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Immunotherapies and BRAF and MEK inhibitors have dramatically improved outcomes in advanced melanoma. The availability of these novel approaches has necessitated changes to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). The NCCN Guidelines feature algorithms that aid clinicians in selecting initial therapy, which now includes anti-programmed death protein receptor-1 PD-1 inhibitors among the recommended systemic therapy options for patients with metastatic or unresectable disease.

Over the past 5 years, a host of new agents have radically changed the therapeutic landscape in advanced melanoma; gone are the days when the only active agents were interferon and dacarbazine. Nearly 25 years ago, few patients with stage IV melanoma reached 2-year survival; today, these survival curves have risen substantially. At the NCCN 21st Annual Conference, John A. Thompson, MD, discussed updates with longer duration of patient follow-up for immune checkpoint therapies. He also reviewed some of the newer approvals in advanced melanoma, including the combination of ipilimumab and nivolumab, high-dose ipilimumab, the oncolytic virus therapy talimogene laherparepvec, and the molecularly targeted combination of the BRAF and MEK inhibitors vemurafenib and cobimetinib.

The 2014 version of the NCCN Guidelines for Melanoma lists 6 pre-ferred regimens, most with a category 1 recommendation, and 8 “other active regimens.” Effective new agents include ipilimumab, a monoclonal anti-CTLA4 antibody, and agents targeted against mutated BRAF and MEK. Researchers are now focused on the optimal way to combine or sequence these agents, while exploring other new classes.

Immune checkpoint inhibitors (ICIs) are now FDA-approved for the treatment of 8 different cancers, and more approvals are likely, including use of these drugs in combinations. Although ICIs represent a true advance in cancer care, they can cause a range of immune-related adverse events. As more experience with ICIs is gained, more information is becoming available on immunotoxicity and optimal management. Physicians and patients need to be educated about potential adverse events and management of ICI-associated toxicity. In recognition of the need for better information, NCCN in collaboration with ASCO has developed the first set of NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

The 10-year survival rate for patients with metastatic melanoma is less than 10%. Although surgery and radiation therapy have a role in the treatment of metastatic disease, systemic therapy is the mainstay of treatment for these patients. After decades of failed attempts to improve treatment outcomes, recent successes with ipilimumab and vemurafenib have ushered in a new era in systemic therapy. Both ipilimumab and vemurafenib are associated with significant improvements in overall survival of patients in randomized phase III trials, an end point that had proven elusive so far. These breakthroughs not only provide more treatment options for patients with melanoma but also spur the investigation of a new generation of drugs for cancer therapy in general. This article reviews both the current systemic treatment options for metastatic melanoma and promising investigational approaches.

The use of immune checkpoint inhibitors (ICIs) is rapidly expanding to the treatment of many cancer types, both in the metastatic setting and as an adjuvant to other therapies. Clinical trials using ICIs have largely excluded patients with preexisting autoimmune diseases due to concerns for increased toxicity. However, emerging evidence shows that ICIs may be considered in some patients with autoimmunity. This review discusses the commonalities between clinical autoimmune diseases and ICI-induced immunotherapy-related adverse events, and summarizes the existing case series that describes patients with solid tumors who have a preexisting autoimmune disease. This review also discusses which patients with autoimmunity could be considered reasonable candidates for ICI therapy.

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.