Managing Metastatic Melanoma in 2022: A Clinical Review

Benjamin Switzer, DO, MHSA, MS; Igor Puzanov, MD, MSCI; Joseph J. Skitzki, MD; Lamya Hamad, RPh, MPH; and Marc S. Ernstoff, MD


J Oncol Pract. 2022;18(5):335-351. 

In This Article

Abstract and Introduction


Cutaneous melanoma remains the most lethal of the primary cutaneous neoplasms, and although the incidence of primary melanoma continues to rise, the mortality from metastatic disease remains unchanged, in part through advances in treatment. Major developments in immunomodulatory and targeted therapies have provided robust improvements in response and survival trends that have transformed the clinical management of patients with metastatic melanoma. Additional advances in immunologic and cancer cell biology have contributed to further optimization in (1) risk stratification, (2) prognostication, (3) treatment, (4) toxicity management, and (5) surveillance approaches for patients with an advanced melanoma diagnosis. In this review, we provide a comprehensive overview of the historical and future advances regarding the translational and clinical implications of advanced melanoma and share multidisciplinary recommendations to aid clinicians in the navigation of current treatment approaches for a variety of patient cohorts.


Although the incidence of primary cutaneous melanoma has steadily increased for several decades and remains the most lethal of the primary cutaneous neoplasms, the 3-year overall survival (OS) rates have remained relatively constant from 26.4% to as low as 4.7% across the subcategories of stage IV metastatic disease from 2004 to 2009.[1,2] As of 2018, the SEER database estimated that the 5-year survival rate is 29.8% in those with stage IV disease at the time of diagnosis in the United States.[3] Noncutaneous forms of melanoma, including mucosal and ocular subtypes, classically portend an even worse prognosis.[4] In 2021, it is estimated that there will be 106,110 new cases of invasive melanoma with 7,180 melanoma-related deaths in the United States, and according to GLOBOCAN for 2020, there were 324,635 cases of melanoma worldwide, representing 1.7% of all cancers and 57,043 melanoma deaths or 0.6% of cancer-related mortality.[5]

Once considered among the most refractory of cancers to traditional modes of therapy including chemotherapy, radiation therapy, and the early days of targeted therapy, the clinical and therapeutic approaches toward patients with melanoma have witnessed dramatic improvements in cancer cell biology and immunology over the past decade. Striking responses to novel targeted and immunotherapies, with resultant improvements in both quality of life and OS, have substantially altered our approach to patients with metastatic melanoma. In this review, we will provide oncologists with a navigational map to approach this powerful and growing armamentarium.