tivantinib (ARQ 197) / Daiichi Sankyo, Kyowa Kirin, Merck (MSD) - LARVOL DELTA

Haematological toxicities with targeted drugs in tumors: A systematic review and network meta-analysis of randomized controlled trials (ASH 2025) - "1 patient treated with sorafenib plus chemotherapy was reported to have died as a result of pancytopenia and 1 patient treated with chemotherapy (gemcitabine plus cisplatin) died due to anemia. Our study confirmed that chemotherapy with or without a placebo, one targeted drug with chemotherapy was associated with more severe hematologic toxicities compared with the use of one targeted drug, tepotinib plus gefitinib, tivantinib plus erlotinib. In the targeted drug monotherapy category, for the primary outcome, we found that alectinib and gefitinib had a higher risk of all-grade (grade 1-5) and severe-grade (grade 3-5) anemia, respectively...Ganitumab plus chemotherapy had the highest risk of grade 1-5 anemia and thrombocytopenia. Afatinib plus chemotherapy had the highest risk of grade 3-5 anemia and thrombocytopenia. Ramucirumab plus chemotherapy had the highest risk of grade 1-5 and 3-5 neutropenia. Veliparib plus chemotherapy had the highest risk of grade 1-5 and 3-5..."

Retrospective data • Review • Febrile Neutropenia • Leukopenia • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia

Targeting leukemic stem cells: enhanced eradication via tivantinib (ARQ197) and asciminib (ABL001) with molecular docking-guided screening of therapeutic derivatives. (PubMed, J Chemother) - "Targeting c-MET, alone or in combination with BCR::ABL1 inhibition, presents a compelling strategy for eradicating LSCs, which underpin resistance and relapse in CML therapy - thus marking a crucial advancement in the pursuit of more effective treatment paradigms. In silico studies indicated that various tivantinib and asciminib analogues could also have potential therapeutic effects as c-MET and ABL1 inhibitors for future anti-leukaemia research."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

Personalized treatment for hepatocellular carcinoma (HCC) patients (AACR 2025) - "Anticancer agents such as sorafenib and regorafenib were found to increase drug resistance in 3D cell culture models of HCC...Drug resistance profiles varied among HCC patients, with some demonstrating sensitivity to sorafenib and lapatinib, while others showed resistance to tivantinib...In particular, one individualized HCC patient showed the best drug response to lenvatinib and sunitinib. Furthermore, our prediction model revealed that lapatinib exhibited higher drug resistance, mirroring patterns observed in tumor cells associated with regulatory T cells, tissue-resident memory T cells (TRM), and tumor-associated macrophages (TAMs). These findings suggest that our approach offers a promising framework for predicting drug responses in HCC, supporting its application in personalized medicine."

Clinical • Hepatocellular Cancer • Oncology • Solid Tumor

Evaluating c-MET Inhibitors Tivantinib and Cabozantinib as Novel Therapeutic Options in Penile Cancer (AUA 2025) - "Therefore, tivantinib, a c-MET-specific inhibitor, and cabozantinib, a multi-tyrosine kinase inhibitor, were tested for their efficacy in treatment-naive, cisplatin- and osimertinib-resistant PeCa cell lines with clinical relevance in second-line treatment... The results of this study demonstrate that cabozantinib is a promising option for treatment of penile cancer, significantly reducing cell viability and tumor volume in in vivo models. In contrast, tivantinib exhibited more limited effects, underscoring the need for further research to optimize treatment strategies for this rare disease."

Genito-urinary Cancer • Oncology • Penile Cancer • Rare Diseases • Solid Tumor • MET

IMMUNOSARC II MASTER TRIAL PHASE II OF SUNITINIB AND NIVOLUMAB): RESULTS FROM THE CLEAR CELL SARCOMA CCS) COHORT. A GEIS, ISG, AND UCL STUDY (CTOS 2024) - "MET inhibitors were prospectively explored, obtaining an Overall Response Rate (ORR) of 3.8%, median Progression-Free Survival (mPFS) of 4.4 months, 6-month PFS rate of 27%, and median RECIST 1.1 Overall Survival (mOS) of 9.2 months in 28 treated patients with crizotinib, and an ORR of 9%, and mPFS of 2 months in 11 patients treated with tivantinib. This phase 2 study matched the primary end-point showing that the combination of sunitinib and nivolumab is active in CCS, and looks promising compared to past treatments deserving further investigation. Translational studies are ongoing"

