Abstract
BackgroundMetastasized 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 methodsIn 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.ResultsTMB 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.ConclusionHigh 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.
Highlights
Checkpoint inhibitors such as pembrolizumab, nivolumab, or combination of ipilimumab and nivolumab have significantly improved prognosis of patients with metastatic melanoma
High Tumor Mutation Burden (TMB), > 50% decrease of cell-free DNA concentration, and undetectable circulating tumor DNA (ctDNA) at first follow-up seem to be associated with response and overall survival under combined immunotherapy
About half of the patients were female (46%) and the largest part of the patients (63%) started ipilimumab and nivolumab as their first line systemic treatment. 10 patients (29%) had been treated with targeted therapy before and 3 (9%) with progressive disease (PD)-1 antibodies. 89% of the tissues sequenced were therapy naïve, 43% issued from lymph node metastases, 51% from other than lymph node metastases and in 6% the primary melanoma was used for sequencing as no metastasis was accessible
Summary
Checkpoint inhibitors such as pembrolizumab, nivolumab, or combination of ipilimumab and nivolumab have significantly improved prognosis of patients with metastatic melanoma. Programmed cell death ligand 1 (PD-L1) expression on the tumor cell surface was shown not to be a reliable predictive biomarker for response or survival as checkpoint inhibitors are effective in patients with PD-L1 negative tumors [5,6,7]. 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. 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
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