Jacob S. Choi

The emergence of immunotherapy has dramatically altered the landscape of cancer treatment, leading to improved clinical outcomes for several malignancies. However, gastrointestinal immune-related adverse events are commonly encountered, and among patients with underlying autoimmune disorders, the risks and sequelae of such events may be more significant. Here, we present the case of a 76-year-old woman who developed isolated enteritis with diffuse ulceration shortly after the initiation of ipilimumab and nivolumab and ultimately passed away from refractory gastrointestinal bleeding. The clinical, endoscopic, and histologic findings were suggestive of a preexisting enteropathy that was rapidly accelerated by immune checkpoint inhibitor exposure.

It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAF^V600 mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAF^V600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAF^V600 melanoma.

Purpose of Review Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for patients with metastatic melanoma; however, there remains an unmet clinical need for alternative treatment options for those patients who are either intolerant or refractory to immunotherapy. Here we review the role and clinical efficacy of targeted therapies for BRAF^V600 wild-type melanoma. Recent Findings Genomic analyses in BRAF^V600 wild-type melanoma have previously identified driver mutations along the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT pathways that can be targeted with small molecule inhibitors. New drugs such as bispecific antibodies and antibody drug conjugates may have significant clinical activity even in rare subtypes of melanoma that are less responsive to ICIs. Summary Historically, molecular-targeted therapies have modest clinical success in treating BRAF^V600 wild-type melanoma; nevertheless, they may have a significant clinical role in select, genetically distinct groups of patients. Next-generation immunotherapies or immunomodulators may represent the latest breakthrough in the treatment of melanoma. Additional studies are needed to identify novel drug targets and synergistic drug combinations to expand treatment options and optimize clinical outcomes.