LXS196 for Metastatic Uveal Melanoma - finally some progress

Abstract

Metastatic uveal melanoma continues to have a poor prognosis with distinct pathophysiology from cutaneous melanoma and limited effective treatment options. Targeted therapy with darovasertib towards protein kinase C is well tolerated with signals of early efficacy, warranting further exploration and combination strategies.

High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

“…Of interest, darovasertib is currently in clinical trials in mUM patients in combination with crizotinib with early promising results. 50 Crizotinib is used as a MET and ALK kinase inhibitor, but an unbiased activity-based protein kinase profiling strategy showed that FAK act as a direct target of crizotinib. 51 Thus, we asked if the combination of darovasertib and crizotinib is synergistic and related to inhibition of FAK.…”

Immuno-oncology approaches in uveal melanoma: tebentafusp and beyond

“…Combination darovasertib (protein C kinase inhibitor, downstream of GNAQ and GNA-11) and crizotinib (cMET inhibitor) presents a novel synergistic approach that converges on the MAPK pathway. 111 It is hypothesised that hepatocyte growth factor signalling may limit darovasertib activity, but this may be overcome by combination with MET inhibition. The darovasertib crizotinib phase I trial included 35 patients in any line, with an ORR of 31%.…”