Cross-resistance between targeted agents and immune checkpoint inhibitors is also an emerging concern. According to Dr Amaral, targeted therapy “can induce non-genomic alterations and tumor alterations, which might represent a possible mechanism of cross-resistance to immunotherapy with anti-PD-1/PD-L1.10
“At this point there is very little information on the topic, but probably there is indeed a better sequence for targeted and immunotherapy. We need to understand how the different therapies change the tumor environment and the extra-cellular compartment/matrix, as this might implicate further therapies outcomes.”
Some patients will likely benefit from immune checkpoint blockade monotherapy, in part because of lower toxicity levels. But biomarkers or reliable selection criteria for monotherapy and those likely to suffer toxicities from combination therapy still need to be identified and validated.
Combined CTLA-4 and PD-1 checkpoint inhibition with ipilimumab plus nivolumab is the only US Food and Drug Administration (FDA)-approved immunotherapy combination for patients with metastatic melanoma. Other investigational combinations include talimogene laherparepvec (T-VEC) plus nivolumab, T-VEC plus pembrolizumab, and indoximod combined with ipilimumab, nivolumab, or pembrolizumab.
For patients with brain metastases or mucosal or uveal melanoma, participation in multicenter clinical studies is crucially important. Immunotherapy has proven less effective against mucosal or uveal tumors than cutaneous melanoma, and treatment options for these patients remain limited, Dr Amaral noted.
The optimal durations of immunotherapy are not yet known.
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- Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol. 2017;43:604-11. doi: 10.1016/j.ejso.2016.07.145
- Amaral T, Sinnberg T, Meier F, et al. The mitogen-activated protein kinase pathway in melanoma part I – Activation and primary resistance mechanisms to BRAF inhibition. Eur J Cancer. 2017;73:85-92. doi: 10.1016/j.ejca.2016.12.010
- Amaral T, Sinnberg T, Meier F, et al. MAPK pathway in melanoma part II-secondary and adaptive resistance mechanisms to BRAF inhibition. Eur J Cancer. 2017;73:93-101. doi: 10.1016/j.ejca.2016.12.012
- Long GV, Eroglu Z, Infante JR, et al. Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600–mutant unresectable or metastatic melanoma (MM). J Clin Oncol. 2017;35(1suppl; abstr 9505).
- NCCN clinical practice guidelines in oncology: Melanoma, version 1.2017. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Updated November 10, 2016. Accessed September 2017.
- Hugo W, Shi H, Sun L, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162(6):1271-85. doi: 10.1016/j.cell.2015.07.061