glesatinib (MGCD265) / BMS - LARVOL DELTA

Integrating GWAS and Transcriptomic Data Using PrediXcan and Multimodal Deep Learning Reveals Genetic Basis and Drug Repositioning Opportunities for Alzheimer's Disease. (PubMed, medRxiv) - "Based on predictive results and enrichment analysis, we further identified candidate drugs, including sirolimus, dasatinib, and MGCD-265. This study demonstrates the complementary advantages of bioinformatics pipelines and AI-based multi-modal fusion methods in elucidating the complex pathological mechanisms of AD and enhancing phenotype prediction accuracy. It also provides new theoretical support for personalized drug interventions based on individual genetic characteristics, laying a solid foundation for optimizing early screening, prediction, and personalized treatment strategies."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • APOC1 • APOE • KAT8 • TRAPPC4

In silico screening to search for selective sodium channel blockers: When size matters. (PubMed, Brain Res) - "Four of them were acquired and submitted to experimental confirmation via patch clamp: three of these candidates, Eltrombopag, Sufugolix, and Glesatinib, showed blocking effects on NaV1.2 currents, although no subtype selectivity was observed. The different predictive abilities of the NaV1.1 and NaV1.2 models may be attributed to the different sizes of the datasets used to train and validate the respective models."

Journal • CNS Disorders • Epilepsy • NAV1

Comprehensive Analysis of APOBEC-Driven Mutagenesis in NSCLC Indicates Its Role in Resistance Beyond EGFR and ALK (IASLC-TTLC 2025) - "Of those, 9 patients were treated with targeted therapy: 6 patients were treated with EGFR TKI(s) for EGFR exon 19 deletions (osimertinib, 3; osimertinib/gefitinib combo, 2; or erlotinib, 1), one patient with lorlatinib for EML4::ALK fusion, one patient with selpercatinib for KIF5B::RET fusion and one patient with glesatinib for METex14 mutation.Putative resistance mechanisms were identified in 6/9 cases with acquired APOBEC mutagenesis: two cases of squamous cell transformation, one RET p.G810S in KIF5B::RET-positive NSCLC, one HRAS p.A59T in a case with EML4::ALK, one MET p.H1094Y occurring in an APOBEC-preferred trinucleotide context in a NSCLC with METex14, and a case of EGFR-mutant NSCLC that developed KRAS p.G12A and RAF1 p.S257L, the latter occurring in an APOBEC-preferred context. In one case, a tumor with KIF5B::RET and high APOBEC-MB at presentation developed APOBEC-attributable resistance mutation RET p.L730V upon progression on pralsetinib... APOBEC..."

Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • APOB • BRAF • EGFR • EML4 • HER-2 • HRAS • KIF5B • KRAS • MET • NTRK1 • NTRK2 • NTRK3 • RET • ROS1 • TMB

Emerging AXL Inhibitors in Oncology: Chemical and Biological Advances in Targeted Cancer Therapy. (PubMed, Anticancer Agents Med Chem) - "In conclusion, developing AXL inhibitors represents a promising avenue for improving cancer treatment outcomes. Continued research efforts are essential to overcome the existing challenges and translate these compounds into effective clinical therapies."

Journal • Gene Therapies • Oncology

MST1R-targeted therapy in the battle against gallbladder cancer. (PubMed, Cell Biosci) - "Overall, targeting MST1R and its downstream genes, particularly combining MGCD-265 with SKLB325, holds promise as a therapeutic strategy for GBC."

Journal • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • MST1R

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons. (PubMed, Cell Mol Life Sci) - "Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons. (PubMed, Res Sq) - "Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor

MRTX-500: Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=161 | Terminated | Sponsor: Mirati Therapeutics Inc. | Completed ➔ Terminated; This study was terminated as a result of Sponsor portfolio reprioritization.

Combination therapy • Metastases • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Phase II study investigating the efficacy and safety of glesatinib (MGCD265) in patients with advanced NSCLC containing MET activating alterations. (PubMed, Lung Cancer) - "Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET)."

Journal • Metastases • P2 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • MET

Phase II study investigating the efficacy and safety of glesatinib (MGCD265) in patients with advanced NSCLC containing MET activating alterations (Lung Cancer) - P2 | N=68 | NCT02544633 | Sponsor: Mirati Therapeutics Inc. | "Sixty-eight patients were enrolled: n = 28 and n = 8 with MET exon 14 skipping mutations in tumor tissue and ctDNA, respectively, and n = 20 and n = 12 with MET gene amplification in tumor tissue and ctDNA, respectively. Overall, ORR was 11.8 %, median progression-free survival was 4.0 months, and median overall survival was 7.0 months. Among patients with MET activating mutations, ORR was 10.7 % with tumor testing and 25.0 % with ctDNA testing. For MET amplification, responses were observed only in patients enrolled by tumor testing (ORR 15.0 %)."

P2 data • Non Small Cell Lung Cancer

Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung Cancer and Other Advanced Solid Tumors. (PubMed, Target Oncol) - P1, P2 | "The safety profile of single-agent glesatinib was acceptable. SDD 750 mg twice daily was selected as the preferred glesatinib formulation and dose based on clinical activity, safety, and PK data. Observations from this study led to initiation of a phase II study of glesatinib in patients with NSCLC stratified by type of MET alteration (NCT02544633)."

