by Dr. C.H. Weaver M.D. 11/2021
Individuals with stage IV, or metastatic, melanoma have cancer that has spread from its site of origin to distant lymph nodes or other distant sites in the body, such as the liver, lungs, or brain. Great advances in the treatment of advanced melanoma have been made in recent years including the development of precision cancer medicines and immunotherapy. Immunotherapy has largely replaced chemotherapy and over 50% of patients now survive 5 years or longer as a result of these advances.
As promising as these therapies are they still stop working in half of patients at some point because melanoma cells find another pathway that lets them start growing again. Melanoma frequently involves the brain and this is a common site of recurrence that needs to be considered. To overcome this resistance current research is focused on identifying combinations of two or more precision cancer medicines to improve outcomes. Patients should discuss the role of genomic testing for determining the best precision cancer medicines to be used.
Systemic Treatment of Stage IV Melanoma
Systemic therapy is any treatment directed at destroying cancer cells throughout the body and is necessary in the management of stage IV melanoma because melanoma cells have already broken away from the primary cancer and traveled through the lymph and blood system to other locations in the body. Newer precision cancer medicines and immunotherapy drugs are the current standard of care because they delay the time to cancer recurrence and prolong survival. Currently, immunotherapy treatment regimens appear superior to most "targeted" medications possibly due to their increased effectiveness in treating cancer that has spread to the brain. Patients should discuss the role of genomic testing for determining the best therapy to be used. Systemic therapies commonly used in the treatment of Melanoma include:
Precision Cancer Medicines
Precision cancer medicines that target the genetic makeup of the cancer and immuno-oncology (drugs that use your immune system to help fight cancer) improve the outcomes of individuals with melanoma when compared with traditional chemotherapy. These therapies are designed to target the cancer cells while minimizing damage to normal, healthy cells. The ability to test a patient’s cancer for unique biomarkers that can identify differences at the genetic level, and to make treatment decisions based on those differences, is the hallmark of precision medicine.
Immunotherapy treatment of melanoma has progressed considerably and become the preferred initial treatment for the majority of patients with stage IV disease. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.6,7
About 40% of patients with stage IV melanoma will have brain metastases at diagnosis and 75% develop them at some point. Combination treatment with Opdivo (nivolumab) and Yervoy (ipilimumab) demonstrate overall survival benefit for patients with melanoma that has spread to the brain. Final results from the CheckMate 204 study evaluating this combination confirm an overall survival rate of 72% in asymptomatic patients at three years. In patients with symptomatic brain metastases or on corticosteroid therapy, responses were lower but remained durable, with 36.6% overall survival. Combination immunotherapy is effective and should be considered as a front-line option for asymptomatic patients with melanoma brain metastases.19
Yervoy® (ipilimumab) is a monoclonal antibody that targets CTLA4, found on the surface of T cells. CTLA4 is thought to inhibit immune responses. By targeting this molecule, Yervoy enhances the immune system’s response against tumor cells. Yervoy has been demonstrated to improve survival in melanoma patients who are at high risk of recurrence following complete surgical resection.6
PD-1 “Checkpoint Inhibitors” PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by immune cells. Drugs that block the PD-1 pathway can enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.
- Opdivo (nivolumab) is a checkpoint inhibitor that enhances the ability of the immune system to fight cancer. In patients with advanced melanoma without a mutation in BRAF Opdivo doubled the time until cancer recurrence compared to treatment with the chemotherapy drug dacarbazine. Opdivo has also been found to be superior to Yervoy for the management of stage IV melanoma following complete surgical resection.7
- Keytruda (pembrolizumab) is a checkpoint inhibitor that when compared directly to Yervoy was associated with a 30 percent improvement in survival. Overall 50 percent of patients treated with Keytruda survived nearly three years after starting treatment compared to 39 percent of patients treated with Yervoy. In addition, Keytruda nearly doubled the rate of progression-free survival.8
BRAF & MEK Kinase Inhibitors
The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Some melanomas carry another mutation known as V600K. BRAF and MEK inhibitors block the activity of the V600E and V600K mutations respectively.1-5
Given the success of immunotherapy physicians have debated whether patients with a BRAF mutation should be first treated with BRAF-MEK Inhibitor and save immunotherapy for treatment of a recurrence or proceed immediately to immunotherapy?
Giving Immunotherapy Before Targeted Rx Improves Survival
More people with advanced melanoma survive for two years or more when they receive a combination of two immunotherapy drugs given before a combination of two targeted therapies, if needed, compared to people who start treatment with targeted therapies.
It provides strong evidence for how best to treat patients with melanoma that has a specific mutation: Immunotherapy is the better initial approach even for people whose tumors have a mutation that could be treated by targeted therapies.
The DREAMsea clinical trial was conducted at 849 U.S. locations with 265 trial participants with BRAFV 600 metastatic melanoma who were randomly assigned to treatment with either dabrafenib and trametinib targeted therapy or immunotherapy Opdivo and Yervoy.
The two-year overall survival rate for people who first received immunotherapy was 72%, compared to 52% for those who initially treated with targeted therapy. Other trial findings revealed that some patients don’t do well on initial immunotherapy treatments, and for some reason switching to targeted therapies did not help. Doctors are focused on trying to determine why there was no benefit for this small group of patients.
Given the clearer advantage for starting with immunotherapy, which is not dependent on having a BRAF mutation, the researchers believe all patients with metastatic melanoma who don’t have other complicating factors should now be treated first with immunotherapy. What this study does not resolve is what immunotherapy regimen is the best initial treatment. That question is continuing to be addressed in other clinical trials.
- Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor
- Braftovi® **(**enorafenib) BRAF inhibitor
- Mekinist®(trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
- Mektovi® (binimetinib) MEK inhibitor
Combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with BRAF inhibition alone. The combination of Taflinar plus Mekinist significantly improves survival compared to treatment with single agent Taflinar, and the combination of Zelboraf and Cotellic appear to delay cancer recurrence when compared to Tafinlar.5
Proleukin® (interleukine 12) is an immunotherapy agent has traditionally been given in high doses to patients with melanoma, administered either intravenously by rapid infusion or by continuous infusion. Although high doses of Proleukin® historically have been associated with severe side effects management of these has significantly improved over the past decade making this treatment more tolerable.
Long-term results from a clinical trial evaluating high-dose Proleukin® in 270 patients with metastatic melanoma reported that 16% of patients achieved a partial or complete disappearance of their cancer and the average duration of all responses was approximately 9 months. Approximately seven years following therapy, the overall survival rate was approximately 11%. These long-term anti-cancer responses and survival indicate that high-dose Proleukin® remains an extremely effective treatment option for a subset of patients with metastatic melanoma.9
Although once the standard of care, chemotherapy has largely been replaced by the newer precision cancer medicines and immunotherapies in the management of advanced melanoma. Chemotherapy is still being used in some situations and may represent an appropriate treatment option for selected patients alone or in combination with newer targeted immunotherapies. DTIC (dacarbazine) has been the standard chemotherapy for the treatment of metastatic melanoma, with an overall response rate of approximately 15-20% and no clinical trials directly comparing DTIC to different chemotherapy combinations have demonstrated clear superiority of drug combinations over DTIC alone.10,11
- DTIC (dacarbazine)
- Tamadol (temazolamide)
Checkpoint Inhibitors + Avastin for Recurrent Ovarian Cancer
Anit-angiogenic - immunotherapy combination represents new treatment option for recurrent ovarian cancer.
Imlygic® (talimogene laherparepvec), the first ever FDA-approved oncolytic virus therapy, has been approved for the treatment of melanoma sites in the skin and lymph nodes that cannot be surgically removed. Imlygic is given through a series of injections directly into the melanoma over the course of 6 months.
Imlygic is a genetically modified live oncolytic herpes virus therapy. When Imlygic is injected into the site of the cancer the modified herpes virus replicates inside cancer cells and causes the cancer cells to rupture and die. Imlygic may also promote tumor shrinkage, trigger a systemic immune response and prolong survival in some patients with advanced melanoma. After acting locally within the tumor, it is intended to prompt an immune response against cancer cells elsewhere in the body.
Preliminary results showed that 64 percent of injected tumors shrank by half. The vaccine shrank tumors that were directly injected as well as those that were not injected—indicating that the vaccine was triggering the immune system to fight the distant tumors.12
Role of Surgery
Surgery plays a role in the management of some patients with metastatic melanoma. Patients who have a limited number of metastases may benefit from surgical removal if they have favorable other prognostic features, such as a long period of time between diagnosis and recurrence.
Role of Radiation Therapy
Radiation therapy can relieve symptoms, especially pain from cancer that has spread to the bone. Radiation therapy should also be considered in patients who have had surgical removal of a single brain melanoma.
Treatment of Brain Metastasis
Melanoma that has spread to the brain accounts for 10-50% of reported deaths from melanoma. Individuals with multiple brain metastasis are treated with immunotherapy and higher dose therapy with Opdivo and Yervoy appears to produce the best results.
Patients are often treated with steroids to reduce "swelling" and its safest to discontinue steroids prior to starting immunotherapy.
A single brain metastasis can be removed with surgery - sterotactic radiation therapy should also be considered. There is a suggestion that radiation therapy in this situation improves survival and reduces recurrences. The decision to recommend surgery should be based primarily on whether the entire melanoma can be removed, and the status and number of other organs involved with metastatic lesions.
Strategies to Improve Treatment
The progress that has been made in the treatment of melanoma has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of melanoma.
Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth. Inhibiting LAG-3 allows T cells to regain their cytotoxic function and potentially affect cancer cell growth. Targeting the LAG-3 pathway in combination with other potentially complementary immune pathways may be a key strategy to more effectively activate the anti-tumor immune response.
Proof-of-concept data show that combining anti-LAG-3 with Opdivo in PD-1/PD-L1 refractory patients may help patients overcome resistance and restore T cell function. These results indicate that anti-LAG-3 therapy in combination with Opdivo may offer clinical benefit, particularly for patients whose cancers contain immune cells that express LAG-3.17
Yervoy + GM-CSF Yervoy® is a monoclonal antibody that targets a protein receptor, CTLA-4 that prevents the body’s defenses from attacking cancer cells. GM-CSF (granulocyte-macrophage colony-stimulating factor) is a protein that spurs the growth of white blood cells in the immune system. Patients with metastatic melanoma treated with the combination of Yervoy® and GM-CSF had a one-year survival rate of 69% and an average survival of 17.5 months compared to 54% and 12.7 months if treated with Yervoy alone.13 Larger trials and longer follow-up are necessary to confirm these results.
BRAF & MEK: The combination of a novel BRAF inhibitor encorafenib (LGX 818) with a MEK inhibitor binimetinib (ARRY 162) significantly delayed cancer recurrence compared to treatment with Zelboraf (vemurafenib) alone. Zelboraf was the first BRAF inhibitor approved for treatment of advanced melanoma and represented a breakthrough by significantly improving survival compared with chemotherapy, replaced the latter as a treatment option.14
Ulixertinib is a novel ERK1/2 kinase inhibitor. A great number of cancers, including melanoma and lung cancers, have mutations in the MAPK/ERK pathway, and while current therapies target proteins in this cascade, many patients develop resistance to current drugs.
The ERK gene is the final regulator in the MAPK/ERK pathway, and when upstream inhibition of this protein cascade fails, ERK signaling is reactivated, resulting in renewed MAPK signaling. Targeting ERK for inhibition may allow the opportunity to thwart resistance from upstream mechanisms. Ulixertinib has demonstrated clinical responses in BRAF-mutant cancers resistant to BRAF and MEK inhibitors. Ulixertinib has been given fast track designation by the FDA and will undergo further evaluation in a variety of cancers.15
Epacadostat is an agent that blocks an enzyme called IDO1, which is implicated in the growth and spread of cancer cells. The immunosuppressive effects of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity help cancer cells evade immunosurviellance. In single-arm studies, epacadostat combined with the PD-1 inhibitors Keytruda or Opdivo (nivolumab) improved response rates compared with studies of the immune checkpoint inhibitors alone.16
PV-10 is a 10% solution of Rose Bengal, which was originally used as an agent to stain necrotic tissue in the cornea. Its potential use in melanoma was discovered while exploring different formulations for use in photodynamic cancer therapy. PV-10 was developed to be administered directly into solid tumors was discovered to destroy tumors without the need for light activation. Initial trials report an overall response rate of 51%, and a complete response rate of 26% in individuals with refractory melanoma.18
Vaccines: Currently, no vaccine has been approved for the treatment melanoma. Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.
- Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine. 2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.
- Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New England Journal of Medicine. 2011;364(26):2517-26. doi: 10.1056/NEJMoa1104621.
- Opdivo (nivolumab) in Combination with Yervoy (ipilimumab) and Opdivo Monotherapy Significantly Improved Overall Survival Versus Yervoy Alone in Patients with Previously Untreated Advanced Melanoma
- Cancer, Vol 88, No 9, pp 2042-2046, 2003
- Rao RD, Holtan SG, Ingle JN et al. Combination of Paclitaxel and Carboplatin as Second-Line Therapy for Patients with Metastatic Melanoma. Cancer. 2006;106:375-82.
- Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009; 115: 119-127.
- Andtbacka RH, Ross MI, Delman K, et al: Responses of injected and uninjected lesions to intralesional tal-imogene laherparepvec (T-VEC) in the OPTiM Study and the Contribution of Surgery to Response. Presented at the Society of Surgical Oncology Cancer Symposium in Phoenix, Arizona March 12-15, 2014. Abstract 52.
- Hodi, F. Stephen, MD, et al. “Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial.” The Journal of the American Medical Association. doi:10.1001/jama.2014.13943. November 5, 2014.
- Dummer R et al “Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext) [BRAF-mutant melanoma (COLUMBUS): A multicenter, open-label, randomized phase III trial”](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext) [Lancet Oncol](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext) [2018; DOI:10.1016/S1470-2045(18)30161-X.](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930142-6/fulltext)
- Cancer Discovery ulixertinib
- Press Release. Updated Phase 1 Data Reinforce the Clinical Profile of Epacadostat in Combination with Keytruda® (Pembrolizumab). Available here. Accessed September 30, 2016.
- Thompson JF, Agarwala S, Smithers M, et al. Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma. Annals of Surgical Oncology, October 2014.