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Predicting Response to Immunotherapy in Metastatic Melanoma

By: Joseph Fanelli
Posted: Tuesday, July 2, 2019

Tumor mutational burden and the interferon-gamma (IFNG) expression each independently predict response to PD-1 therapy in patients with cutaneous metastatic melanoma, suggesting the potential role of the two as biomarkers, according to results presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract 9511). The findings may indicate defects in both immune recognition or activation in nonresponders to immunotherapy, concluded Ines Esteves Domingues Pires Da Silva, MD, of the Melanoma Institute Australia, Sydney, and colleagues.

In the clinical analysis, the authors dissected tumors from 77 patients diagnosed with cutaneous metastatic melanoma who were treated with PD-1 (53 patients) or PD-1 plus CTLA4 inhibitors (24 patients). Pretreatment tumors were investigated with whole-genome sequencing, RNA sequencing, and immunohistochemistry. 

The authors observed no difference in the expression of specific genes reported to confer resistance or response in responders versus nonresponders. IFN and TCR signaling pathways were enriched for responders, and cytolytic activity (P = .002), T-cell proportion confirmed by immunohistochemistry (I = .033), and PD-L1 expression (P = .026) were also higher in responders.

Multivariate analysis including DNA, RNA, immunohistochemistry, and clinical factors all identified tumor mutational burden and IFNG.6 as independent predictors of response to treatment (AUC = 0.83). Additionally, 15 outliers with discordant molecular features and clinical outcomes experienced varying profiles, including 5 nonresponders with a high tumor mutational burden but low IFNG.6 expression. Those findings suggest a failure of immune activation, the authors concluded.

Disclosure: The study authors’ disclosure information may be found at

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