Combining forces: the promise and peril of synergistic immune checkpoint blockade and targeted therapy in metastatic melanoma

Abstract

Both immune checkpoint inhibitors and molecularly targeted agents have dramatically improved clinical outcomes for patients with metastatic melanoma. These two therapeutic approaches harness distinct mechanistic pathways-on the one hand, monoclonal antibodies against the immune checkpoints CTLA-4 and PD-1/PD-L1 stimulate the T cell mediated host immune response, while targeted inhibitors of the proto-oncogenes BRAF and MEK disrupt constitutive kinase activity responsible for tumor growth. The prospect of combining these two treatment modalities has been proposed as a potential way to increase overall response rate, extend durability of the anti-tumor response, and circumvent the immune-mediated resistance to targeted therapy. This review explores the preclinical rationale-building upon a wealth of in vitro and in vivo studies-for improved anti-tumor efficacy from combined immune checkpoint inhibition and targeted therapy. In the process, we detail the early clinical trials that have assessed the compatibility of combining these two therapies and the unexpected challenges faced from studies showing increased toxicity from these regimens. Ultimately, with more clinical data expected to mature and accrue in the near future, we elucidate a potentially novel and promising strategy for patients with advanced melanoma.

Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

“…[43][44][45] Studies have begun to investigate the extent to which combination therapies pose clinical safety and tolerability challenges, and whether these challenges will limit their usefulness as anticancer therapy. [46][47][48][49] The only current FDA-approved regimen using combined ICI therapy is nivolumab plus ipilimumab for treating advanced melanoma, RCC, or microsatelliteunstable tumors. 50,51 Nivolumab plus ipilimumab resulted in enhanced survival outcomes compared with ipilimumab monotherapy in advanced melanoma.…”

Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits

“…Melanoma is one of the most threatening malignancies and has high metastatic potential. Although in the recent years, significant progresses have been made in melanoma treatment with the appearance and widespread application of the combinational immunotherapy [1][2][3][4], it is still necessary to explore other treatment options to get better clinical output because the response rates to immunotherapy are not 100%. This might be mainly due to that the antigens selected for these approaches do not cover the full spectrum of melanoma cells present in a tumor [5,6].…”

Immunotherapy of Melanoma: Facts and Hopes

“…Controversy exists over the impact of adding MAPK pathway inhibitors to ICIs. While several preclinical studies initially reported that MAPK inhibitors can positively modulate the immune microenvironment (114), more recent data have demonstrated that PD-1-resistant melanomas have a transcriptional signature consistent with innate anti-PD-1 resistance (IPRES), defined as having upregulation of genes modulating mesenchymal transition, cell adhesion, angiogenesis, and extracellular matrix remodeling. This IPRES signature is very similar to that induced by combined BRAF/MEK or BRAF inhibition, suggesting that these drugs may mediate resistance to anti-PD-1 (81).…”