Cancer Today - Summer 2016

Transformative Treatments for Metastatic Melanoma
Advances in Immunotherapy and Targeted Treatments

The rates of melanoma, the most fatal form of skin cancer, have been steadily rising over the past 30 years. The American Cancer Society predicts there will be more than 76,000 new melanoma diagnoses, and more than 10,000 deaths, in 2016.

When caught early, cutaneous melanoma, the most common form, has a very high cure rate. However, melanoma metastasizes very aggressively, and up to 10 percent of cases aren’t caught until lymph nodes or distant organs are involved. Until recently, the prognosis for patients with advanced or metastatic Stage IV melanoma was poor.  

A rapid pace in medical oncology breakthroughs
Historically, the normal course of medical oncology treatment for metastatic cutaneous melanoma was chemotherapy with dacarbazine (DTIC), which had a low response and overall survival rate.  Since 2011, the U.S. Food and Drug Administration (FDA) has approved seven new molecular treatments that have shown success against metastatic melanoma. The treatments include targeted therapies that use drugs to destroy or incapacitate molecules that encourage the growth of cancer, and immunotherapy treatments that activate the patient’s own immune system to work against melanoma.

Immunotherapeutic checkpoint inhibitor agents      
Melanoma has complex pathobiology, and is highly immunogenic, which makes the disease particularly  receptive to immunotherapies. Instead of targeting cancer cells directly, immunotherapy activates T cells to recognize and destroy cancer, or enhances the immune system’s response to antigens produced by melanoma cells. 

In the immune system, there are “checkpoint” proteins in T cells that stop those cells from attacking healthy cells. Melanoma can sometimes use immune checkpoint molecules to trick the immune system into identifying cancer cells as normal cells. Drugs called “checkpoint inhibitors” reactivate T cells to attack cancer.

Three monoclonal antibodies that function as checkpoint inhibitors have been approved by the FDA  and are used at Stony Brook for metastatic melanoma.

"Thanks to the ongoing development of scientific breakthroughs and new treatment modalities, patients now have many, many options which were not present in the past.”
-Andrzej Kudelka, MD
Medical Oncologist, Stony Brook University Cancer Center

• Ipilimumab (Yervoy®) binds to and deactivates the CTLA-4 molecule that stops T cells from attacking melanoma cells. It shrinks metastatic melanoma tumors in approximately 10 to 15 percent of patients and may increase long-term survival by as much as 20 percent (approved March 2011).
• Pembrolizumab (Keytruda®) blocks the checkpoint action of PD-1 and activates the immune system to attack tumors. Approximately 20 to 40 percent of patients experience a shrinkage of their melanoma (approved September 2014).
• Nivolumab (Opdivo®) is the second anti-PD-1 antibody approved by the FDA for advanced melanoma. Approximately 20 to 40 percent of patients receiving nivolumab experience tumor shrinkage (approved December 2014).

A fourth new drug, Imlygic™ (T-VEC), isn’t a checkpoint inhibitor but rather the first oncolytic viral therapy in the U.S. It is injected directly into subcutaneous metastasis to shrink the tumor (approved October 2015).  

In 2015, the FDA approved using ipilimumab and nivolumab concurrently for patients with unresectable or metastatic melanoma who also have the BRAF mutation. This combination has shown a response in the range of 40 to 50 percent with significantly prolonged progression-free survival.

Genetic mutations in melanoma
The majority of melanoma malignancies have mutations in their genome. Several known pathways such as BRAF and MEK have mutated genes that help melanoma grow and spread. In fact, about 50 percent of cutaneous melanomas have a mutation in the BRAF oncogene.

Drugs targeted to specific mutations include two BRAF inhibitors and one MEK inhibitor:
• Vemurafenib (Zelboraf®) and Dabrafenib (Tafinlar®) are small molecules that bind the ATP-binding site of the tyrosine kinase BRAF. Tumors in roughly 40 percent of patients shrank by half in just a few weeks (approved August 2011 and August 2013 respectively).
• Trametinib (Mekinist®) targets the MEK protein, which is downstream from BRAF and encourages cancer growth and survival. Tumor shrinkage was seen in 10 percent of patients (approved 2013).  

To more effectively target both the BRAF and MEK pathways, FDA approval was given in May 2014 for the use in two combination therapies —dabrafenib with trametinib and vemurafenib with cobimetnib. Response rates and overall survival increased slightly versus giving the drugs individually.

Although the initial response to these targeted therapies is greater than that from immunotherapy, eventually the response is lost and the cancer begins to grow again. Research teams continue to search for effective solutions with the goal of eventually providing a cure.

Fo rthe full issue: Cancer Today • Summer 2016