cabozantinib

Overview

Cabozantinib is a small-molecule multi-kinase inhibitor targeting MET, VEGFR2, AXL, RET, and related receptor tyrosine kinases. It is FDA-approved for hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. In the UCLA sarcoma PDTO screen, it showed significant differential sensitivity in osteosarcoma and was identified as an NCCN-listed option for osteosarcoma.

Evidence in the corpus

  • In the UCLA sarcoma PDTO biobank (sarcoma_ucla_2024, n=194 specimens), osteosarcoma PDTOs were significantly more sensitive than the pan-sarcoma average to cabozantinib (p=0.024). PMID:39305899
  • Cabozantinib was among NCCN-listed top-five regimens recurrently identified for osteosarcoma in the PDTO functional screen, alongside etoposide, cisplatin, sorafenib, regorafenib, doxorubicin, gemcitabine, docetaxel, and everolimus. PMID:39305899
  • Sarcoma specimens with prior systemic therapy were more sensitive to cabozantinib than treatment-naïve specimens (p=0.036), alongside lenvatinib, cediranib, and everolimus — suggesting post-treatment selection for drug-sensitive clones or upregulation of target pathways. PMID:39305899
  • Nivolumab+cabozantinib data were not available in the HiTME training cohorts; this was cited as an open limitation in the ccRCC IO/TKI decision-tree model PMID:22138691
  • Activating RET mutation in metastatic MTC patient PN8 guided cabozantinib selection; PN8 achieved a partial response lasting 164 days in the POG NEN WGTA cohort PMID:24326773
  • Listed among candidate targeted therapies for advanced HCC in a 2014 review of HCC genomics that maps driver alterations (MET, FGF axis, VEGFA, mTOR) to ongoing clinical trials PMID:24735922
  • Phase III CELESTIAL trial: cabozantinib vs placebo in HCC, median OS 10.2 vs 8.0 months (HR 0.76, 95% CI 0.63–0.92, P=0.0049); approved as second-line for HCC regardless of prior-line count (≤2) PMID:24798001
  • Cited as a multi-kinase TKI (VEGFR2, MET, AXL) under investigation in R/M NPC for anti-angiogenic and anti-metastatic activity PMID:24952746
  • Cited as matched agent for RET fusions (level 2A) in 860-patient MSK-IMPACT LUAD cohort; 53.3% of RET-fusion patients received matched therapy with 72.7% clinical benefit PMID:28336552.

Resistance mechanisms

  • Not specifically characterized in the sarcoma corpus.

Cancer types (linked)

  • OS — osteosarcoma; significantly more sensitive than pan-sarcoma average; NCCN-listed indication in the functional screen context.

Sources

  • PMID:39305899 — Al Shihabi et al. (Cell Stem Cell 2024). UCLA sarcoma PDTO biobank; osteosarcoma differential sensitivity to cabozantinib; prior-therapy enrichment of sensitivity.

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