Multikinase Inhibition with Tinengotinib in Advanced Solid Tumors: Results from a Multicenter Phase Ib/II Trial

PURPOSE: Tinengotinib, a multikinase inhibitor targeting Aurora kinases A/B, fibroblast growth factor receptors (FGFRs) 1-3, vascular endothelial growth factor receptor-2, and Janus kinases 1-2, was evaluated in this phase Ib/II study to assess safety, pharmacokinetics, efficacy, and genomic correlates of response and resistance in patients with advanced solid tumors. METHODS: Patients with advanced/metastatic solid tumors lacking standard treatment options were enrolled at seven sites in the United States (NCT04742959). Tinengotinib was administered at 12 mg once daily in Arm A and at multiple dose levels/dosing schedules in Arm C. RESULTS: Among 197 patients receiving tinengotinib, treatment-related treatment-emergent adverse events occurred in 160 (81.2%) patients, most commonly hypertension. Hyperphosphatemia and ocular toxicities were uncommon. Clinical benefit was achieved by 33/159 (20.8%) evaluable patients, including 1 complete response, 20 partial responses, and 12 stable diseases ≥6 months. Antitumor activity was most pronounced with 10‑mg and 12‑mg dose levels. The objective response rate was 33.3%, 30.0%, and 13.0% in prostate cancer (n=15), breast cancer (n=20), and cholangiocarcinoma (n=23), respectively. Pharmacokinetic analyses supported the 10‑mg once‑daily regimen. Exploratory genomic analyses identified potential molecular correlations of response, including FGFR2 fusions in cholangiocarcinoma responders. Additional observations in breast cancer, including ROS1 alterations, were exploratory and should be considered hypothesis-generating. Exploratory analyses also suggested associations between EGFR or MLL mutations in cholangiocarcinoma and MYC alterations in prostate cancer with shorter progression-free survival, consistent with emerging evidence linking MYC-driven lineage plasticity to androgen receptor-independent disease biology. Reductions in circulating tumor DNA variant allele frequency further supported pharmacodynamic target engagement. CONCLUSIONS: Tinengotinib demonstrated manageable toxicity with antitumor activity across advanced solid tumors, with infrequent hyperphosphatemia and ocular toxicities. Integrated pharmacokinetic-biomarker analyses support the continued clinical development of tinengotinib and the exploration of biomarker‑informed precision oncology strategies.