brivanib alaninate (BMS-582664) / BMS, ZAI Lab - LARVOL DELTA

Identification of the role of MED6 in the development and prognosis of lung adenocarcinoma based on multi-omics profiling. (PubMed, J Cancer) - "Based on MED6 expression, drugs such as paclitaxel, afatinib, and brivanib were identified as potential treatments. This study revealed the role of MED6 in LUAD and its potential as a biomarker. Our findings suggest that MED6 has an effect on LUAD progression and provide valuable insights for patient stratification and personalized treatment strategies."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Machine Learning Models of Early Longitudinal Toxicity Trajectories Predict Cetuximab Concentration and Metastatic Colorectal Cancer Survival in the Canadian Cancer Trials Group/AGITG CO.17/20 Trials. (PubMed, JCO Clin Cancer Inform) - P3 | "We used an innovative machine learning approach to analyze longitudinal joint drug toxicities, demonstrating their role in predicting patient outcomes through a putative pharmacokinetic mechanism."

Journal • Colorectal Cancer • Fatigue • Oncology • Solid Tumor • EGFR

Health-related quality of life outcomes in hepatocellular carcinoma patients undergoing systemic therapies: a systematic review (AGW-GESA 2024) - "Eighteen (62%) studies assessed sorafenib and four (14%) studies assessed atezolizumab-bevacizumab (atezo-bev). Of the remaining studies, five (17%) studies investigated PD-1 inhibitors (three pembrolizumab, two nivolumab), two (7%) studied lenvatinib, two (7%) studied ramucirumab, and one study each evaluated cabozantinib, dovitinib, brivanib, regorafenib and durvalumab-tremelimumab... Despite worsening HRQOL outcomes compared to baseline, the first-line agents atezo-bev and lenvatinib improved HRQOL in comparison to sorafenib. Patients on PD-1 inhibitors or nivolumab experienced no change in HRQOL. Sorafenib significantly worsened HRQOL compared to TARE."

Clinical • HEOR • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. (PubMed, Int J Mol Sci) - "Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations."

Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Transplantation

Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry. (PubMed, Ann Med) - "PAAD with high MCM3 expression was sensitive to c-75, brivanib, flavopiridol and VNLG/124 drugs, with stable molecular docking models. MCM3 is likely to be a critical element in promoting the initiation and growth of PAAD. Flavopiridol may exert its anti-PAAD effect through the interaction between MCM3, classic CDK1 targets in the cell cycle checkpoint and p53 pathway as well as related molecules in other pathways."

Biomarker • Journal • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • CDK1 • MCM3

Quantification and analyses of seven tyrosine kinase inhibitors targeting hepatocellular carcinoma in human plasma by QuEChERS and UPLC-MS/MS. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Herein, seven TKIs, namely sorafenib tosylate, axitinib, erlotinib, cediranib, brivanib, linifanib, and golvatinib, were successfully analyzed in human plasma by following a quick, easy, cheap, effective, rugged, and safe (QuEChERS) pretreatment method combined with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)...In this study, dovitinib was used as the internal standard...The intraday and interday accuracy values ranged from -6.12 % to 7.31 %, with a precision (RSD) of ≤ 10.57 %. The method was rapid, accurate, specific, simple, reproducible, and suitable for the quantitative determination of the seven TKIs in human plasma."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Plasma Cetuximab Concentrations Correlate With Survival in Patients With Advanced KRAS Wild Type Colorectal Cancer. (PubMed, Clin Colorectal Cancer) - "The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS."

Journal • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Pharmacological effects of Niraparib and its combination with angiogenic inhibitor in ovarian cancer. (PubMed, J Cancer) - " Our current findings revealed that OC cells harboring BRAC1/2 mutations were more sensitive to Niraparib treatment compared to those with BRAC wild-type, and the addition of Brivanib enhanced programmed cell death (PCD) to sensitize OC cells with BRAC mutations to Niraparib treatment in vitro and in vivo. Our work illustrates that the combination regimen of PARPi and angiogenic inhibitor treatment should be beneficial for the OC patients with BRAC mutations, at least partially owing to the induction of multiple forms of programmed cell death (PCD)."

