. Combined immunotherapy led to an ORR of 16.2% in the total study population of 31 patients, with 60% of TMBThe ORR of 16.2% found in our study is comparable but not superior to previously published data on nivolumab (ORR 22.2%) and pembrolizumab (ORR 20%) monotherapy in two other comparatively small cohorts of relapsed/refractory CUP patientsThe predictive value of TMB in the context of immunotherapy has been previously demonstrated in several entitiesIn our total cohort of 31 platinum-pretreated patients, median PFS and OS were 2.53 and 3.8 months, respectively, which is lower than previously published data reporting a median PFS of 4–4.1 and OS of 11.3–15.9 months after second-line immunotherapyIn addition to TMB, retrospective data suggest that high tumor aneuploidy levels are associated with poor outcome following ICI treatment across multiple cancer types with low but not high TMBWhile PD-L1 expression was associated with a trend towards prolonged OS as well, the TMB effect persisted after adjustment for PD-L1, which suggests that its predictive value might be independent of PD-L1 expression. Similar constellations have been previously described in several other entities including non-small cell lung cancer, where dual checkpoint inhibition with nivolumab and ipilimumab significantly prolonged PFS and OS particularly in patients with high TMB regardless of PD-L1 expressionThe immune cell composition of the tumor microenvironment is known to impact on response to ICI therapyTwo randomized clinical trials suggest that gene expression profiling-based tissue-of-origin prediction with subsequent primary site-directed treatment is not superior to platinum-based chemotherapy in the first-line treatment of patients with unfavorable CUPAdditional important questions remain regarding the role of combination strategies and optimal sequence of therapies. With regard to combination treatment, dual immune checkpoint blockade with nivolumab and ipilimumab failed to improve efficacy as compared to nivolumab or pembrolizumab monotherapyThe limited sample size constitutes a main limitation of the CheCUP trial. Due to slower than expected recruitment, the trial was terminated early by the sponsor, thereby highlighting once more and similar to earlier attempts the accrual challenge with CUP trials even in a multicenter setting. As a result, the trial was underpowered and all analyses were exploratory. Nevertheless, the study does offer meaningful insights into the value of immunotherapy in CUP as, despite these limitations, both hazard ratio and PFS approximated the initially assumed values.For early response monitoring, we used combined quantitative ultra-deep targeted NGS of patient-specific hotspot tumor mutations and tumor-specific CNA profiling by low-coverage sWGS of ccfDNA in comparison to radiologic response evaluation. The targeted NGS part of our approach is able to detect very low amounts of ctDNA but relies on a specifically designed fingerprint panel that only covers patient-specific hotspot mutations previously identified by mutational profiling of tumor tissue. As a limitation, this technique does neither capture metastatic heterogeneity nor newly acquired mutations during immunotherapy.Combined targeted NGS/sWGS allowed for longitudinal ctDNA monitoring in 90% of CUP patients. ctDNA dynamics paralleled radiological response assessment, indicating that ctDNA evaluation might be a valuable surrogate of treatment response in CUP. As the timing of ctDNA sample collection was predefined to occur in parallel to radiological response assessment in three-monthly intervals, trial data are not suited to determine the optimum timepoints of ctDNA analysis for prediction of immunotherapy response. Nevertheless, on-treatment ctDNA kinetics three months after immunotherapy initiation identified patients achieving long-term remission when radiologic findings still indicated stable disease. Since radiologic stable disease can stretch from minimal response to beginning progression, ctDNA monitoring might enable early-on discrimination between patients who will eventually derive treatment benefit and those with progressive disease. Given the toxicity profile of immunotherapy, the development of biomarkers predicting treatment response is essential not least to spare toxicities.In conclusion, combined ipilimumab/nivolumab treatment led to high response rates in patients with unfavorable CUP relapsed or refractory to platinum-based chemotherapy and a TMB of at least 12 mutations/Mb, irrespective of PD-L1 expression levels and number of previous chemotherapy lines. Early reduction of ctDNA levels from baseline predicted benefit from immunotherapy better than radiologic tumor burden assessment. These results underline the role of immunotherapy as an effective second-line treatment in CUP, and TMB as well as ctDNA kinetics as independent predictors of benefit from ICI treatment.