merestinib (LY2801653) / Eli Lilly - LARVOL DELTA

DDR2 inhibition reveals a T cell immune checkpoint that controls lung cancer immunosurveillance (ELCC 2025) - "In conclusion, merestinib and WRG-28 restrain lung cancer immunosurveillance. DDR2 is a potential novel T-cell immune checkpoint."

IO biomarker • Lung Cancer • Oncology • Solid Tumor • CD69 • CD8 • DDR2 • ICOS • IFNG • PD-1 • TIGIT • TYK2

Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury. (PubMed, Free Radic Biol Med) - "The results show that MTB effectively blocks elesclomol-CuCl2 (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases."

Journal • Cardiovascular • CNS Disorders • Hepatology • Liver Failure

A Study of Anti-PD-L1 Checkpoint Antibody (LY3300054) Alone and in Combination in Participants With Advanced Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=164 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Breast Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Hepatology • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Melanoma • Microsatellite Instability • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Skin Cancer • Solid Tumor • ER • HER-2 • MSI • PGR

TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers. (PubMed, NPJ Precis Oncol) - "Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib...While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FLT3 • ROS1

Altered ribosomal profile in acquired resistance and reversal associates with pathological response to chemotherapy in inflammatory breast cancer. (PubMed, NPJ Breast Cancer) - "Given the common hyperactivation of MAPK in IBC tumors, including rSUM149, we evaluated Merestinib, a multikinase inhibitor in clinical trials. It effectively targeted pERK and peIF4E pathways, suppressed downstream targets, induced cell death in drug-resistant rSUM149 cells, and showed synergistic effects with another tyrosine kinase inhibitor (Lapatinib) in parental cells. This underscores its significant impact on protein synthesis signaling, crucial for combating translational dependence in cancer cells. In summary, our study elucidates adaptive changes in IBC cells in response to therapy and treatment pauses, guiding precision medicine approaches for this challenging cancer type."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CDK1 • RPL5 • SOD2 • XIAP • XPO1

A Study of Anti-PD-L1 Checkpoint Antibody (LY3300054) Alone and in Combination in Participants With Advanced Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=215 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Mar 2024 ➔ Jul 2024

Combination therapy • Metastases • Trial completion date • Breast Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Hepatology • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Melanoma • Microsatellite Instability • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Skin Cancer • Solid Tumor • ER • HER-2 • MSI • PGR

Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib (AACR 2024) - "Merestinib has strong antitumor activity in GAC, especially when administered with nab-paclitaxel, demonstrating a synergistic effect. These results provide compelling evidence for the potential clinical relevance of this combination therapy in improving the survival of GAC patients."

Preclinical • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AXL • DDR1 • EGFR • MET

An altered profile of ribosomal proteins and ERK-eIF4E translational control in an inflammatory breast cancer model of acquired resistance and reversal is associated with pathological complete response in patients (AACR 2024) - "Additionally, Merestinib synergized with EGFR-TKI (lapatinib) in increasing cell death in all three states. Overall, our study describes adaptive changes in response to both therapeutic stress and therapy break that have the potential to serve as biomarkers or extended for pharmacological interrogation toward precision medicine for this rare, understudied cancer. Overall, our study describes adaptive changes in response to both therapeutic stress and therapy break that have the potential to serve as biomarkers or extended for pharmacological interrogation toward precision medicine for this rare, understudied cancer. Furthermore, the ability of Merestinib, in clinical trials, to target translational dependence is attractive as cancer cells often appropriate these signaling pathways to gain tolerance to various stress stimuli. Support: NIH-R01CA264529; DoD Breast Cancer Breakthrough level 2 Award W81XWH2010153"

Clinical • IO biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • CDK1 • EIF4E • RPL5 • SOD2 • XIAP • XPO1

Merestinib In Non-Small Cell Lung Cancer And Solid Tumors (clinicaltrials.gov) - P2 | N=12 | Terminated | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Mar 2024 ➔ Oct 2023 | Active, not recruiting ➔ Terminated; Funding was pulled

Trial completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • MET • NTRK • NTRK1

A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer (clinicaltrials.gov) - P2 | N=309 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2023 ➔ Dec 2025

Metastases • Trial completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of Anti-PD-L1 Checkpoint Antibody (LY3300054) Alone and in Combination in Participants With Advanced Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=215 | Active, not recruiting | Sponsor: Eli Lilly and Company | Phase classification: P1a/1b ➔ P1 | Trial completion date: Dec 2023 ➔ Mar 2024

Combination therapy • Metastases • Phase classification • Trial completion date • Breast Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Hepatology • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Melanoma • Microsatellite Instability • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Skin Cancer • Solid Tumor • ER • HER-2 • MSI • PGR