Journal • Oncology • Ovarian Cancer • Solid Tumor • ANXA5

Optimal First-Line Therapy for HCC (APPLE 2023) - "The agents which failed to prove their activity in HCC were sunitinib, linifanib, brivanib, nintedanib in the first-line treatment and axitinib, ramucirumab, brivanib, erlotinib, everolimus, tivantinib, ADI-PEG20 in the second-line treatment after sorafenib failure. Recently, lenvatinib, another angiogenesis inhibitor, showed non-inferior overall survival in the 1st-line treatment compared with sorafenib in the REFLECT trial...For the patients who failed sorafenib treatment, regorafenib and cabozantinib, mainly angiogenesis inhibitors overcame placebo control in RESORCE and CELESTIAL trials. In addition, nivolumab showed meaningful results for HCC in phase II checkmate 040 trial...However, the current effects of systemic treatments for HCC are far from satisfaction as ever. By looking at the trials currently conducted for HCC, we are discussing ways to improve the prognosis of HCC patients."

Clinical • IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Oncology • Solid Tumor • BRAF • KDR • PDGFRB

Integration of Systemic and Locoregional Therapy in HCC (APPLE 2023) - "The integration of systemic and locoregional therapy in HCC has undergone a paradigm shift with innovative systemic therapies like atezolizumab plus bevacizumab and durvalumab plus tremelimumab...Although past phase 3 RCTs of combination therapy with TACE and tyrosine kinase inhibitors (such as sorafenib and brivanib) have been unsuccessful for advanced HCC, there is renewed hope for the amalgamation of TACE, TARE or external beam radiotherapy (EBRT) and immunotherapy. While current immunotherapeutic agents have improved overall survival and progression-free survival rates compared to the past, they still fall short compared to outcomes from other cancers. In the absence of definitive biomarkers, it is posited that a combination or sequential approach incorporating locoregional treatments is crucial for enhancing the treatment outcomes in HCC patients."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Front Oncol) - "A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design."

Retrospective data • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Clinical and metabolomic characterization of Brivanib-Induced hypertension in metastatic colorectal cancer. (PubMed, Cancer Med) - "TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity."

Journal • Metastases • Cardiovascular • Colorectal Cancer • Gastrointestinal Cancer • Gynecology • Hypertension • Oncology • Solid Tumor

Predictive and prognostic features of metastatic colorectal cancer arising from the transverse colon: A pooled analysis of the CCTG/AGITG CO.17 and CO.20 randomized trials. (ASCO-GI 2023) - "Canadian Cancer Trials Group (CCTG)/Australasian Gastro-Intestinal Trials Group (AGITG) CO.17 compared Cetuximab (Cet) vs. best supportive care (BSC) in mCRC. CCTG/AGITG CO.20 studied the addition of Brivanib Alaninate to Cet in pre-treated KRAS wildtype (WT) mCRC... Transverse mCRC has comparable prognostic and predictive features to right sided mCRC. In keeping with previous studies, left side was predictive of greater Cet benefit and presented better overall prognosis when single agent Cet was used after 5-FU, oxaliplatin and irinotecan. >"

Metastases • Retrospective data • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • RAS

Preliminary results of niraparib combined with brivanib or toripalimab dual therapy evaluation in recurrent, metastatic and persistent cervical cancer (CQGOG0101): An open-label, two cohorts, phase II clinical trial (ESMO Asia 2022) - P2 | "Conclusions The Cohort 1 (Niraparib combined with Brivanib) seems to show a similar efficacy compared to other recurrent cervical cancer late-line therapies. The treatment of the Cohort 2 (Niraparib combined with Toripalimab) is still ongoing and final data will be reported later."

Clinical • P2 data • Cervical Cancer • Oncology • Solid Tumor

Efficacy and safety of frontline systemic therapy for advanced hepatocellular carcinoma (aHCC): A network meta-analysis of landmark phase III trials. (ASCO-GI 2023) - "These tested respectively: sorafenib (S) vs placebo (SHARP and Asia Pacific), sunitinib (Sun) vs S, brivanib (Bri) vs S, linifanib (Lin) vs S, lenvatinib (L) vs S, nivolumab (Nivo) vs S, atezolizumab+bevacizumab (A+B) vs S, sintilimab+IBI-305 vs S, durvalumab+tremelimumab (D+T) vs S, atezolizumab+cabozantinib (A+C) vs S, donafenib vs S, camrelizumab plus rivoceranib (C+R) vs S, pembrolizumab plus lenvatinib (P+L) vs L, and tislelizumab (TS) vs S as first line treatments for aHCC... Combination of ICI + anti-VEGF antibodies leads to the greatest OS benefit compared to sorafenib, whereas ICI + kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates."

Metastases • P3 data • Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis. (PubMed, PLoS One) - "For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab."

