Stivarga (regorafenib)

The anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) monoclonal antibody ramucirumab was the first antiangiogenic agent approved for HER2-negative metastatic gastric adenocarcinomas and remains a standard second-line treatment either alone or in combination with paclitaxel. Other VEGFR-targeting agents, such as the tyrosine kinase inhibitors (TKI) regorafenib and apatinib, have failed to demonstrate any survival benefit in the first-line settings, while providing modest improvements in pretreated patients, even when combined with Immune Checkpoint Inhibitors (ICI)...Although several biomarker candidates have been explored, reliable predictors are still awaited. This review summarizes current evidence and explores the future of antiangiogenic agents in gastric cancers.

Using the multikinase inhibitor regorafenib as a starting scaffold, we generated a focused library of CRL4CRBN-recruiting bifunctional molecules and profiled their degradation activity using quantitative mass spectrometry-based proteomics...Interestingly, subtle modifications in PROTAC architecture redirected degradation selectivity, yielding JHK-02-102-1 as a selective type II CDK5 degrader derived from the same scaffold. Together, these findings establish the first type II inhibitor-derived selective CDK6 degrader and demonstrate that targeted protein degradation can enable functional CDK targeting from type II kinase scaffolds.

Ponatinib emerged as the top-ranked computational candidate (mean: - 10.07 kcal/mol), followed by Regorafenib (- 9.64), Sorafenib (- 9.46), and Entrectinib (- 9.45), while non-oncology drugs including antrafenine, betrixaban, and maraviroc demonstrated novel multi-target binding profiles...MM-GBSA calculations revealed a binding hierarchy concordant with docking scores (R2 = 0.92): Ponatinib-VEGFR2 (ΔGbind = - 42.38 kcal/mol) > Entrectinib-CDK6 (- 38.56) > Ponatinib-EGFR (- 33.24) > Entrectinib-HER2 (- 28.47) > Dacomitinib-HDAC3 (- 24.63 kcal/mol)...As the present study is entirely computational, the identified compounds should be regarded as hypothesis generating leads requiring experimental validation through in vitro kinase and HDAC3 inhibition assays, cell based studies, and target engagement confirmation before any translational conclusions can be drawn. The online version contains supplementary material available at 10.1007/s40203-026-00681-w.

We present a 57-year-old man with KRAS G13D-mutant, liver-dominant metastatic rectal adenocarcinoma and recurrent fluoropyrimidine-associated coronary vasospasm precluding 5-fluorouracil and capecitabine. After multimodal first-line therapy and regorafenib, trifluridine/tipiracil (TAS-102) plus bevacizumab was initiated and integrated with liver-directed treatments for oligoprogressive disease. This combined strategy achieved approximately 16.6 months of disease control, substantially exceeding the median progression-free survival reported in the SUNLIGHT trial, with manageable hematological toxicity and preserved performance status. This case highlights the value of TAS-102 plus bevacizumab combined with focal liver-directed therapy as a feasible long-term strategy for selected patients with oligoprogressive mCRC when fluoropyrimidines cannot be used.

P1/2, N=73, Active, not recruiting, University of Southern California | Trial completion date: Jun 2026 --> Dec 2027

P2, N=0, Withdrawn, University of Miami | N=30 --> 0 | Recruiting --> Withdrawn

Temozolomide (TMZ) is the only approved first-line therapy, but frequent resistance limits its efficacy, highlighting the urgent need for alternative treatments...Using GBO-DST, FDA-approved drug screening identifies regorafenib and lazertinib as effective treatment alternatives. Additionally, lazertinib demonstrated superior efficacy to standard therapies in GBO transplantation mouse model. These findings underscore the potential of GBO-DST as a robust platform for precision oncology in glioblastoma.

P=N/A, N=715, Completed, Tongji Hospital

P1/2, N=36, Completed, Sun Yat-sen University | Trial completion date: Feb 2025 --> Mar 2026 | Trial primary completion date: Feb 2024 --> Mar 2026 | Active, not recruiting --> Completed

P2/3, N=60, Suspended, Centre Leon Berard | Recruiting --> Suspended

P2/3, N=255, Recruiting, Ningbo Newbay Technology Development Co., Ltd | Not yet recruiting --> Recruiting

P3, N=462, Completed, Australasian Gastro-Intestinal Trials Group | Active, not recruiting --> Completed