Stivarga (regorafenib)

P2/3, N=437, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting | Initiation date: Jul 2026 --> Nov 2025

PRG4 demonstrated antitumor activities in vivo and shows promise as an adjuvant to enhance therapeutic interventions in HCC.

Clinically, higher DDR2 associated with inferior overall survival in The Cancer Genome Atlas papillary cohort (KIRP), with no consistent association in the clear cell cohort (KIRC). Across in vitro, in vivo, and in silico analyses, DDR2-high papillary contexts exhibit preferential regorafenib sensitivity, nominating DDR2-enriched papillary RCC for biomarker-guided repurposing and motivating protein-level and genetic validation.

Type IV hypersensitivity reaction-related polymorphisms were associated with regorafenib-induced EM.

SDH deficient GIST is a unique subtype of gastrointestinal stromal tumor with distinct clinic-pathological features, diagnostic modalities, therapeutic strategies, and genetic implications as compared to C-kit/PDGFR-alpha mutated GIST.

P3, N=377, Active, not recruiting, Institut du Cancer de Montpellier - Val d'Aurelle | Trial completion date: Sep 2025 --> Sep 2026

Second- and third-line TKIs, such as sunitinib and regorafenib, provide limited benefits, highlighting the urgent need to address resistance mechanisms. These findings uncover a TGF-β1/CCN2/Rack1/PGK1 mechanism linking CAF-mediated metabolic reprogramming to imatinib resistance in GISTs. Targeting CAF-GIST interactions and key metabolic pathways presents a promising therapeutic strategy.

Meta-regression suggested MGMT methylation was associated with improved OS, PFS, DCR, and SD, while male sex was associated with better OS and SD. Overall, regorafenib demonstrated a predictable safety profile in recurrent glioblastoma, with outcomes potentially improved in male patients with MGMT-methylated tumors.

P1, N=20, Suspended, City of Hope Medical Center | Recruiting --> Suspended

Importantly, combining Regorafenib with ferroptosis inducers showed synergistic effect of blocking tumor growth in vivo. This study highlights the potential of Regorafenib as an agent that modulates NOX4 expression, offering new insights into the treatment of AML.

It also maintains telomere activity via mitochondrial S1P, which promotes tumor survival and facilitates resistance to regorafenib. In targeted therapy, SphK1 inhibitors (e.g., PF-543) and SphK2 inhibitors (e.g., ABC294640) have shown significant anti-tumor effects in preclinical models...This paper systematically summarizes the mechanisms of action and therapeutic progress of SphK1/SphK2 in HCC. It provides an important theoretical basis for the clinical translation of precision therapy strategies in HCC.

Genetic knockout of FAK or pharmacological inhibition using defactinib or PF-573228 effectively suppressed the sorafenib-induced upregulation of AKT and HMGCR...Importantly, another RAF-targeting multikinase inhibitor, regorafenib, also triggered a similar adaptive FAK-cholesterol response, suggesting that this may be a common resistance mechanism shared among RAF inhibitors...Collectively, this study systematically uncovers a new mechanism of sorafenib resistance in HCC: downregulation of RhoE drives cholesterol biosynthesis through activation of the FAK/AKT axis, thereby activating the SHH pathway and upregulating GLI1. These findings provide a strong theoretical rationale for the use of FAK inhibitors to overcome resistance and highlight the dual clinical relevance of the cholesterol biosynthesis gene signature-both as a molecular marker for predicting resistance and as a potential guide for personalized treatment strategies in HCC.