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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.

Over the past 10+ years, two classes of drugs have dramatically altered the clinical course of advanced melanoma: drugs that target abnormal protein produced in tumors with BRAFV600 mutations, with vemurafenib (Zelboraf) first approved in 2011; and immune checkpoint inhibitors (ICIs) or immunotherapy, led by ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo).

Responses to immunotherapy can be durable, and this has been demonstrated with both anti PD-1 and anti CTLA-4 treatment. Prior to the availability of the newer drugs, metastatic melanoma had a 5-year survival rate of about 10-15%. Today more than half of patients treated with combination ipilimumab and nivolumab are still alive at 5 years. Outcomes will almost certainly continue to improve as sequencing strategies, novel combinations, and new therapies work their way into clinical practice.

As the therapeutic options for advanced melanoma increase, clinical decision-making will evolve. Understanding the indications and recognizing the strengths and limitations of treatment options can help maximize patient outcomes.

Immunotherapy

The concept of inducing a patient's own immune system to treat cancer goes back several decades; however, early efforts produced only limited results. The concept of redirecting the immune system was reinvigorated by an improved understanding of the molecular biology of cancer, leading to recognition that the immune system has a system of "checkpoints" that prevent overreaction and potentially harmful effects.

Cancer has the ability to "hijack" the checkpoints and remain hidden from the immune system indefinitely. ICIs block cancer's interaction with checkpoints and facilitate a more robust immune response to cancer.

To date, the FDA has approved three types of immunotherapy for advanced melanoma: the cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab; the PD-1 inhibitors pembrolizumab and nivolumab; and more recently the inhibitor of lymphocyte-activation gene (LAG)-3, relatlimab (Opdualag). Additionally, the FDA approved the PD-L1 inhibitor atezolizumab (Tecentriq) for use in combination with targeted combination therapy for advanced melanoma associated with specific mutations. Two other FDA-approved anti-PD1/L1 agents, durvalumab (Imfinzi) and avelumab (Bavencio), do not have melanoma indications.

Ipilimumab (Yervoy)

Approved in March 2011, ipilimumab represented the first true breakthrough in the treatment of unresectable/metastatic melanoma. Almost 4 years earlier, a pivotal showed that adding ipilimumab to a cancer vaccine significantly improved median overall survival (OS) versus the vaccine alone. The positive outcome marked the first time any new therapy had improved OS in unresectable/metastatic melanoma. The FDA subsequently to include adjuvant therapy for stage III completely resected melanoma.

Ipilimumab is a monoclonal antibody that irreversibly binds to , a negative regulator of antitumor T cells. In the normal state, CTLA-4 binds to B7 to prevent T-cell activation, providing a natural checkpoint that prevents potentially harmful overactivation of T-cell immunity. Cancer disrupts normal signaling to keep T cells permanently in check. By blocking CTLA-4 binding to B7, ipilimumab inactivates the checkpoint to restore the signaling process that leads to T-cell activation.

In 2016, the FDA approved ipilimumab for use in combination with the PD-1 inhibitor nivolumab to treat advanced melanoma, irrespective of BRAF mutation status. Support for the approval came primarily from the , which showed that the combination significantly improved progression-free survival (PFS) compared with ipilimumab alone in patients with previously untreated advanced melanoma. Single-agent ipilimumab remains an approved therapy for melanoma, but is used infrequently as initial treatment.

Ipilimumab is associated with several types of (irAEs), some of which can become severe and even life-threatening. The most common irAEs (all grades) are dermatologic manifestations, enterocolitis, hepatotoxicity, endocrinopathies, and neurologic toxicity. With close monitoring, early recognition, and appropriate treatment, irAEs are manageable for most patients.

Pembrolizumab (Keytruda)

Pembrolizumab is a monoclonal antibody against programmed-death receptor-1 (PD1). Like ipilimumab, pembrolizumab is an ICI but it is focused on a different checkpoint in the immune system. In the , interaction between PD1 and its ligand (PD-L1) reduces antigen-specific T-cell activation, proliferation, and effector function. In the , the interaction between PD-L1 on cancer cells and PD1 on T cells allows cancer cells to escape immune-system attack by inhibiting activation of new cytotoxic T cells.

The FDA granted to pembrolizumab for previously treated, unresectable/metastatic melanoma in September 2014. The approval was based on the response rate and durability of response in 89 patients. A little more than a year later, pembrolizumab received approval as for advanced melanoma. Support for that approval came from the , which showed that pembrolizumab significantly improved PFS and OS as compared with ipilimumab.

In late 2021, the FDA approved pembrolizumab as for completely resected stage IIB or IIC melanoma. The showed that adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo. Clinical trials are underway to evaluate pembrolizumab, as well as other immunotherapy drugs, as for locally advanced and high-risk melanoma. In late 2022, the SWOG S1801 trial demonstrated that three doses of neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves relapse-free survival compared with adjuvant pembrolizumab alone.

In general, pembrolizumab and other drugs in the anti-PD1/L1 therapeutic class are less toxic as compared with ipilimumab. Immune-related skin, gastrointestinal, and thyroid problems are common, but most cases are mild or moderate in severity. Monitoring for irAEs should be ongoing, as severe immune-related toxicity (such as myocarditis) can occur.

Nivolumab (Opdivo)

Nivolumab became the second FDA-approved PD1 inhibitor for advanced melanoma in December 2014. The accelerated approval stipulated use in advanced melanoma previously treated with ipilimumab and/or a BRAF inhibitor. In a , about a third of patients had objective responses with nivolumab as compared with 11% of patients who received investigator's choice of chemotherapy. The FDA subsequently approved the combination for patients with advanced melanoma .

Nivolumab has FDA approval for use as a single agent or in combination with ipilimumab as initial treatment for unresectable/metastatic melanoma. The monoclonal antibody also has an approved indication as adjuvant therapy for completely resected stage III/IV melanoma.

In early 2022 the the combination therapy of nivolumab and relatlimab for patients age 12 or older with unresectable/metastatic melanoma. The approval was the first for an immunotherapy combination other than PD1/CTLA-4. Relatlimab is an (LAG)-3, an immune checkpoint that suppresses T-cell activation and immune response. Support for the approval came from a showing that nivolumab-relatlimab more than doubled progression-free survival in unresectable/metastatic melanoma compared with nivolumab alone. Treatment-related grade ≥3 adverse events occurred about twice as often with the combination (18.9% vs 9.7%), but the therapy was generally well tolerated.

Targeted Therapy

One individual drug and three targeted combination therapies have FDA approval for treating certain patients with unresectable/metastatic melanoma. All of the therapies target abnormal protein produced by , which occur in about half of all melanomas. BRAF activates the MAPK/ERK signaling pathway, and most theories regarding BRAF V600 mutations' role in melanoma involve disruption of downstream signaling in the pathway.

Vemurafenib (Zelboraf) ushered in the targeted-therapy era for melanoma with its approval in 2011. The approval was based on results of a comparing the BRAF inhibitor and dacarbazine in patients with untreated metastatic melanoma and BRAF V600E mutation. Patients treated with vemurafenib had a 63% reduction in the risk of death and a 74% reduction in the risk of disease progression or death relative to dacarbazine.

In clinical trials and subsequently in clinical practice, vemurafenib was associated with a variety of toxicities, notably skin toxicity. Most concerning was a risk of treatment-induced squamous cell carcinoma (SCC), which occurred in as many as 25% of patients. Laboratory studies showed that frequently co-occurred with BRAF mutations. BRAF inhibition resulted in paradoxical activation of MAPK/ERK signaling that stimulated and accelerated the growth of cells harboring RAS mutations. Exposure to a MEK inhibitor blocked MAPK/ERK activation.

Additionally, responses to single-agent vemurafenib were usually short lived, on the order of 6 or 7 months.

The observations led to the development of combination therapies that simultaneously inhibit BRAF and MAPK/ERK signaling. Since 2014 the FDA has approved three such combinations, each including a BRAF inhibitor and a MEK inhibitor, the first being the combination of .

Two showed that dabrafenib-trametinib significantly improved PFS, OS, and objective response rates in patients with advanced melanoma as compared with single-agent vemurafenib. The combination was associated with a significantly lower incidence of cutaneous SCC in both trials. In 2018 the FDA for dabrafenib/trametinib to include adjuvant treatment after surgery for BRAF-mutant melanoma.

In 2015 the FDA approved (Cotellic). A randomized trial showed that the combination increased median PFS by 5 months as compared with single-agent vemurafenib for unresectable/metastatic melanoma with a BRAF mutation.

In 2020 the agency approved the (Tecentriq) for use in combination with vemurafenib-cobimetinib for untreated BRAF-positive advanced melanoma. A randomized trial showed that the addition of the PD-L1 inhibitor to the targeted combination improved median PFS by 4.5 months as compared with vemurafenib-cobimetinib plus placebo.

The for BRAF-mutated melanoma is encorafenib (Braftovi) plus binimetinib (Mektovi). A randomized trial showed that the combination doubled the median PFS and OS compared with vemurafenib.

Options and Sequencing

The availability of more therapeutic options for advanced melanoma has introduced new considerations into clinical decision-making. Though outcomes have improved substantially, many patients still do not benefit from treatment or obtain only short-lived benefits. With that in mind, optimizing the use of available therapies has a major role in extending survival and maintaining quality of life for patients with advanced melanoma.

For patients without a BRAF mutation, first-line treatment options are single-agent anti PD-1 (pembrolizumab or nivolumab) or combination therapies of ipilimumab with nivolumab or relatlimab with nivolumab. Although combination immune therapy has demonstrated improved response rates, PFS, and OS compared with single-agent anti PD-1, anti PD-1 monotherapy may be the best choice for a patient with low-volume disease or other comorbidities where minimizing treatment side effects is important.

For patients with a BRAF mutation, the recent DREAMseq and SECOMBIT studies have both demonstrated improved survival with front-line combination ipilimumab and nivolumab compared with targeted therapy. During the initial months on treatment, DREAMseq patients receiving combination targeted therapy had improved outcomes compared with immune therapy until the advantage of immune therapy demonstrated improved PFS around 6 months and improved survival around 10 months.

This indicates there may be patients who benefit from targeted therapy front-line, and encourages individualizing each patient's treatment plan.

The pros and cons of each therapeutic class should be discussed with patients to arrive at a shared decision about the best initial option.

Read previous installments in this Medical Journeys 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

Part 6: Managing Unresectable/Metastatic Melanoma: What to Know

Part 7: Case Study: Did This Melanoma Metastasize or Is It Something Else?