Progress in Melanoma Treatment Development Improves Prognosis for Advanced Disease

For many years, researchers, patients and clinicians saw little progress in the development of new medications for advanced melanoma. But recent, unprecedented advances in drug development have led to the approval of effective new drugs to treat advanced disease. Cleveland Clinic has been a leader in testing the new generation of immunotherapy drugs to treat local and distant metastatic melanoma. Survival rates have improved, reaching 50 percent at three years in recent studies, with the potential to continue to increase.

“We are very excited about what has been accomplished in treating patients with melanoma. The field continues to move forward at a rapid pace in terms of research discoveries and advances in therapy,” says Ahmad Tarhini, MD, PhD, Director of the Melanoma and Skin Cancer Program and Director of the Center for Clinical and Translational Immuno-Oncology Research at Cleveland Clinic Cancer Center.

New adjuvant therapy drugs approved

Melanoma is a clear example of how understanding the molecular basis of the tumor and its interaction with the host (the immune system and tumor microenvironment) can lead to unique advances in the treatment of advanced disease with the potential for similar benefits in the adjuvant setting. Large, clinically annotated tumor banks of primary tumors are being analyzed to better understand the biology of melanoma, predict its behavior and develop new preventative and adjuvant strategies.

Systemic adjuvant therapy may benefit patients with resected melanoma who carry a high postoperative risk of relapse and death. In numerous randomized clinical trials (RCTs), interferon (high-dose and pegylated) has been shown to reduce the risk of relapse in high-risk melanoma patients (stages IIB-IIC, III or IV with a mortality risk of 35-40 percent at five years) and has received regulatory approval.

The monoclonal antibody ipilimumab is approved to treat inoperable metastatic melanoma at doses of 3 mg/kg and 10 mg/kg. An ongoing phase 3 clinical trial is comparing ipilimumab at 3 and 10 mg/kg with high-dose interferon (HDI) in high-risk resected patients. Preliminary findings show that the 10 mg/kg dose is associated with significantly more toxicity and treatment-related deaths compared with the 3 mg/kg dose with no differences in recurrence-free survival (RFS) at a median follow-up of 3.1 years.

Recently, trials testing a variety of therapies, including BRAF/MEK inhibitors for patients with BRAF-mutant melanoma and anti-PD-1 antibodies, have reported significant benefits as adjuvant therapy and have led to regulatory approval of dabrafenib-trametinib and nivolumab. Cleveland Clinic is participating in a trial co-led nationally by Dr. Tarhini comparing HDI or ipilimumab with another anti-PD-1 antibody, pembrolizumab. “The optimal adjuvant treatment approaches must be individualized to each patient based on the patient’s characteristics and preferences and may include immune or targeted therapies,” says Dr. Tarhini.

Neoadjuvant therapy beneficial in advanced melanoma

Neoadjuvant therapy has the potential to significantly improve the clinical outcome of patients with locally/regionally advanced melanoma, particularly with the availability of new targeted and immunotherapeutic agents.

“Neoadjuvant therapy is being tested mainly in patients with stage III bulky disease that is usually treated with surgery but may have a high morbidity rate. It has the potential to shrink the tumor to minimize the surgical intervention and at the same time reduce the risk of tumor relapse,” says Dr. Tarhini.

Neoadjuvant studies led by Dr. Tarhini and others have tested chemotherapy and biochemotherapy with a variety of agents, including temozolomide, interferon, ipilimumab, ipilimumab in combination with interferon, and pembrolizumab in combination with interferon. The findings support continued testing of combination studies. Studies of other neoadjuvant therapies, including molecularly targeted and immunotherapeutic agents and combinations, are in progress.

“The most recent studies testing interferon in combination with ipilimumab or pembrolizumab show that we can achieve a complete pathologic response in about 35 percent of patients. Ultimately, our goal is to eliminate the cancer in the majority of patients and test for biomarker studies that may help us predict which patients may benefit from treatment,” says Dr. Tarhini.

Future studies

Dr. Tarhini is planning an immunotherapy study of checkpoint inhibitors and cytokine therapies. He is also working on biomarkers to predict the likelihood of immunotherapy benefit and toxicity. “This is an active area of research in the quest to make patient care more personalized,” says Dr. Tarhini.