The Status of Adjuvant and Neoadjuvant Melanoma Therapy, New Developments and Upcoming Challenges

Abstract

The global incidence of malignant melanoma, the leading cause of skin cancer death, has steadily increased in recent years. Surgical excision is the treatment of choice for early-stage melanoma. However, 40-60% of patients with high-risk melanoma or with nodal involvement eventually experience loco-regional relapse or tumor progression. Adjuvant therapy aims to reduce the rate of recurrence in radically operated high-risk patients with melanoma and thus improves survival. Interferon-α has long been the only approved drug for adjuvant melanoma therapy, despite an unclear survival benefit. The landmark success of immune-checkpoint inhibitors and BRAF/MEK-directed targeted therapies in the treatment of patients with stage IV melanoma led to the initiation of clinical trials in the adjuvant setting. These trials demonstrated the efficacy of immune-checkpoint inhibitors and targeted therapies for the adjuvant treatment of high-risk patients with melanoma, as shown both by an increase in recurrence-free survival and the emergence of long-term survivors, finally resulting in the approval of the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab, PD1 inhibitors (nivolumab, pembrolizumab), and BRAF/MEK inhibitors for adjuvant melanoma therapy. This review aims to delineate the advances in adjuvant melanoma therapy, issuing particularly recent results from clinical trials. Moreover, we also discuss pending issues and future challenges, which comprise the adequate selection of adjuvant regimens for patient subgroups and the identification of markers likely to predict the individual response to adjuvant treatments. Last, we outline the role of emerging neoadjuvant approaches, which may complement adjuvant strategies and are currently investigated in clinical trials.

Fig. 1

Schematic overview of the concept of adjuvant melanoma therapy and its underlying mechanisms of action. Following the initial excision of the primary tumor and if necessary existing lymph node metastasis (A), the adjuvant application of either immune-checkpoint inhibitors or BRAF/MEK-directed targeted therapy can be considered for patients with stage IIC–IIID melanoma (B). Immune-checkpoint inhibitors reinforce the anti-tumor immune response to melanoma cells both in peripheral lymph nodes and the tumor microenvironment (left panel, B). Here, the anti- cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody ipilimumab mainly affects the priming and activation of T cells in lymph nodes (top center). By contrast, anti- programmed cell death protein 1 (PD-1) antibodies mainly serve to restore effector cell function of T cells within the tumor microenvironment via blockade of the T-cell bound checkpoint molecule PD-1 on effector T cells (bottom center). Targeted therapy confers anti-tumor activity via the blockade of the RAF-MEK-ERK-signaling cascade, thus disrupting melanoma cell proliferation and differentiation (right panel, B). Notably, both targeted therapy and immune-checkpoint inhibitor therapy target residual melanoma cells and micrometastases, which have not been cleared by initial excision, thus reducing the risk of melanoma progression in adjuvant therapy. APC antigen-presenting cells, CTL , DC dendritic cell, MDSC , MHC II major histocompatibility complex II, PD-L1 programmed death-ligand 1, TAM , Treg regulatory T cell

Fig. 2

Immunomodulatory effects of BRAF/MEK inhibitors in the context of melanoma therapy. Next to the direct antiproliferative effects conferred by targeted therapy, it has been found that these might further exert immunomodulatory properties within the tumor microenvironment. In particular, BRAF inhibition resulted in a stronger expression of tumor antigens, thus favoring the immunological recognition of melanoma cells. Furthermore, BRAF inhibitors were initially shown to reduce programmed death-ligand 1 (PD-L1) expression on melanoma cells. More importantly, BRAF inhibition may result in a paradoxical activation of effector T cells thus enhancing anti-melanoma immune response. Last, BRAF-MEK inhibitors were found to reduce the secretion of cytokines such as interleukin (IL)-1, IL-6, or IL-10, which impairs the infiltration of immunosuppressive tumor-associated macrophages and myeloid derived suppressor cells. Overall, BRAF/MEK inhibitors may therefore tip the scale towards an inflamed tumor microenvironment favoring an anti-melanoma immune response. CAF, HLA human leukocyte antigen, MDSC, MMP, TAM, TCR, Teff, TIL, TGF-β transforming growth factor-β, VEGF vascular endothelial growth factor