NRAS wild-type

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

While clinical benefit was observed with the combination, it did not meet its pre-specified endpoint for efficacy in patients with KRAS/NRAS/BRAF WT EGFR therapy-naïve mCRC patients. Clinicaltrials.gov Identifier: NCT03446157.

P1/2, N=48, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed

The farnesyltransferase inhibitor tipifarnib blocked mutant HRAS-PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cells, whereas KRASG12C inhibitors blocked mutant KRAS-MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cells. Synergy was abolished in MEFs lacking all RAS proteins and in cancer cell lines in which nonmutated RAS family members were deleted. Our data highlight the critical role of wild-type RAS family members in supporting mutant RAS signaling and its importance as a therapeutic cotarget in RAS-mutated cancers.

Hepatectomy, with or without RFA, is associated with significantly improved survival in selected patients with ≥10 liver metastases. Further prospective studies are needed to confirm these findings.