Journal • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • MET

Diagnosis of MET Gene Alterations in Advanced NSCLC with Next Generation Sequencing (IASLC-ACLC 2022) - "This is clinically applicable to a variety of TKIs targeting MET such as crizotinib, capmatinib, carbozantinib, savolitinib, tepotinib, glesatinib, merestinib or monoclonal antibody drug classes.4.Conclusions :-MET gene alternations have many forms, now there are important targets for MET: MET Ex14 Skipping, MET Amplifications, MET point mutations.-There are many medecines suitable for these targets. This leads to the need to diagnose these MET gene mutations with next-generation sequencing techniques."

Biomarker • Next-generation sequencing • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MET

"14/15 #TumorBoardTuesday 👩‍🏫Mini tweetorial 10 Type II MET inhibitors (cabozantinib, glesatinib, merestinib) Resistance pathways may be primary or acquired and can vary by MET TKI Type. New agents: Amivantamab (Phase 2, MET expansion cohort) …to be continued at #ASCO22" (@Latinamd)

P2 data • Oncology

MRTX-500: Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=211 | Completed | Sponsor: Mirati Therapeutics Inc. | Active, not recruiting ➔ Completed | Trial primary completion date: May 2021 ➔ Nov 2021

Combination therapy • Trial completion • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Phase I Study of Glesatinib (MGCD256) in Combination with Erlotinib or Docetaxel in Patients with Advanced Solid Tumors. (PubMed, Target Oncol) - P1/2 | "The safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/m every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors."

Clinical • Combination therapy • Journal • P1 data • Fatigue • Oncology • Solid Tumor

Functional proteomics of patient derived head and neck squamous cell carcinoma cells reveal novel applications of trametinib. (PubMed, Cancer Biol Ther) - "These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume)...Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AXL

Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=206; Active, not recruiting; Sponsor: Mirati Therapeutics Inc.; Trial completion date: Jun 2021 ➔ Dec 2021

Combination therapy • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

[VIRTUAL] Non-interventional cohort study on patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping in the US (ELCC 2021) - "Treatment patterns were heterogeneous across therapy lines and included available and experimental treatments (immune checkpoint inhibitor [ICI] therapy; MET inhibitors [crizotinib, cabozantinib, and glesatinib])...Conclusions Pts were generally at advanced age, were frequent smokers and had high-PD-L1 expression. Findings from this study help better characterize this rare population; treatment patterns and effectiveness outcomes underline the high unmet medical need."

Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET • PD-L1

Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=206; Active, not recruiting; Sponsor: Mirati Therapeutics Inc.; Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

AXL inhibition overcomes erlotinib resistance in AXL-activated non-small cell lung cancer cells (AACR 2018) - "RNA-sequencing analysis identified that several groups of genes involved in cell survival inhibition or apoptosis promotion were upregulated, whereas genes involved in cell cycle process, DNA replication or cancer metabolism were downregulated in cells treated with the combination of erlotinib and MGCD265. Taken together, our results indicated that AXL mutations may confer resistance to EGFR TKI treatment, and effective blockade of the AXL pathway may represent a novel strategy to overcome erlotinib resistance for the treatment of NSCLC patients."

Non Small Cell Lung Cancer

A study of MGCD265 given with erlotinib or docetaxel in subjects with advanced malignancies or non-small cell lung cancer (clinicaltrials.gov) - P1/2, N=150; Recruiting; N=100 -> 150; Completion date: Jan ‘12 -> Sep ’12

Completion date • Enrollment • Trial delayed • Non Small Cell Lung Cancer • Oncology

Has MET met its match? (Ann Transl Med) - KEE: Balazs Halmos; "All in all, last year clearly put MET exon 14 skipping mutations on the map as a key actionable lung cancer oncogene with significant frequency to warrant incorporation into routine testing algorithms in order to be able to offer patients with advanced MET exon 14 skipped lung cancers an additional line of highly active treatment option. Finally, it does seem that after 20 years of active research of this intriguing pathway, MET has 'met its match'. It is up to translational medicine to follow the lead and extend the benefits quickly and broadly to those of our patients harboring malignancies driven by oncogenic MET signaling."

Review • US NSCLC KEE

MethylGene reports Second Quarter 2011 financial results and provides clinical update (Marketwire) - 265-103; P1/2, N=100; In the erlotinib-arm (MGCD265 in combination with full-dose erlotinib), three pts with gastric cancer have been enrolled, two of which were on study for six & eleven months, respectively, & one who experienced complete resolution of ascites & a decrease in gastric wall thickness has been on study for 16 months; Molecular profiling of the archived tumor biopsy from this pt showed high levels of Met & phospho-Met protein expression in the absence of MET & EGFR gene amplification or detectable mutations

P1/2 data • Oncology

MethylGene Reports Second Quarter 2010 Financial Results and Provides Clinical Update for MGCD265 (Marketwire) - The increase was due primarily to higher professional fees which were partially offset by lower compensation expenses. MethylGene incurred a foreign exchange gain of $54,000 in the second quarter of 2010 versus a loss of $726,000 in the second quarter of 2009.

Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=209; Not yet recruiting; Sponsor: Mirati Therapeutics Inc.

New P2 trial • Biosimilar • Non Small Cell Lung Cancer • Oncology