Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer. The clinical impact of MCC has been increasing due to steadily rising incidence rates. Since 2001, more than 24,000 cases of MCC have been reported to the US National Program of Cancer Registries database, and in 2018, more than 2,500 incident cases are expected. MCC is highly aggressive, and one-third of patients will either present with or develop metastatic disease. Outcomes in patients with metastatic MCC have historically been poor; median time to progression with cytotoxic chemotherapy is only 3 months. MCC has long been appreciated to be immunogenic, with reports of spontaneous regression and responsiveness to immunotherapy. However, the mechanisms of this immunogenicity have only been understood over the past decade, with approximately 80% of cases in the United States associated with the Merkel cell polyomavirus (MCPyV) and expression of viral antigens (virus-positive [VP] MCC), and the remaining 20% of cases caused by UV radiation–induced damage leading to a high mutational burden and expression of neoantigens (virus-negative [VN] MCC). These insights have led to multiple successful trials of immunotherapies for MCC. PD-1 axis checkpoint inhibitors are now regarded as the preferred frontline systemic therapy in eligible patients (including both VP- and VN-MCC), with impressive frequency, durability, and depth of objective responses, which compare favorably to those of most solid tumors. This article reviews the safety and efficacy data from the key clinical trials of immune checkpoint inhibitors for metastatic MCC, and discusses several issues relevant to the clinical use of these agents. Finally, emerging immunotherapies for MCC, including cellular therapies and adjuvant systemic therapies, are reviewed.
Kelly G. Paulson and Shailender Bhatia
Shailender Bhatia and John A. Thompson
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.
Laura C. Kennedy, Shailender Bhatia, John A. Thompson, and Petros Grivas
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.
Featured Updates to the NCCN Guidelines
John A. Thompson, Bryan J. Schneider, Julie Brahmer, Stephanie Andrews, Philippe Armand, Shailender Bhatia, Lihua E. Budde, Luciano Costa, Marianne Davies, David Dunnington, Marc S. Ernstoff, Matthew Frigault, Benjamin H. Kaffenberger, Matthew Lunning, Suzanne McGettigan, Jordan McPherson, Nisha A. Mohindra, Jarushka Naidoo, Anthony J. Olszanski, Olalekan Oluwole, Sandip P. Patel, Nathan Pennell, Sunil Reddy, Mabel Ryder, Bianca Santomasso, Scott Shofer, Jeffrey A. Sosman, Yinghong Wang, Ryan M. Weight, Alyse Johnson-Chilla, Griselda Zuccarino-Catania, and Anita Engh
The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.
John A. Thompson, Bryan J. Schneider, Julie Brahmer, Stephanie Andrews, Philippe Armand, Shailender Bhatia, Lihua E. Budde, Luciano Costa, Marianne Davies, David Dunnington, Marc S. Ernstoff, Matthew Frigault, Brianna Hoffner, Christopher J. Hoimes, Mario Lacouture, Frederick Locke, Matthew Lunning, Nisha A. Mohindra, Jarushka Naidoo, Anthony J. Olszanski, Olalekan Oluwole, Sandip P. Patel, Sunil Reddy, Mabel Ryder, Bianca Santomasso, Scott Shofer, Jeffrey A. Sosman, Momen Wahidi, Yinghong Wang, Alyse Johnson-Chilla, and Jillian L. Scavone
The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.