Cost effectiveness • HEOR • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Oncology • Solid Tumor

Disparities in multinational phase III liver cancer clinical trials by regions of the world (AACR 2023) - P3 | "In phase III multinational liver cancer studies seeking FDA approval does not include patients from all geographical regions.Table 1: Regional characteristics of multinational phase III clinical trials of Liver Cancer Trial name, identifierTreatmentTotal patientsEuropeAfricaSouth AmericaNorth AmericaAsiaOceaniaOther/ MultipleBRISK-FLNCT00858871Brivanib, Sorafenib11552697152*7189-BRISK-PSNCT00825955Brivanib395166-67*162--NCT00699374Sunitinib, Sorafenib1074----812-262SEARCHNCT0901901Sorafenib, Erlotinib720369-173*178--REACHNCT01140347Ramucirumab565248-65*252--NCT01009593Linifanib, Sorafenib1035----689-346RESORCENCT01774344Regorafenib573----216-357NCT01761266Lenvatinib, Sorafenib954----640-314CELESTIALNCT01908426Cabozantinib707339--16717526-REACH-2NCT02435433Ramucirumab292----141-151ClarIDHyNCT02989857Ivosidenib18549--12412--IMbrave150NCT03434379Atezolizumab, Bevacizumab,..."

Clinical • P3 data • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

[VIRTUAL] Evaluation of firstline systemic treatments for unresectable hepatocellular carcinoma (uHCC): A network metaanalysis (ESMO Asia 2020) - "In total, 1398 records were screened and 27 were eligible for analysis, and the treatments included were atezolizumab+bevacizumab, brivanib, FOLFOX4, donafenib, dovitinib, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies and three other combination therapies. This NMA suggested that greater ORR and TTP benefits with first-line use of Lenvatinib than others. Although Atezolizumab+Bevacizumab showed more benefit in PFS, more discontinuation because of AE should also take into consideration."

Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

[VIRTUAL] Evaluation of first:line systemic treatments for unresectable hepatocellular carcinoma (uHCC): A network meta:analysis (ESMO Asia 2020) - "Results In total, 1398 records were screened and 27 were eligible for analysis, and the treatments included were atezolizumab+bevacizumab, brivanib, FOLFOX4, donafenib, dovitinib, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies and three other combination therapies. Legal entity responsible for the study: The authors. Funding: Has not received any funding."

Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

[VIRTUAL] Evaluation of firstline systemic treatments for unresectable hepatocellular carcinoma (uHCC): A network metaanalysis (ESMO Asia 2020) - "In total, 1398 records were screened and 27 were eligible for analysis, and the treatments included were atezolizumab+bevacizumab, brivanib, FOLFOX4, donafenib, dovitinib, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies and three other combination therapies. This NMA suggested that greater ORR and TTP benefits with first-line use of Lenvatinib than others. Although Atezolizumab+Bevacizumab showed more benefit in PFS, more discontinuation because of AE should also take into consideration."

Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity. (PubMed, Cell Rep) - "Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8 T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment."

Journal • Oncology • CD8 • CGAS • FGFR

Recent updates on 1,2,3-, 1,2,4-, and 1,3,5-triazine hybrids (2017-present): The anticancer activity, structure-activity relationships, and mechanisms of action. (PubMed, Arch Pharm (Weinheim)) - "Moreover, several triazine hybrids such as brivanib (indole-containing pyrrolo[2,1-f][1,2,4]triazine), gedatolisib (1,3,5-triazine-urea hybrid), and enasidenib (1,3,5-triazine-pyridine hybrid) have already been available in the market. This review focuses on the anticancer activity of 1,2,3-, 1,2,4-, and 1,3,5-triazine hybrids, together with the structure-activity relationships and mechanisms of action developed from 2017 to the present. The enriched structure-activity relationships may be useful for further rational drug development of triazine hybrids as potential clinical candidates."

Journal • Review • Oncology

Clustering on longitudinal quality-of-life measurements using growth mixture models for clinical prognosis: Implementation on CCTG/AGITG CO.20 trial. (PubMed, Cancer Med) - "GMM can be used to analyze longitudinal QoL data in cancer studies, by identifying unobserved subpopulations (patient clusters). As demonstrated by CO.20 data, these classes can have important implications, including clinical prognostication."

HEOR • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

BRISK PS: Comparison of Brivanib and Best Supportive Care to Placebo for Treatment of Liver Cancer for Those Subjects Who Have Failed Sorafenib Treatment (clinicaltrials.gov) - P3; N=587; Completed; Sponsor: Bristol-Myers Squibb; Terminated ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

BRISK TA: Phase III Trans-Arterial Chemo-Embolization (TACE) Adjuvant HCC (clinicaltrials.gov) - P3; N=734; Completed; Sponsor: Bristol-Myers Squibb; Active, not recruiting ➔ Completed; Trial completion date: Jan 2018 ➔ Jan 2018

Trial completion • Trial completion date • Biosimilar • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor