Discussing Updates in the Management of Patients With Metastatic Melanoma

Marc Ernstoff, MD

Cutaneous melanoma remains the most lethal of the primary cutaneous neoplasms. While the incidence of patients with primary melanoma continues to rise, mortality rates remain the same. This can be attributed to a number of advances in treatment options for patients.

In the metastatic melanoma space alone, there have been a number of developments, including the use of immune checkpoint inhibitors (ICI) and MAP kinase targeted therapies, which have allowed for robust improvements in patient responses and rates of survival.

Some of these advancements include ICIs such as agents targeting PD1 like nivolumab (Opdivo) and pembrolizumab (Keytruda), the anti-CTLA4 antibody ipilimumab (Yervoy), and the anti-LAG3 antibody relatlimab in combination with nivolumab (Opdualag), which was approved by the FDA in March 2022. There are also combination dual targeted therapies to BRAF, including dabrafenib (Tafinlar) plus trametinib (Mekinist), vemurafenib (Zelboraf) plus cobimetinib (Cotellic), and encorafenib (Braftovi) plus binimetinib (Mektovi), respectively.

Additionally, advances in immunologic and cancer cell biology in this space have contributed to further optimization in risk stratification, prognostication, treatment, toxicity management, and surveillance approaches.

“While the incidence continues to increase over time, recently, the mortality rates have decreased in both men and women. That might be related to early diagnosis or may be related to new treatment paradigms that have been put together,” explained Marc S. Ernstoff, MD, in an interview with Targeted Oncology^TM.

In the interview, Ernstoff, branch chief for the ImmunoOncology branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, at the National Cancer Institute, discusses recent updates in the management of metastatic melanoma.

Targeted Oncology: Can you discuss the incidence of primary melanoma?

Ernstoff: The incidence of primary melanoma is probably in the order of 20 per 100,000 patients or so. Obviously, it's a disease most common in Caucasians or people with fair skin, more frequent in men than women. While the incidence continues to increase over time, least from the most recent data, more recently, the mortality rate has decreased in both men and women, and that might be related to either early diagnosis or may be related to new treatment paradigms that have been put together.

Can you provide an overview of the current era of metastatic melanoma?

Metastatic melanoma is either stage III or stage IV. Stage III melanoma is primary melanoma with regional lymph nodes involved. Patients are managed differently than patients with stage IV disease, which is disease that spreads beyond the regional lymph nodes. There is a subset of stage IV disease who have oligo metastases which means that there are a small number of metastases that sometimes can be resected, in which case they are managed similarly to stage III patients with disease.

In the current era, it's important to have your melanoma molecularly defined. Our current understanding is that there is a particular pathway that signals the cell to grow which is called the RAS/MAP kinase pathway. There is a specific mutation in that pathway in a gene called BRAF and if your tumor has this mutation, it turns that protein on and drives your cancer to grow. Understanding this allows the development of specific small molecules to target both the BRAF mutation as well as the downstream protein called MEK.

What recommendations do you have for managing patients with metastatic melanoma?

In 2022, patients with melanoma should have molecular testing to determine whether they have a BRAF mutation. If they have that mutation, it opens the therapeutic options up to both small molecule inhibitors of that pathway, as well as immunotherapy. For many years, we've known that of all the solid tumors, melanoma is one of the most immunogenic.Historically, we used certain cytokines such as interferon alpha and interleukin 2, which showed small modest benefit of therapy and gave a clue that this tumor could be treated through an immunological approach.

In the last 15 years, the identification of immune checkpoints or molecules that are involved with regulating the immune cytotoxic T lymphocytes [CTL] have been identified. Cancers such as melanoma, can induce a state of exhaustion in your CTLs and thus are not able to destroy your cancer. Blocking antibodies to three of the immune checkpoints, CTLA-4, PD-1, and LAG-3 given alone or together can restore CTL function and have demonstrate significant improvement in melanoma survival,

How does management in 2022 look vs previous years?

In 2022, the small molecule therapies for BRAF-mutated melanomas are highly effective at controlling the cancer with rapid shrinkage of tumor, but ultimately, most tumors become resistant.

