Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma – results of a prospective biomarker study

Abstract

Background Metastasized or unresectable melanoma has been the first malignant tumor to be successfully treated with checkpoint inhibitors. Nevertheless, about 40–50% of the patients do not respond to these treatments and severe side effects are observed in up to 60%. Therefore, there is a high need to identify reliable biomarkers predicting response. Tumor Mutation Burden (TMB) is a debated predictor for response to checkpoint inhibitors and early measurement of ctDNA can help to detect treatment failure to immunotherapy in selected melanoma patients. However, it has not yet been clarified how TMB and ctDNA can be used to estimate response to combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma. Patients and methods In this prospective biomarker study, we included 35 melanoma patients with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy. In all patients, a tumor panel of 710 tumor-associated genes was applied (tumor vs. reference tissue comparison), followed by repetitive liquid biopsies. Cell-free DNA was extracted and at least one driver mutation was monitored. Treatment response was evaluated after about three months of therapy. Results TMB was significantly higher in responders than in nonresponders and TMB > 23.1 Mut/Mb (TMB-high) was associated with a survival benefit compared to TMB ≤ 23.1 Mut/Mb (TMB-low or TMB-intermediate). Furthermore, a > 50% decrease of cell-free DNA concentration or undetectable circulating tumor DNA (ctDNA), measured by tumor-specific variant copies/ml of plasma at first follow-up three weeks after treatment initiation were significantly associated with response to combined immunotherapy and improved overall survival, respectively. It is noticeable that no patient with TMB ≤ 23.1 Mut/Mb and detectable or increasing ctDNA at first follow-up responded to immunotherapy. Conclusion High TMB, > 50% decrease of cell-free DNA concentration, and undetectable ctDNA at first follow-up seem to be associated with response and overall survival under combined immunotherapy. The evaluation of ctDNA and cell-free DNA three weeks after treatment initiation may be suitable for early assessment of efficacy of immunotherapy. Electronic supplementary material The online version of this article (10.1186/s40425-019-0659-0) contains supplementary material, which is available to authorized users.

MDM2, MDM4 and EGFR Amplifications and Hyperprogression in Metastatic Acral and Mucosal Melanoma

“…In our cohort, patients with liver metastases had a significant worse rate of survival. The inferior outcome of patients with liver metastases treated by ICI has already been shown in other collectives, including patients treated with pembrolizumab and combined ipilimumab and nivolumab [42][43][44]. This might be due to a lower density of CD8 + T cells in the liver metastases and also in the distant non-liver metastases of these patients [42].…”

Identification of a gene set correlated with immune status in ovarian cancer by transcriptome-wide data mining

“…Consistently, PPI network analysis also suggested that several key genes related to immune response were located in the center of the module (Figure 4). Nevertheless, these predictions could be biased by previous knowledge [40,41]. The real biology of these genes in regulating the anti-tumor immune response in OCs need more investigations.…”

Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma

“…Moreover, clinical response of metastatic patients treated with PD-1 inhibitors can be monitored by levels of ctDNA, as the level of ctDNA at the initiation can be predictive of treatment response. It has been demonstrated that undetectable ctDNA level at baseline, as well as a decrease > 50% 3 weeks after treatment initiation are associated with better OS and PFS [79,80]. Concerning ctDNA molecular features, mutations in the BRAF, NRAS, KIT and TERT genes are considered melanoma-driving mutations and their detection could help to adapt the strategy for patient monitoring.…”