darovasertib (IDE196)

P2, N=160, Active, not recruiting, IDEAYA Biosciences | Recruiting --> Active, not recruiting

In 2022, tebentafusp became the first approved systemic therapy to improve overall survival in metastatic UM...As half of the patients are HLA A02:01 negative, alternative strategies are under investigation, including the protein kinase C inhibitor darovasertib in the NADOM neoadjuvant/adjuvant trial and in combination with crizotinib in metastatic UM. DYP688, a first-in-class PMEL17-targeting antibody-drug conjugate that inhibits GNAQ/11 signaling, has shown promise in metastatic UM and other GNAQ/11-mutant melanomas. The landscape of UM treatment is rapidly evolving following the identification of new targets and pathways such as PKC or PRAME. Combination of liver-directed therapies with personalized systemic immunotherapies or targeted agents in the metastatic disease, as well as the early use of systemic therapies in the primary tumor setting will refine treatment strategies in UM and suggest improved outcomes in the near future.

P3, N=520, Recruiting, IDEAYA Biosciences | Initiation date: Oct 2025 --> Jan 2026

P2/3, N=420, Active, not recruiting, IDEAYA Biosciences | Recruiting --> Active, not recruiting

P2/3, N=297, Not yet recruiting, Ideaya Biosciences Inc.

P2, N=160, Recruiting, IDEAYA Biosciences | N=82 --> 160 | Trial completion date: Jan 2029 --> Apr 2030 | Trial primary completion date: Jan 2026 --> Apr 2027

P3, N=520, Recruiting, IDEAYA Biosciences | Not yet recruiting --> Recruiting | Trial completion date: Dec 2027 --> Mar 2031 | Trial primary completion date: May 2027 --> Oct 2030

Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+"RAF-MEK clamp" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes.

This localized approach may provide significant benefit for patients with limited extrahepatic spread. Future research should focus on optimizing these novel strategies-tebentafusp, darovasertib, melphalan, and combination therapies-and on expanding our understanding of UM's molecular drivers to enable the development of more effective, personalized treatments.

P3, N=520, Not yet recruiting, IDEAYA Biosciences

P1/2, N=341, Recruiting, IDEAYA Biosciences | Trial completion date: May 2025 --> Mar 2027 | Trial primary completion date: Oct 2024 --> Dec 2026

Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.