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6 recordsLinked to original sources
PubMed2026

Cabozantinib for advanced grade 3 neuroendocrine tumors: subgroup analysis of the phase 3 CABINET trial (Alliance A021602).

Well-differentiated grade 3 neuroendocrine tumors (NETs) have recently been described as a distinct category, and randomized data regarding efficacy of therapy for these patients are scarce. In the phase 3 CABINET trial, cabozantinib improved PFS compared with placebo in patients with advanced, previously treated, progressive extra-pancreatic NETs (epNETs) and pancreatic NETs (pNETs) of all grades. Here, we evaluate if these results remain consistent in a subgroup of patients with well-differentiated G3 NETs. Patients with locally advanced or metastatic epNETs or pNETs were randomized 2:1 in independent cohorts to receive cabozantinib 60 mg daily vs placebo. We analyzed outcomes of the subset of patients with G3 NETs (Ki-67 > 20%), combining patients in the pNET and epNET cohorts due to small sample sizes. Twenty-four patients had G3 NETs, 16 randomized to cabozantinib and 8 to placebo. Primary sites included pancreas (n = 12), GI tract (n = 7), unknown primary sites (n = 3), and lung/thymus (n = 2). Median PFS for patients with G3 NETs treated with cabozantinib was 7.9 vs 3 months with placebo (HR = 0.15, 95% CI: 0.04-0.57, 1-sided log-rank P = 0.0034). The confirmed overall radiographic response rate was 25% (4/16) with cabozantinib vs 0% (0/8) with placebo. Safety outcomes were consistent with published data for the trial as a whole. Subset analysis of the CABINET trial showed improved PFS associated with cabozantinib vs placebo for G3 NETs of pancreatic and extra-pancreatic origin. Despite limited numbers, these results suggest that cabozantinib can be an effective option for patients with advanced G3 NETs. ClinicalTrials.gov Identifier: NCT03375320.

Humans↗
PubMed2026

Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Renal Cell Carcinoma With Bone Metastases: RADICAL (Alliance A031801).

PURPOSE: Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS: This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS: The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% (P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION: Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Humans↗
PubMed2026

A phase II study to evaluate the efficacy of commercially available molecularly matched targeted therapies in the second-line setting.

BACKGROUND: Initial studies have shown improved outcomes in patients receiving cancer therapies matched to their molecular alterations. To improve the chances of finding a therapeutic match for patients, this study evaluated the preliminary antitumor activity of 3 commercially available multitargeted agents in the United States, regorafenib, afatinib, and cabozantinib. METHODS: In this phase II trial, patients who did not benefit from first-line treatment for non-small cell lung cancer (NSCLC), upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma underwent next-generation sequencing to identify actionable genomic alterations. Eligible patients, based on identified mutations deemed treatable by regorafenib, cabozantinib, or afatinib, were enrolled to receive matched targeted therapies. Outcomes were monitored via Response Evaluation Criteria in Solid Tumors criteria, with dose modifications per National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03 guidelines for adverse events (AEs). RESULTS: One hundred patients with metastatic cancers were enrolled across tumor types. Median treatment durations were 12 weeks (regorafenib), 10.7 weeks (afatinib), and 24.1 weeks (cabozantinib). The overall objective response rate was 7.0%, with 1 complete response and 8 partial responses. The clinical benefit rate, including responses and stable disease >6 months, was 16.0%. Median progression-free survival ranged from 1.9 months for urothelial carcinoma to 3.2 months for NSCLC. Toxicities were common for all medications; for regorafenib, 90.7% of patients had AEs (50% Grade 3/4); for afatinib, 86% of patients had AEs (54% Grade 3/4); for cabozantinib, 100% of patients had AEs (36% Grade 3/4). The most common AEs were diarrhea, fatigue, nausea, decreased appetite, and stomatitis. CONCLUSIONS: Regorafenib, afatinib, and cabozantinib had modest effects when used as molecularly matched targeted therapies in patients with NSCLC, upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma in the second-line setting. Future research could examine more precise matching of therapies to genomic alterations and evaluate combination therapies.