P2 data • Oncology • Sarcoma • Solid Tumor • ATF1 • EWSR1

IMMUNOSARC II master trial (phase II of sunitinib and nivolumab): Results from the clear cell sarcoma (CCS) cohort: A GEIS, ISG, and UCL study (ESMO 2024) - P1/2 | "MET inhibitors were prospectively explored, obtaining an ORR of 3.8%, mPFS of 4.4 months, 6-month PFS rate of 27%, and mOS of 9.2 months in 28 treated patients with crizotinib, and an ORR of 9%, and mPFS of 2 months in 11 patients treated with tivantinib. While further studies are needed, initial findings suggest NiSu could be a valuable addition to the current armamentarium for CCS management."

P2 data • Oncology • Sarcoma • Solid Tumor • ATF1 • EWSR1

Repurposing of c-MET Inhibitor Tivantinib Inhibits Pediatric Neuroblastoma Cellular Growth. (PubMed, Pharmaceuticals (Basel)) - " Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers."

Journal • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • MYCN

Efficacy and safety of second-line therapies for advanced hepatocellular carcinoma: a network meta-analysis of randomized controlled trials. (PubMed, BMC Cancer) - "Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC."

Clinical • Journal • Metastases • Retrospective data • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

The in vitro dynamics of pseudo-vascular network formation. (PubMed, Br J Cancer) - "Our framework is shown to enable quantitative analysis of both the capacity for network formation, linked vasculogenic mimicry, as well as dynamic responses to treatment."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor

Repurposing non-oncology drugs with MET inhibitory effect to overcome osimertinib resistance in lung cancer (AACR 2024) - "This study investigated the repurposing of non-oncology MET inhibiting drug to overcome osimertinib resistance. A few clinically-approved drugs with putative MET inhibitory effects were identified by a computational drug repurposing tool called "DRAR-CPI" via analysis of the chemical-protein interactome of known MET inhibitors (crizotinib, cabozantinib, foretinib, and tivantinib)... These findings advocate the clinical evaluation of repurposing FEX to overcome osimertinib resistance."

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

Tepotinib and tivantinib as potential inhibitors for the serine/threonine kinase of the mpox virus: insights from structural bioinformatics analysis. (PubMed, J Biomol Struct Dyn) - "Nevertheless, it is sensible to experimentally test all top 10 compounds, as scoring functions and energy calculations may not consistently align with experimental findings. These insights are poised to provide an attempt to identify an effective inhibitor for the Mpox virus.Communicated by Ramaswamy H. Sarma."

Journal

Pharmacological mechanisms underlying the interaction of the nucleoside analogue gemcitabine with the c-MET inhibitor tivantinib in pancreatic cancer. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "Moreover, these drugs affected the expression of microRNAs miR-21 and miR-34, which regulate key oncogenic pathways. These findings might have an impact on the selection of patients for future trials."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • MIR21 • MIR34A

MET receptor serves as a promising target in melanoma brain metastases. (PubMed, Acta Neuropathol) - "We found phospho-METY1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor

Tailored horseshoe-shaped nicotinonitrile scaffold as dual promising c-Met and Pim-1 inhibitors: Design, synthesis, SAR and in silico study. (PubMed, Bioorg Chem) - "The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay...Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BAX • BCL2 • CASP3 • MET • PIM1

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

The effectiveness of tivantinib for MET-high hepatocellular carcinoma: A protocol for meta analysis. (PubMed, Medicine (Baltimore)) - "Tivantinib may not benefit to the treatment of MET-high hepatocellular carcinoma."

Journal • Retrospective data • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor

Proposing the best MET inhibitor to improve anti-PD-1 efficacy in HCC (AACR 2023) - "We first validated that both MET selective (Capmatinib and Tivantinib) and non-selective (Cabozantinib) inhibitors all induced PD-L1 on HCC cell lines in vitro...Molecular studies are focused on understanding the superior ICB potentiating capacity of Type I MET inhibitors versus the other classes. Given the clinical availability of numerous MET and PDL-1 inhibitors, we hope to inform near-term optimization of MET and αPD-1 clinical trial design for HCC."

Clinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD8 • HGF • MAGEE1

Phase II study of tivantinib (ARQ 197) and cetuximab in patients with EGFR inhibitor-resistant, MET-High, KRAS wild-type (KRASwt) metastatic colorectal cancer (mCRC) (ESMO-GI 2017) - P2; " This investigator-initiated, multicenter, single-arm, Simon 2-stage, phase II study (NCT01892527), enrolled patients with: MET-High (≥ 2+ in ≥ 50% of tumor cells at immunohistochemistry), KRASwt, mCRC; ≥1 prior line of systemic therapy; stable disease (SD) or better response to last treatment regimen containing cetuximab or panitumumab; tumor progression on cetuximab or panitumumab within 3 months before enrollment; ECOG PS ≤ 2; adequate bone marrow, liver, and kidney functions. The combination in study tested the hypothesis that resistance to EGFR inhibitors could be reverted by MET inhibition. The study did not meet its primary endpoint, although PFS and OS data are interesting, given that half the patients were heavily pretreated. AEs were consistent with the known safety profile of tivantinib and cetuximab."

Clinical • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology

JET-HCC: A phase 3 randomized, double-blind, placebo-controlled study of tivantinib as a second-line therapy in patients with c-Met high hepatocellular carcinoma (ESMO 2017) - P3; "Main inclusion criteria were HCC patients refractory or intolerant to a prior sorafenib therapy, Child Pugh A, ECOG PS ≤ 1, at least one measurable lesion according to RECIST 1.1, and diagnosed as c-Met high (regarded as ≥ 2+ in ≥ 50% of tumor cells, by IHC). Although favorable survival were observed in the tivantinib group, this study in Japan could not show the significant clinical benefit of tivantinib as a second-line therapy for c-Met high HCC."

Clinical • P3 data • Hepatocellular Cancer

Exome sequencing of tumor samples from S1107 “Randomized phase II evaluation of tivantinib and tivantinib in combination with erlotinib in patients with papillary renal cell carcinoma (pRCC)” (ESMO 2017) - P2; "S1107 patient cohort had a high proportion of pts with molecular subtypes not driven by MET abnormalities and would not be expected to respond well to MET inhibition. Although MET remains a reasonable therapeutic target in pRCC, careful selection of pts exhibiting MET alterations is required to better benefit from therapy with MET inhibitors."

Clinical • Combination therapy • P2 data • Renal Cell Carcinoma

Tivantinib alleviates inflammatory diseases by directly targeting NLRP3. (PubMed, iScience) - "In vivo, Tivantinib reduces IL-1β production in mouse models of lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate (MSU)-induced peritonitis and Con A-induced acute liver injury (ALI), and also has remarkable preventive and therapeutic effects on experimental autoimmune encephalomyelitis (EAE). In conclusion, our study identifies the anticancer drug tivantinib as a specific inhibitor of NLRP3 and provides a promising therapeutic agent for inflammasome-driven disease."

Journal • CNS Disorders • Hepatology • Immunology • Inflammation • Liver Failure • Multiple Sclerosis • Oncology • IL1B • NLRP3

Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer. (PubMed, Lung Cancer) - "MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions."

Journal • Metastases • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EPHB4 • STAT3 • TP53

Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial. (ASCO 2017) - P3; "Tivantinib at the 120mg BID dose did not improve OS or PFS over placebo in patients with advanced MET-High HCC who failed previous treatment with sorafenib."

Clinical • P3 data • Biosimilar • Hepatocellular Cancer

Comparison of Second-Line Treatments for Patients with Platinum-Resistant Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Bayesian Network Meta-Analysis. (PubMed, Cancers (Basel)) - "These studies compared 20 different treatments, including the standard of care (SOC: docetaxel, methotrexate, or cetuximab), PD-1 inhibitors (nivolumab or pembrolizumab), durvalumab, tremelimumab, durvalumab + tremelimumab, palbociclib + SOC, tivantinib + SOC, sorafenib + SOC, EMD1201081 + SOC, vandetanib + SOC, PX-866 + SOC, 5-fluorouracil + SOC, cixutumumab + SOC, gefitinib + SOC, cabazitaxel, nolatrexed, duligotuzumab, zalutumumab, gefitinib, and afatinib. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS."

Journal • Retrospective data • Review • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now? (PubMed, Biomedicines) - "Small molecule inhibitors tested in clinical trials thus far include sorafenib, sunitinib, pazopanib, tivantinib, and erlotinib. Monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, trastuzumab, and seribantumab...In conclusion, the tyrosine kinases remain attractive targets for treating ovarian cancers. Future development will need to consider effective drug combination, frequency of target, and developing predictive biomarker."

IO biomarker • Journal • Review • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor