Melanoma Treatment: Stage IV

Melanoma Treatment: Stage IV

Stage 4 melanoma, although the most life threatening, offers the most treatment options. Whereas, stage 1 and 2 are normally cured by simple outpatient surgery, stage 3 has few adjuvant therapies and is watched similarly with the hope of new therapies in the wing.

Old Therapies

Although chemotherapy in very few instances produces dramatic regression of disseminated melanoma, it only rarely results in long-term survival. Indeed, in a recent review of chemotherapy for cancer in advanced stages, melanoma patients were classed with those who could expect only “minor response—no demonstrable prolongation of survival” from chemotherapy. Another option that is an older therapy includes immunological hormones called cytokines, such as IL2 also called Interleukin. In a few patients, disease may actually melt away and have a sustained response. But the rate of response is in less than 6% of patients with much associated toxicity. The role of IL2 intermixed with Ipilimumab and other therapies may hold promise in the future although that remains unproven.

NEW Therapies

New Targeted Therapies for Melanoma: BRAF and MEK
When you are diagnosed with melanoma, your oncologist may bring up the term BRAF or MEK with you. Zelboraf, a BRAF inhibitor, was approved for prescription by the FDA in the fall of 2011. Approximately 50% of melanoma patients’ tumor tissue tests positive for this genetic mutation. A mutated BRAF accelerates tumor cell growth and this change can increase the growth and spread of cancer cells. Therefore, these BRAF drugs target the cancer-causing mutation in melanoma. The BRAF oral medication should not be given to those without the mutation, as it could actually accelerate tumor progression. BRAF mutations usually arise from sun exposed skin and rarely from those melanomas such as mucosal, ocular or acral, whose origin is not clearly known yet. In order for these therapies to work most effectively, you need first to be BRAF positive. Your tumor tissue must test positive for the BRAF gene before you can be prescribed this oral agent. MEK, on the other hand, is a bit different with less information available on its performance. It does appear that you can be BRAF Negative and respond to the MEK drugs, if you are NRAS positive (another mutation to be tested for). BRAF and MEK have been combined in clinical trial, showing promising results and Dabrafenib and Mekinist were approved by the FDA in 2013 for prescription. Currently another mek to be combined with Zelboraf is waiting approval by the FDA, Cobimetinib is the current name. Testing for BRAF should be current with the COBAS test or other FDA approved tests. Testing performed years back should be reviewed, as it may change with newer methods. The BRAF drugs often give a pronounced reduction in tumor burden but the duration of response can be limited. Research is showing that patients shouldn’t wait until progression of disease on these drugs before considering an alternative therapy. Also, sometimes going off this therapy and returning to it a few months later can produce a response. Side effects vary with fevers, rash, joint pain, and nausea being among the common ones.

Immunotherapy for Melanoma
It is a well-known fact that melanoma is an immune responsive disease. Cracking the code to turn on the body’s immune system to effectively eliminate melanoma tumors, however, has remained elusive until recently. Older immunotherapies, IL2 and Interferon, although still in use, may be toxic to the whole body and seemingly ineffective for the majority of patients. Bio-chemo, mixing interferon, IL2 and chemo together has been proven ineffective in providing a survival advantage. Advances in research have led to an improved understanding of the interactions between the immune system and tumors, generating renewed interest in novel immunologic approaches to the treatment of melanoma. Indeed, there have been multiple FDA approvals of immunologic agents in recent years and there are many ongoing trials of immunotherapies in lung cancer, colorectal cancer, and melanoma. The safety and efficacy of these new agents have much improved the outlook for immunotherapy treatments for melanoma. The first, Ipilimumab, was approved by the FDA and, more recently, in several global sites for melanoma treatment. The response rate is from 15 to 20% for patients. There are reported cases of long term response. The side effects can be different for individuals, this is understood and closely watched to prevent from progressing with the use of steroids and other medications. The introduction of PD1 brings us even higher promise. The latest reports show PD1 Keytruda having a 38% response rate and the Opdivo Pd1 32% for melanoma patients. The safety profile for PD1 is also remarkable, with little toxicity associated with the treatment. Still in the works are combination strategies with the immunotherapy agents. Mixing Yervoy with PD1 is showing promising results. Both PD1 agents, Keytruda and Opdivo have now been approved by the FDA for third line treatment. You must have progressed on the BRAF therapy (if BRAF positive) and Yervoy before getting the Pd1 agents. This will hopefully change early in 2015. Yervoy and the BRAF targeted agent however, showed liver toxicity and therefore switched to a sequential treatment protocol. The sky is the limit on how these immunotherapies and other agents may pan out, either alone, together or sequentially. The exciting frontier of melanoma research may begin to produce a therapy that provides a long-standing remission of this terrible disease melanoma. It is long past due for the melanoma world.

There are many clinical trials to explore, with new therapies arising every day. Contact our helpline, 866-463-6663 or email cpoole@melanomainternational.org, to find help matching you to a treatment trial if that is what you choose to do. Also be sure to look at the ongoing discussions of current therapies at our forum. You can also go to: www.clinicaltrials.gov and put melanoma in the search for a list of trials.

Updated: April 29, 2015

Sources: 2010 ASCO Proceedings published by Cancer Care BRAF article edited by Keith Flaherty, MD Dir. of Therapeutics at Mass General Hospital
Melanoma: Not Just Skin Cancer, Catherine M. Poole, Amazon Publishing: 2015