Humans↗
PubMed2025

Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC), the dominant form of liver cancer, is a leading cause of cancer death worldwide. Sorafenib and lenvatinib have long been the 2 limited options of first-line treatments for patients with unresectable advanced HCC. However, the single-drug treatment strategy only shows modest survival benefit, mostly because of the survival ability of cancer cells to activate alternative pathways for compensation. In this study, we aim to identify druggable targets contributing to lenvatinib resistance and evaluate the efficacy of combining respective inhibitors and lenvatinib on HCC. METHODS: Genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 knockout library screening was applied on the vehicle group and lenvatinib treatment group. Identified druggable candidates were validated individually on HCC cell models. Therapeutic effects of the combined treatment of inhibitors of candidate genes and lenvatinib were evaluated in vitro and in vivo. RESULTS: We successfully identified NFKB1 and MET as critical drivers for the development of lenvatinib resistance in HCC cells. By perturbing the 2 genes with either CRISPR knockout or RNA interference approaches, lenvatinib treatments were significantly sensitized. Moreover, using small molecules QNZ and cabozantinib to target NFKB1 and MET, respectively, this together with lenvatinib could synergistically induce apoptosis and suppress HCC growth in vitro and in vivo. CONCLUSION: Our results demonstrated that genome-wide CRISPR/Cas9 screening is a powerful tool for the design of rational combinational cancer therapy and provided candidate genes possible for combined treatments with lenvatinib to improve therapy efficacy.

Carcinoma, Hepatocellular↗
PubMed2026

Unravelling bioanalytical innovations, degradation processes, and impurity landscapes of VEGFR inhibitors.

From pre-formulation studies to clinical trials, VEGFR-targeted small-molecule tyrosine kinase inhibitors (TKIs) require rigorous analytical standards. Bioanalysis, stability-indicating studies, and impurity profiling are used to examine chromatographic advances for VEGFR-targeted TKIs like sunitinib, pazopanib, axitinib, sorafenib, cabozantinib, vandetanib, apatinib, lenvatinib, nintedanib, and regorafenib. An LC-MS/MS and UPLC-MS/MS routinely show sub ng/mL performance, as shown by LLOQs (0.2 ng/mL) for sunitinib and axitinib, 1 ng/mL for pazopanib, 5-7 ng/mL for sorafenib, 0.5-1.5 ng/mL for regorafenib metabolic products, and 0.1-0.5 ng/mL for lenvatinib. These approaches are used for pharmacokinetics and therapeutic drug monitoring due to their good correlation coefficient of 0.1-10,000 ng/mL, accuracy of 95%-108%, and precision of 15% RSD. UPLC-QTOF-MS/MS distinguishes degradants and metabolites during forced degradation studies, enabling structural elucidation following ICH M7 risk evaluation protocol. HPTLC/MLC offers fast, sensitive screenings, while RP-HPLC/DAD or HPLC-UV offer reliable, cost-effective routine quality-control solutions with LOD/LOQ in the μg/mL range and linearity of 10-240 μg/mL. This review lists the structures and CAS numbers of ten VEGFR-2 TKI degradants and metabolites, as well as pharmacopeial impurities in SMILES forms. It will be useful for future method development and regulatory applications. To ensure VEGFR-targeted TKI quality, safety, and therapeutic efficacy, LC-MS/MS for trace quantification and HRMS for structure elucidation provide a robust, future-oriented framework. To improve VEGFR-targeted TKI quality, safety, and regulatory compliance, analytical development should focus on HRMS-based impurity characterization, AI-assisted degradation prediction, green chromatography, and harmonized bioanalytical validation.

Humans↗
PubMed2026

OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets. METHODS: The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation. RESULTS: OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC > 0.7 across 14/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts. DISCUSSION: Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.

Humans↗