darovasertib (IDE196)

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.

We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196...We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).

P2, N=15, Active, not recruiting, Anthony Joshua, FRACP | Recruiting --> Active, not recruiting | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

P2/3, N=380, Recruiting, IDEAYA Biosciences | Not yet recruiting --> Recruiting