Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) were tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study.,Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens.,Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for ≤24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200+IPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200+IPI100).,Primary end points were incidence of grade 3-5 treatment-related adverse events (TRAE) and objective response rate (ORR) per RECIST v1.1 by independent central review.,Per protocol-defined thresholds, grade 3-5 TRAE incidence ≤26% indicated meaningful toxicity reduction and ORR ≥48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumab combinations.,Median follow-up on February 18, 2019, was 16.3 months in PEM200+IPI50 (N = 51) and 16.4 months in PEM200+IPI100 (N = 51).,Grade 3-5 TRAEs occurred in 12 (24%) patients in PEM200+IPI50 and 20 (39%) in PEM200+IPI100.,One patient in PEM200+IPI50 died from treatment-related autoimmune myocarditis.,Immune-mediated AEs or infusion reactions occurred in 21 (42%) patients in PEM200+IPI50 and 28 (55%) in PEM200+IPI100.,ORR was 55% in PEM200+IPI50; 61% in PEM200+IPI100.,Pembrolizumab 200 mg Q3W plus ipilimumab 50 mg Q6W or 100 mg Q12W demonstrated antitumor activity above the predefined threshold; pembrolizumab plus ipilimumab 50 mg Q6W had lower incidence of grade 3-5 TRAEs than the predefined threshold, suggesting a reduction in toxicity.,See related commentary by Jameson-Lee and Luke, p.,5153
Integrins are a large family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions.,Among the 24 integrin isoforms, many have been found to be associated with tumor angiogenesis, tumor cell migration and proliferation, and metastasis.,Integrins, especially αvβ3, αvβ5 and α5β1, participate in mediating tumor angiogenesis by interacting with the vascular endothelial growth factor and angiopoietin-Tie signaling pathways.,Melanoma patients have a poor prognosis when the primary tumor has generated distant metastases, and the melanoma metastatic site is an independent predictor of the survival of these patients.,Different integrins on the melanoma cell surface preferentially direct circulating melanoma cells to different organs and promote the development of metastases at specific organ sites.,For instance, melanoma cells expressing integrin β3 tend to metastasize to the lungs, whereas those expressing integrin β1 preferentially generate lymph node metastases.,Moreover, tumor cell-derived exosomes which contain different integrins may prepare a pre-metastatic niche in specific organs and promote organ-specific metastases.,Because of the important role that integrins play in tumor angiogenesis and metastasis, they have become promising targets for the treatment of advanced cancer.,In this paper, we review the integrin isoforms responsible for angiogenesis and organ-specific metastasis in malignant melanoma and the inhibitors that have been considered for the future treatment of metastatic disease.