Mekinist (trametinib)

P2, N=16, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Dec 2025 --> Dec 2026

Using electrophilic probes, we show that treatment of BRAFV600E mutant melanoma cells with vemurafenib or trametinib decreases overall cysteine and lysine reactivity in BRAFV600E and MEK1/2, likely reflecting composite changes in amino acid accessibility across multiple reactive residues associated with inhibitor binding...Comparative analysis of ATP-competitive BRAFV600E inhibitors vemurafenib and dabrafenib indicated differences in aspartate and glutamate labeling patterns, consistent with the possibility that ABPP may detect inhibitor-associated variations in residue accessibility, which could reflect differences in inhibitor-bound conformations...Moreover, global proteome analyses of cysteine and lysine reactivity upon BRAFV600E inhibition revealed probe-accessible cysteine labeling changes on KSR2, suggesting a potential MAPK pathway remodeling. Together, these findings highlight ABPP as a valuable chemical biology approach for investigating inhibitor-dependent changes in kinase residue reactivity, offering a framework to investigate how kinase conformational dynamics and signaling pathway adaptation influence the therapeutic response and resistance in cancer.

Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

Map2k4 mutant cells were particularly sensitive to paclitaxel, and Rho kinase inhibitor (ROCKi) increased trametinib sensitivity in both Map2k4- and Nf1-mutant organoids. This organoid mutagenesis strategy is powerful for unraveling the genetic and phenotypic complexity of HGSC, and identified Map2k4 as a potential therapeutic target in select HGSC cases.

P1/2, N=74, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2026 --> Jul 2026 | Trial primary completion date: Nov 2026 --> Jul 2026

P2, N=20, Terminated, Cancer Trials Ireland | Trial completion date: Jun 2026 --> Mar 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2025 --> Mar 2026; Study terminated due to futility

P1, N=50, Suspended, University of California, San Francisco | Recruiting --> Suspended

In the absence of head-to-head trials comparing 1L nivolumab plus relatlimab (NIVO+RELA) to BRAF/MEK inhibitors, we compared its efficacy to dabrafenib+trametinib (DAB+TRAM), encorafenib+binimetinib (ENCO+BINI), vemurafenib+cobimetinib (VEM+COBI) and atezolizumab (ATEZO)+VEM+COBI using matching-adjusted indirect comparisons (MAICs)...These MAICs suggest that 1L dual IO therapy with NIVO+RELA confers a long-term OS advantage in BRAF-mutant advanced melanoma compared with BRAF/MEK inhibitor combinations despite lower ORR, consistent with prior evidence for 1L NIVO+IPI in this setting. As unanchored analyses, potential residual confounding remains, and results should be interpreted cautiously.

The patient had an excellent clinical and radiological response to targeted therapy with the MEK inhibitor, trametinib. This case underscores the critical importance of molecular biology, beyond the BRAF mutation, in the differential diagnosis of complex fibro-inflammatory lesions. The coexistence of diagnostic criteria for both entities in the same patient suggests that the presence of IgG4 cellularity in ECD should be represent a true pathogenic overlap, where the neoplastic clone triggers a secondary immune response, rather than a mere reactive epiphenomenon.

P1, N=6, Recruiting, City of Hope Medical Center | Trial completion date: Feb 2026 --> Oct 2027 | Trial primary completion date: Feb 2026 --> Oct 2027

P1, N=91, Terminated, Deciphera Pharmaceuticals, LLC | Phase classification: P1/2 --> P1 | N=144 --> 91 | Trial completion date: Aug 2028 --> Mar 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2027 --> Mar 2026; Trial terminated due to business decision, not based on any safety or efficacy concerns.