Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.

This corrects the article DOI: 10.1038/bjc.2017.85.

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Most MPs expected their physician to advise them about IRs they could use in addition to medical consultations. Peer support services were quite underused by MPs. The various preferences of media by MPs should be considered when deve-loping and providing IRs.

There is a scarcity of available data on unmet information needs (UINs) of melanoma patients (MPs) from Germany and of MPs with clinical stage IV. In a multicenter cross-sectional survey, we explored the UINs of 529 MPs by applying a standardized questionnaire. Subgroup differences in scope and contents of UINs were determined by univariate analyses. Predictors of the presence of UINs were identified by binary logistic regression. Overall, 55% of MPs reported UINs. Most MPs felt poorly or not informed about psychosocial support (24-31%). In MPs currently receiving medical treatment [odds ratio (OR): 1.9; P=0.017], MPs aging of at least 55 years (OR: 1.7; P=0.029), and in MPs who generally had a high need for information on their condition (OR: 2.4; P=0.001), the presence of UINs was significantly more likely than in post-treatment MPs, MPs more than 55 years of age, and those whose general information need was low. Most UINs concerned treatment-related information and were reported by MPs with tumor progression. Presence and scope of UINs did not differ significantly between metastatic and nonmetastatic MPs (57 vs. 53%; P=0.436). We highlighted differences in the presence, scope, and contents of UINs between MP subgroups, which should be considered when educating them in medical consultations and providing information via media. In particular, MPs felt insufficiently informed about psychosocial support and desired more treatment information.

For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70%, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long-term survival rates of approximately 20%, the anti-CTLA-4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune-mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti-PD-1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45% and one-year survival rates of > 70%. The combination of ipilimumab and nivolumab has shown response rates of up to 58% and a median progression-free survival of > 11 months. While this combination is expected to result in a rapid and long-lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long-term survival a possibility, not only acute but also long-term therapeutic side effects must be taken into account.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

No abstract