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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Recent advances in systemic therapy have transformed treatment for unresectable and metastatic melanoma. Improved understanding of the molecular biology and genetics of cancer fueled development of more effective and less toxic therapies, as compared with conventional chemotherapy. Targeted agents and immunotherapy offer the potential for prolonged clinical responses. Both progression-free survival (PFS) and overall survival (OS) have improved substantially, and more patients than ever live 5 years or longer. Some of the earliest patients treated with ipilimumab (Yervoy), the first approved immune checkpoint inhibitor, .

Enthusiasm for the progress, however, is tempered by the recognition that not all patients with advanced melanoma benefit from immunotherapy and that the benefits of targeted agents are limited to patients with specific tumor mutations. Patients with metastatic melanoma continue to be encouraged to consider enrollment in clinical trials that are evaluating combination therapies and other strategies to improve on the gains made with immunotherapy and targeted therapy.

Despite the limitations of current therapies and the ongoing unmet need for better treatment, the outlook has improved dramatically for patients with advanced melanoma, which not too long ago was associated with survival measured in months or even weeks.

Unresectable and Metastatic Melanoma: The Basics

The term unresectable may apply to stage III (locally advanced) or stage IV (distant metastasis) melanoma. Though most types of stage III melanoma remain amenable to surgery, a lesion might be unresectable because of its size or anatomical location, or because other characteristics make surgery too challenging or risky, because the patient is not a good candidate for surgery, or because the patient declines to have surgery.

If a lesion is considered unresectable because of anatomic or other lesion-specific factors, systemic therapy becomes the primary treatment. Following completion of the prescribed therapy, the lesion should be re-evaluated for surgery.

On the other hand, some stage IV melanomas are resectable. In particular, patients with disease may be candidates for surgery. Following complete resection of limited advanced disease, a patient with no evidence of residual disease might be offered adjuvant systemic therapy. Patients who have residual disease after surgery should be treated in accordance with current practices for disseminated metastatic melanoma.

Principles of Systemic Therapy

With the emergence of multiple effective therapies for metastatic melanoma, observation is no longer considered appropriate as a front-line strategy, even for patients with very limited metastatic disease. Two types of systemic therapy demonstrated improvement in PFS and OS in randomized clinical trials of metastatic melanoma: immune checkpoint inhibitors (ICIs) and targeted agents for melanomas associated with an activating BRAF V600 mutation.

The most extensively studied and FDA-approved ICIs for melanoma are ipilimumab, nivolumab (Opdivo), and pembrolizumab (Keytruda). Nivolumab has demonstrated efficacy as a single agent and in combination with ipilimumab.

Approved targeted therapies consist of three two-drug combinations (one targeting BRAF and the other targeting MEK). Single-agent BRAF inhibition is no longer recommended, as the combinations resulted in more prolonged responses and fewer skin-related adverse events -- particularly treatment-related nonmelanoma skin cancer.

ICIs and targeted therapies currently form the basis of first-line treatment for unresectable/metastatic melanoma. The targeted combinations are indicated only when patients have melanomas associated with BRAF V600 mutations, which occur in about half of all melanomas. Nivolumab and pembrolizumab have demonstrated efficacy in patients with and without BRAF mutations, making the drugs options for a larger patient population.

Anti-PD-1 antibody front-line therapy is an effective, well-tolerated treatment for unresectable/metastatic melanoma. showed that first-line use of the agents increased from less than 10% in 2010 to 63% in 2019. The trend was associated with a doubling of median OS over the same time period.

Ipilimumab

The first approved checkpoint inhibitor, ipilimumab is a monoclonal antibody directed against the immune checkpoint receptor CTLA-4. FDA approval of ipilimumab for unresectable/metastatic melanoma includes patients with untreated or previously treated disease. However, the (NCCN) no longer recommends the drug by itself as a first-line option. The decision is based on results of the randomized trial, which showed improved outcomes with single-agent nivolumab or the combination of nivolumab and ipilimumab as compared with ipilimumab alone.

Nivolumab

A monoclonal antibody directed against programmed death receptor (PD)-1 or its ligand (PD-L1), nivolumab has demonstrated improved PFS and OS as a single agent and in combination with ipilimumab. Nivolumab has as initial therapy for unresectable/metastatic melanoma. The FDA also approved nivolumab as adjuvant therapy after complete resection of early-stage or limited metastatic melanoma.

