Neoadjuvant Immunotherapy for Locally Advanced Melanoma

Abstract

Patients with clinical stage III melanoma, defined as palpable lymph nodes with or without in-transit metastases, have poor prognosis even with recent advances with targeted and checkpoint inhibitor therapy in the adjuvant setting. Neoadjuvant therapy for clinical stage III melanoma is an attractive treatment paradigm as patient outcomes may be improved by earlier introduction to systemic therapy. Additionally, preoperative therapy that shrinks disease has the potential to improve surgical morbidity. Neoadjuvant therapy also provides for pathologic response assessment which can serve as a way to stratify patient outcomes and subsequent disease relapse risk. Early trials of neoadjuvant immunotherapy are yielding promising results, with high rates of pathologic complete response (pCR) and improved relapse-free survival rates. Ipilimumab, nivolumab with or without ipilimumab, and pembrolizumab have been investigated in the neoadjuvant setting. A meta-analysis has shown a 1-year relapse-free survival rate of over 80% with neoadjuvant immunotherapy. Importantly, pooled data also shows that pCR strongly correlates with outcomes. Early phase trials have also highlighted the importance of dosing of neoadjuvant therapy to appropriately balance response and immune related toxicities, which can be severe. The combination of ipilimumab 1 mg/kg and nivolumab 3 mg/kg has been identified as an optimal regimen for further study. Translational studies have highlighted the ability of neoadjuvant immunotherapy to expand tumor-specific T cells in both the tumor microenvironment and peripheral blood. At this time, surgical resection and adjuvant therapy remains standard of care for clinical stage III melanoma; however, appropriate patients should be considered for ongoing neoadjuvant clinical trials.

Keywords: Checkpoint inhibitors; Immunotherapy; Melanoma; Neoadjuvant; Pathologic response; Stage III.