Systemic Therapy in Metastatic Melanoma

Future Directions

Angiogenesis promoters, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, fibroblast growth factor, and interleukin-8, are overexpressed in melanoma. Bevacizumab, an anti-VEGF antibody, has been shown to have some benefit in combination with carboplatin and paclitaxel as a triple therapy. ⁶⁷ However, grade 3 AEs were seen in a portion of patients.

The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has also been studied as a target for melanoma therapy. Everolimus, an mTOR inhibitor, was studied in a phase 2 trial in combination with bevacizumab for treatment of metastatic melanoma. The combination showed improved median PFS and OS with the combination (4 months and 8.6 months, respectively), with 43% of patients alive after 12 months of follow-up. ⁶⁸ This study points to the direction of possible benefits with the combination of anti-VEGF and immunotherapy. A recent study failed to show survival advantage with combination of bevacizumab and temozolomide. ⁶⁹

Buparlisib (BKM120), a PI3K inhibitor, has been shown to have activity in vivo and in vitro against melanoma brain metastases. ⁷⁰ More studies need to be done to assess the possible combination with other established therapies.

Oblimersen is an antisense oligonucleotide that suppresses B-cell lymphoma-2, thereby suppressing its anti-apoptotic effect. The triple combination of oblimersen with temozolomide and albumin-bound paclitaxel has shown to be safe and efficacious in a phase 1 trial, thereby creating a need for further clinical trials. ⁷¹

Treatment Approach

Systemic therapy for metastatic melanoma depends on several factors, including BRAF mutation status, functional status of the patient, disease burden, and severity of symptoms. Assessing the BRAF mutation status has become an important component in the management of patients with metastatic melanoma. It can help recognize patients who will benefit from molecular targeted therapy. In case of a BRAF-positive melanoma, treatment can be initiated with either immunotherapy or BRAF inhibitors. There are no randomized studies comparing immunotherapy to molecular targeted therapy.

Patients who have good PS and lymph node metastases can be treated initially with IL-2, which has the advantage of inducing cure in a minority of patients but should only be considered in patients with well-preserved organ function who can be monitored in an intensive care setting. On the other hand, patients who have bulky, symptomatic disease and poor PS should be treated initially with BRAF inhibitors. Combination of BRAF and MEK inhibitors can also be used and has an improved PFS and OS with potential to cause early tumor regression. There are studies to suggest suboptimal outcomes in patients who are treated with ipilimumab after progression on a BRAF inhibitor compared with initial treatment with ipilimumab followed by a BRAF inhibitor. ^72-74 However, all these studies are retrospective and there is no prospective data to suggest the above. BRAF mutation-positive patients who progress on a BRAF inhibitor
can be treated with PD-1 inhibitors.

Patients who do not have a BRAF mutation are unlikely to benefit from a BRAF inhibitor and primarily receive immunotherapy with ipilimumab or IL-2. Whenever possible, such patients should be enrolled in a clinical trial, as they have a poor prognosis. Patients who progress on ipilimumab can be treated with one of the PD-1 inhibitors (pembrolizumab, nivolumab). These PD-L1 inhibitors are still being investigated for use in such situations.