Based on the and trials, ipilimumab/nivolumab is now the preferred first-line therapy. The choice between nivolumab monotherapy and combined nivolumab-ipilimumab involves a risk/benefit consideration. The combination may improve survival compared with nivolumab alone but is associated with increased risk of potentially severe immune-related adverse events (AEs). Treatment decisions by assessment of a patient's overall health, medical history, concomitant medications, comorbidities, and compliance with monitoring and management of AEs.

Long-term survival follow-up from CheckMate 067 demonstrated that nearly 50% of patients treated on study with ipilimumab/nivolumab were still alive at 6.5 years, which provides a strong rationale for upfront combination therapy. The SECOMBIT results, reported in 2021, demonstrated improved OS for patients with BRAF V600 mutation treated with ipilimumab/nivolumab upfront followed by targeted therapy versus targeted therapy with dabrafenib/trametinib upfront followed by ipilimumab/nivolumab. There are caveats to these data for patients with high-volume disease and poor performance status, but patients generally benefit from combination immune therapy frontline.

Pembrolizumab

The first FDA-approved anti-PD-1 antibody, pembrolizumab has approval as initial treatment for unresectable/metastatic melanoma and as adjuvant therapy following complete surgical resection of early-stage or limited metastatic melanoma. Like nivolumab, pembrolizumab demonstrated superior PFS and OS versus standard chemotherapy for unresectable/metastatic melanoma. The NCCN considers both anti-PD-1 agents as appropriate treatment options for BRAF-mutant and BRAF-wild type melanoma.

In contrast to nivolumab, pembrolizumab only recently has been evaluated in combination with ipilimumab. A large, comparing the combination with pembrolizumab and placebo showed no significant difference in PFS or OS and a higher rate of grade 3-5 AEs with the combination, including a substantially higher number of deaths. The trial was terminated early for futility following an interim analysis.

Targeted Combinations

The FDA has approved three targeted therapy doublets for unresectable/metastatic melanoma associated with BRAF V600-activating mutations. Each combination consists of a BRAF inhibitor and a MEK inhibitor: dabrafenib (Tafinlar)/trametinib (Mekinist), vemurafenib (Zelboraf)/cobimetinib (Cotellic), and encorafenib (Braftovi)/binimetinib (Mektovi).

The NCCN considers all three combinations as category 1 (strongest supporting evidence) options for BRAF-mutant melanoma. Each of the three combinations achieved better outcomes, as compared with monotherapy, in one or more phase III randomized trials. Indications for the targeted combinations stipulate use of an FDA-approved test to confirm BRAF mutation status.

Vemurafenib and dabrafenib have FDA approval as single-agent therapy for unresectable/metastatic melanoma, but the individual agents are rarely used, given the consistent superiority of dual BRAF/MEK inhibition. Use of BRAF inhibitor alone is limited to rare occasions when combination therapy is contraindicated. Even in those cases, a PD-1 inhibitor would likely be an appropriate option.

Regarding choosing between a targeted combination and a PD-1 inhibitor for BRAF V600-mutant melanoma, the NCCN suggests several factors that might help , including the "tempo of disease," presence of significant symptoms, and patient history of autoimmune disease or risk of triggering an autoimmune reaction by immunotherapy. For example, if a patient is highly symptomatic, in poor health, or appears to have rapidly progressing disease, a targeted therapy combination might be preferable, given that responses to immunotherapy can take longer than the brisk response associated with targeted therapy.

Intralesional Injection

Selected cutaneous or subcutaneous metastases may be amenable to direct injection with talimogene laherparepvec (T-VEC, Imlygic), an oncolytic viral immunotherapy derived from herpes simplex virus 1. Intranodal or intralesional injection of T-VEC may help with disease control by reducing tumor size.

The effect on PFS or OS remains unknown. Ongoing trials are evaluating T-VEC in combination with other therapies, particularly PD-1 inhibitors. One of these trials, combining T-VEC and pembrolizumab, showed that the combination compared with the PD-1 inhibitor and placebo.

Clinical Trials

Despite progress in treating unresectable/metastatic melanoma, only a minority of patients obtain lasting benefit from currently available therapies. Because of that, referral for a clinical trial remains a reasonable option for many patients with advanced-stage disease. Ongoing trials are evaluating promising new therapies, as well as novel combinations of existing treatment options. These trials should be included in a discussion of treatment options with patients.

Read previous installments in this series:

Part 1: Melanoma: Epidemiology, Diagnosis, and Treatment

Part 2: Recognizing Melanoma: What It Is, What It Isn't

Part 3: Basics of Melanoma Diagnosis

Part 4: Case Study: The Dangers of Melanoma Recurrence

Part 5: Managing Early-Stage Melanoma