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Strategies to Improve Treatment

The progress that has been made in the treatment of melanoma has resulted from improved development of treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of melanoma will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of melanoma.

PD-1 Inhibitors Investigational immunotherapy drugs known as anti-PD-1 drugs have produced very promising response rates in early-phase clinical trials. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. These drugs include Keytruda® (pembrolizumab) and nivolumab.

Nivolumab like other PD-1 drugs enhance the ability of the immune system to fight cancer. A randomized Phase III clinical trial called CheckMate -066 evauated nivolumab as initial, or first line, therapy for patients with advanced melanoma without a mutation in the BRAF gene. Analyses revealed evidence of superior overall survival in patients receiving nivolumab compared with those who received the chemotherapy dacarbazine and the the study was halted early to allow the dacarbazine patients to switch nivolumab.

At one year, almost 73% of patients in the nivolumab group were alive, compared with 42% in the dacarbazine group, and Median progression-free survival more than doubled among patients receiving nivolumab: just over five months compared with just over two months for dacarbazine.

Keytruda® (pembrolizumab) is a targeted immunotherapy and the first anti-PD-1 drug, aimed at re-energizing a patient’s protective immune response to cancer to have received FDA approval in the U.S for the treatment of cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1, such as Keytruda®, may enhance the ability of the immune system to fight cancer. Data from an ongoing trial evaluating Keytruda® has demonstrated promising survival rates among patients with advanced melanoma. Among 365 patients with measureable disease 28% of those who had previously received Yervoy® and 40% of those who had not received Yervoy® had a promising response to treatment.

New Treatment Regimens: Development of new multi-drug treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research carried out in phase II clinical trials. Combining newer targeted and immunotherapy with chemotherapy and existing biologic agents is the focus of intensive investigation, with many clinical trials ongoing.

Yervoy + GM-CSF Patients with metastatic melanoma treated with the combination of Yervoy® (ipilimumab) and GM-CSF (granulocyte-macrophage colony-stimulating factor), 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.

Yervoy®, an immune checkpoint blocker is a monoclonal antibody that targets a protein receptor, CTLA-4 that prevents the body’s defenses from attacking cancer cells. By blocking CTLA-4 Yervoy® releases the brake, allowing cell-killing T cells to assault the cancer cells. GM-CSF is a protein that spurs the growth of white blood cells in the immune system. Larger trials and longer follow-up are necessary to confirm these results.

New Targeted Therapy Drugs: Unlike conventional chemotherapy drugs that attack both normal and cancerous cells, targeted therapies are designed to block specific substances or pathways in cancer cells that enable cancer to grow. A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Several targeted therapies have been approved for the management of malignant melanoma and doctors are working to determine the best way to use them.

Zelboraf® (vemurafenib) and Tafinlar® (dabrafenib) belong to a new class of drugs known as BRAF inhibitors. It turns off a genetic mutation called BRAF V600, found in about half of patients with advanced melanoma

Mekinist® (trametinib) is a BRAF inhibitor that targets the BRAF mutation in a different way than Zelboraf or Tafinlar®.

As promising as all of the new, targeted therapies are they typically stop working at some point because melanoma cells find another pathway that lets them start growing again. In many cancers, combination therapy improves survival and leads to cures when compared to single agent treatment. Researchers are now testing combinations of two or more targeted therapies.

Tafinlar® plus Mekinist® The COMBI-v clinical trial compared the combination of the BRAF inhibitor Tafinlar® plus the MEK inhibitor Mekinist® with Zelboraf® alone in 704 patients with the BRAF V600mutation. Overall response rates, duration of response and overall survival were improved with combination therapy. The median overall survival was 17.2 months with Zelboraf alone and had not been reached in the Tafinlar®/ Mekinist® treated patients.

Vaccines: No vaccine has been approved for the treatment of metastatic disease or for the prevention of a relapse, however several are being developed. Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent. Adjuvant therapy (treatment following therapy to prevent recurrences), vaccines have shown potential benefit in phase II trials but this benefit has been limited to the minority of patients who generate a measurable immune response following vaccination. There have been some reports of dramatic responses of metastatic melanoma to a variety of vaccines. However, no standard vaccine for recurrent melanoma is available.

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.

Phase I Trials: New anti-cancer drugs continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients with advanced melanoma.

Targeted Therapy
Immunotherapy
Combination Therapy
Chemotherapy
Role of Surgery
Role of Radiation
Treatment of Brain Metastases
Strategies to Improve Treatment
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