Immune checkpoint inhibitors with antibodies to anti-CTLA-4, anti-PD-1, and now an anti-LAG-3 in combination with anti PD-1, are also available to treat patients with melanoma.In 2022, ICI therapies will use a backbone of anti PD-1’s, nivolumab and pembrolizumab which provides a significant survival benefit and can be used in with anti -CTLA-4 ipilimumab or LAG-3 relatlimab in combination with nivolumab which provides potentially enhanced survival benefit. ICIs will be effective in patients with melanoma that harbor the BRAF mutation or not. The DREAMseq trial [NCT02224781] which compared the combination dabrafenib and trametinib vs combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma looked at the sequence of giving dual MAP kinase inhibitors before immunotherapy or immunotherapy before these dual MAP kinase inhibitors. In that study, it appears that there is a benefit for starting with immunotherapy first.

In 2022, I think most of us would recommend either BRAF-mutated or BRAF wild-type disease to start with ICI first. If the patient is willing to tolerate increased toxicity the combination of anti PD-1 and anti-CTLA-4 is suggested as the incidence of toxicity of combination ICIs is frequently higher and more severe. Thus, a discussion between patient and treating physician regarding risk and benefits should precede starting therapy.In the cases where the patient’s tumor has a BRAF mutation and has rapid progression of their disease, many of us would start with a dual MAP kinase inhibitor just to control the cancer because its rapid progression may not permit ICI therapy the opportunity to work.

Central nervous system metastasis is a difficult clinical situation. Patients with brain metastases disease can also be characterized by either CNS symptoms needing steroids to control the associated intracerebral swelling or not having CNS symptoms and do not require steroids. The combination ICI therapy can be effective in controlling brain metastases in the asymptomatic patient with or withoutradiation therapy.

What major developments have there been in regards to targeted therapies in this space? What do you think is next for the future?

When you talk about targeted therapies, you're talking about molecules that interfere with driver mutations in the cancer cell. Challenges in the field relate to identifying the causes of resistance to the current small molecules, which can include other mutations in the RAS/MAPK pathway or other pathways altogether.

Another area of targeted therapy is identifying immune targets for immune cells that would enhance the development of cellular therapy, bispecific, or trispecific antibodies that might allow for immune cells to target the cancer specifically.

CTLs interact with an antigen that is presented within the HLA molecule. We have many HLA molecules and they allow our bodies to recognize self from non-self. We share many HLAmolecules with each other, but the portfolio of HLA molecules makes us immunologically distinct. There's a process by which all the proteins in your body get processed and are put into the pocket of the HLA molecule. It's that combination of the small part of the protein in the pocket of the HLA that the CTL recognizes and uses what is called the T-cell receptor. There are shared antigens between tumors. Many of those are either embryonic antigens or tumor specific antigens, and there are private antigens. Antigens that are private are mutations that occur only in your tumor, and therefore need to be identified. There are techniques to identify those specific antigens and then to develop TCR specifically to that molecule.

Chimeric antigen receptor (CAR) T cells as opposed to TCR modified cells are independent of the HLA molecules. They use an antibody that recognizes a particular marker on the cell surface. TCRs can target proteins that are internal, because those proteins are processed and are put onto the HLA molecules.CAR T cells only can attack molecules on the surface. There are techniques that identify specific targets unique to tumors and unique to individuals which would permit a personalized approach to cell therapy.

What unmet needs do you think still exist in this space?

The overwhelming majority of melanomas are typically early and are cured by surgery. Nevertheless, in the early stages of melanoma, there is a certain small percentage of people that will ultimately have metastases and potentially die from their cancer. Identifying biomarkers to help identify which patients have a tumor that is destined to have metastasize vs. those tumors that have not metastasized would permit us to identify which patients may need adjuvant therapies or not, or may need intense surveillance or not.

Biomarkers of response to therapy would allow us to identify those groups of patients who would benefit from therapy or not and which therapy might be best.

What advice would you give to community oncologists who want to learn more about managing patients with melanoma?

Understanding the basic biology and physiology of cancer is something that physicians should know about. Use of established updated treatment guidelines, such as those published by the National Comprehensive Cancer Network, provides a mechanism to be sure practicing oncologists have not overlooked new developments.

In terms of practice, we have made significant headway in the treatment of melanoma which provides the community physician with FDA approved agents, further improvement is still needed. This is why I encourage everyone to consider upfront participation in clinical trials.