Mekinist (trametinib)

P1/2, N=40, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

Reduced-dose dabrafenib and trametinib were initiated with prophylactic naproxen to mitigate the risk of pyrexia. Treatment has been continued for over 6 months with sustained disease stability. This case suggests that an upfront dose-attenuation strategy combined with proactive toxicity management, including pyrexia prophylaxis, may represent a practical approach to maintain treatment continuity and clinical benefit in selected very elderly or frail patients.

Resistance to RET inhibitors can be acquired through RET copy-number gain and secondary mutations as well as NF1 loss-mediated MAPK pathway activation. This mechanism of resistance can be overcome with dual inhibition of RET and downstream RAS/MAPK signaling, demonstrating clinical potential in RET-mutant MTC.

PTPA promotes oncogene-induced senescence (OIS) in MPM. By preventing OIS, heterozygous PTPA loss may contribute to mesothelial transformation and carboplatin resistance.

Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitization to trametinib in resistant lines. These findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.

A lead mAb (mAb7) sensitized tumors to the US Food and Drug Administration-approved MAPK kinase inhibitor trametinib and the KRASG12C inhibitor adagrasib. Moreover, a murinized antibody (Ms-mAb7) improved antitumor immunity in a KrasG12D syngeneic tumor model by enhancing infiltration and activation of cytotoxic immune cells. These findings provide an important advance in the clinical development of PCDH7-targeting antibodies for lung cancer treatment.

The synergistic effects of the MEK inhibitor trametinib combined with the mTOR inhibitor AZD8055 or the pan-CDK inhibitor flavopiridol were evaluated in PDOs and validated in matched PDXs. We also validated PDOs in predicting clinical gemcitabine/paclitaxel (Gem/PTX) responses...The trametinib/AZD8055 combination is a promising precision therapeutic strategy, and PDOs can serve as a reliable tool to guide clinical therapy selection. Despite limitations such as small sample size, lack of tumor microenvironment and immune components in the model system, this work provides important preclinical evidence for the clinical translation of PDOs in the personalized therapy of PDAC.

In contrast, degradation-governed release from PSiNPs sustained the availability of belzutifan and trametinib in aqueous physiological medium for more than 10 days supporting prolonged intracellular drug exposure when combined with the established cellular internalization of this carrier system. Sustained dual inhibition enhanced cytotoxicity and promoted immunogenic remodeling in MCPyV-negative Merkel cell carcinoma models, including increased calreticulin exposure and reduced PD-L1 expression. These findings identify release synchronization as a critical biomaterial design parameter for combination cancer therapy.

P2, N=216, Completed, Melanoma Institute Australia | Trial completion date: Dec 2025 --> Mar 2026

We systematically evaluated the biochemical, biological, and therapeutic activity of single, dual, and triple regimens combining the KRASG12D inhibitor MRTX1133 with cetuximab (EGFR inhibitor), alpelisib (PI3Kα inhibitor), or trametinib (MEK inhibitor) in a panel of patient-derived tumoroids and xenografts (PDXs) from metastatic CRC. Collectively, our results identify dual KRASG12D - EGFR inhibition as the regimen delivering maximal pathway suppression and therapeutic benefit in clinically relevant CRC models, with no clear advantage from more complex triple combinations. This work encourages prioritizing KRAS-EGFR co-targeting over multi-agent strategies that risk added toxicity, and provides a strong rationale for advancing KRASG12D inhibitors + cetuximab as a backbone targeted therapy in future clinical trials for KRASG12D-mutant CRC.

P3, N=267, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2026 --> Dec 2026

P1/2, N=1000, Recruiting, Oslo University Hospital HF | N=6000 --> 1000