Immunotherapy for Metastatic Melanoma — In the Clinic

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The management of toxicities and re-initiation of these medications should be made on a case by case basis.
The management of toxicities and re-initiation of these medications should be made on a case by case basis.

Staging melanoma requires consideration of multiple factors: thickness, ulceration status, the number of involved lymph nodes, and the presence of metastases.1

Patients with stage II or worse disease are more likely to develop metastases in their lifetime. While the primary treatment for melanoma is surgical excision, patients with metastatic disease require additional therapy; immunotherapy is an innovative class of medications accumulating data for use in this patient-group.

In melanoma, the immune response plays a crucial role via CTLA-4 and PD-1. CTLA-4 is a regulator of the body's activated immune system response to cancer cells and down-regulates T cell activation.2 Ipilimumab is an anti-CTLA-4 monoclonal antibody designed to stimulate the immune system's response to melanoma by bolstering T cell activation.

In a similar mechanism, PD-1 binds to programmed death ligand-1 on activated tumor cells and down-regulates the immune system's response. Nivolumab and pembrolizumab are monoclonal antibodies that target PD-1.

There are clinical studies and US Food and Drug Administration (FDA) indications supporting the use of either of these medication classes alone or in combination to treat patients with melanoma.3-6 Nivolumab is delivered via intravenous infusion and has several dosing regimens depending on whether the cancer is resectable and on concurrent ipilimumab use.7 The FDA-approved dose of pembrolizumab is 200 mg every 3 weeks, though several dosing regimens have been used in clinical trials.8

Clinical trials evaluating nivolumab in patients with melanoma have shown a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with older chemotherapy agents, including dacarbazine, paclitaxel, and carboplatin. When combined with ipilimumab, furthermore, the 3-year PFS and OS rates are even better, though there is an increased risk of systemic toxicities.6,9 The most common toxicities associated with these agents includes dermatitis, endocrinopathies, hepatotoxicity, enterocolitis, and pneumonitis; they appear to result from the same immune-stimulating effects aimed at treating the patient's underlying malignancy.

The drug classes are, furthermore, associated with varying toxicity profiles: the overall incidence and severity of colitis in patients receiving PD-1 agents is, for example, less significant compared with ipilimumab.4,6,9 In contrast, PD-1 agents are associated with more thyroid toxicities than ipilimumab is.

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