NRAS wild-type

P2, N=59, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027

Here, we show that combined treatment with a RAS/PI3K/AKT-pathway inhibitor rigosertib (RGS), and/or a MEK1/2 inhibitor trametinib (T), plus aCD40, overcomes the ICB resistance of BRAFwtNRASwt and BRAFwtNRASmut melanoma tumors growing in C57BL/6 mice. scRNA-Seq analyses confirm CD40-associated CD11b+ Bregs across cancer types in patients. Our data demonstrate that addition of RAS/PI3K/AKT and MEK inhibitors to aCD40 resolves the issue of aCD40 induction of CD11b+PD-L1+ Bregs and provides alternative therapeutic options for ICB-resistant BRAFwtNRASwt or BRAFwtNRASmut metastatic melanoma.

P2, N=16, Active, not recruiting, Gruppo Oncologico del Nord-Ovest | Recruiting --> Active, not recruiting

This is the largest national dataset on melanoma NRAS and KIT status published to date. Variations in NRAS/KIT testing by geographic/demographic factors drives initiatives to ensure consistent care. NRAS mutated melanoma had high incidence which emphasises the unmet need to develop therapies and trials for NRAS mutated melanoma. This study increases our understanding of biomarkers NRAS and KIT and provides a foundation for optimising melanoma care, contributing to advancements in precision oncology.

P2, N=20, Active, not recruiting, Melanoma Institute Australia | Recruiting --> Active, not recruiting

P1, N=2, Active, not recruiting, Roswell Park Cancer Institute | Trial primary completion date: Dec 2025 --> Jul 2025

P2, N=53, Not yet recruiting, The First Affiliated Hospital of Fujian Medical University; The First Affiliated Hospital of Fujian Medical University

P1, N=2, Active, not recruiting, Roswell Park Cancer Institute | Suspended --> Active, not recruiting | N=42 --> 2

To substantiate the preclinical findings, the utility of MEKi in combination with the autophagy inhibitor hydroxychloroquine was analyzed in patients with KRASG12R mutated metastatic PDAC...Three patients had impressive disease control: two had stable disease of 11 and 22.7 months, and one achieved a partial response with an 83% decrease in tumor size that lasted for 8.9 months. Overall, this work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of PDAC patients most likely to benefit from tailored therapeutic strategies.

Using advanced 3D melanoma models that incorporate key TME elements and zebrafish xenograft models, this study highlights the potential of Daunorubicin HCl and Pyrvinium Pamoate as novel first-line therapies for NRASmut melanoma, with a noteworthy effect also on MEKi-resistant cells. These findings support drug repurposing strategies and underscore the importance of physiologically relevant preclinical models in identifying effective therapies.

Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors...Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250)...The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC.

P3, N=563, Completed, Merck Sharp & Dohme LLC | Trial primary completion date: Feb 2023 --> Sep 2024