Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?

Abstract

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.

Keywords: BRAF/MEK inhibitors; Immune-checkpoint inhibitors; Metastatic melanoma; synergistic effects; Sequential therapy; Triple combination therapy.

Fig. 1

Mechanistic basis of the immunomodulatory effects of MAPKi and their synergy with CPI on the TME (A), as well as their individual and combined clinical response kinetics (B). Observations from preclinical studies reported that during the first 4 weeks MAPKi induce favorable changes within the TME that include a stronger infiltration by CD8 T cells, a reduced number of Treg and MDSC, as well as an enhanced priming capacity of antigen-presenting dendritic cells. The clinical response kinetics of MAPKi are visualized in the shape of Kaplan–Meier curves with early survival advantages of MAPKi becoming less pronounced over time and reaching a plateau at approximately 15%. By contrast, the addition of CPI, that have a slower onset of response, prolongs the initial rapid response induced by MAPKi and thus Kaplan Meier curves are characterized by less steep initial slopes but longer and higher plateauing tales at approximately 40%. However, those proposed kinetics did not entirely translate into the results of clinical trials that showed less pronounced benefits from this triple combination regimen. Abbreviations: IPI = ipilimumab; nivolumab = Nivo; DabTram = dabrafenib + trametinib; MAPKi = mitogen activated pathway kinase inhibitors; Dab = dabrafenib; TME = tumor microenvironment; ECM = extracellular matrix; Treg = regulatory T cells; MDSC = myeloid-derived suppressor cells; M1 Mϕ = M1 macrophages; M2 Mϕ = M2 macrophages; CTL = cytotoxic T lymphocytes; TAM = tumor-associated macrophages; PFS = progression-free survival

Fig. 2

Mechanisms of MAPKi and CPI cross-resistance and potential targets to overcome cross-resistance. Abbreviations: MAPKi = mitogen activated pathway inhibitor(s); TME = tumor microenvironment; DC = dendritic cell; ECM = extracellular matrix; Treg = regulatory T cells; MDSC = myeloid-derived suppressor cells; M1 Mϕ = M1 macrophages; M2 Mϕ = M2 macrophages; CTL = cytotoxic T lymphocytes