Combination of an oncokinase inhibitor merestinib with anti-PD-L1 results in enhanced immune mediated antitumor activity in CT26 murine tumor model (AACR 2017) - P1a/1b; "Additionally, the anti-tumor effect of Mer was tested in vivo on established CT26 and B16F10 tumors compared to MET specific TKIs (savolitinib, PF4217903) alone or in combination with PD-L1 antibody (Ab) blockade. The enhanced immune activation of the combination therapy, leading to synergistic anti-tumor efficacy, demonstrates that merestinib has the potential to augment immunotherapy while targeting the tumor directly. This preclinical data provides the rationale for the clinical investigation of merestinib in combination with checkpoint therapies targeting the PD-L1/PD1 axis (NCT02791334)."

Checkpoint inhibition • Combination therapy • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Immunology • Melanoma • Oncology

Evaluation of single agent merestinib (LY2801653) or emibetuzumab (LY2875358) and the combination in a xenograft tumor model bearing MET exon 14 skipping (AACR 2017) - P2; "Merestinib (12 mg/kg) treatment resulted in durable and complete response in 6/7 mice bearing Hs746t tumors with MET ex14 skipping and MET amp. When used singly, merestinib (6 mg/kg) or emibetuzumab (10 mg/kg) resulted in only transient tumor regression in this model, while the combination resulted in substantial tumor regression while on treatment. This combination treatment was however, not as durable as was observed with single agent 12 mg/kg merestinib."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology

Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor (AACR 2017) - P1a/1b; "...In contrast, the MET-specific kinase inhibitor, PF04217903, only weakly inhibited cord formation and endothelial sprouting...In addition, while MET antibody emibetuzumab (human anti-MET antibody) plus ramucirumab (human anti-VEGFR2 antibody) decreased vascular density by 64%, merestinib plus ramucirumab decreased it by 92%...These data suggest that the anti-angiogenic activity of merestinib includes activities of other kinases targeted by merestinib. These data provide rationale and support for the clinical evaluation of combination of merestinib with ramucirumab (NCT02745769)."

Biosimilar • Gastric Cancer • Gastrointestinal Cancer • Oncology

Enhancing nanoparticle paclitaxel antitumor response through targeted inhibition of c-Met pathway by merestinib in gastric cancer models. (ASCO-GI 2023) - "These findings suggest that merestinib has strong antitumor activity in GAC and exhibits an additive effect when administered with nab-paclitaxel. These results provide compelling evidence that this therapeutic approach may lead to a clinically relevant combination to improve GAC patients’ survival."

Preclinical • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • DDR1 • EGFR • EMCN • MET

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical, Clinical, and Correlative Studies (ASH 2019) - "Inhibition of HGF-MET signaling with the specific MET kinase inhibitor crizotinib led to a transient therapeutic effect in AML cells; however, resistance rapidly emerged via increased HGF expression due to activation of alternative kinase pathways such as FGFR1 (Kentsis et al., Nat Medicine, 2012). Preliminary clinical data suggest that merestinib is tolerable and the safety of adding dose-escalated LY2874455 is under investigation. Correlative studies to evaluate the significance of changes in HGF production and in STAT3/5 target genes are on-going."

Acute Myelogenous Leukemia • Cardiovascular • Heart Failure • Immunology • Neutropenia • Oncology • Renal Disease • DNMT3A • FGFR1 • FLT3 • HGF • NPM1 • STAT5 • TP53

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates. (PubMed, Clin Cancer Res) - "We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FGFR • HGF

A Study of Anti-PD-L1 Checkpoint Antibody (LY3300054) Alone and in Combination in Participants With Advanced Refractory Solid Tumors (clinicaltrials.gov) - P1a/1b | N=215 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2022 ➔ Dec 2023

Combination therapy • Trial completion date • Breast Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Hepatology • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Melanoma • Microsatellite Instability • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Skin Cancer • Solid Tumor • ER • HER-2 • MSI • PGR

Gemcitabine and cisplatin plus ramucirumab or merestinib or placebo in first-line treatment for advanced or metastatic biliary tract cancer: A double-blind, randomized phase II trial. (ASCO-GI 2017) - P2; "An exploratory endpoint is to correlate biomarkers with safety and clinical outcome; blood, plasma, serum, and tumor tissue collection is mandatory. The study began in May 2016."

Biomarker • Clinical • P2 data • Biliary Cancer • Biosimilar • Gastrointestinal Cancer • Oncology

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

Comparison of Different First-Line Systemic Therapies in Advanced Biliary Tract Cancer Based on Updated Random Controlled Trials: A Systematic Review and Network Meta-Analysis. (PubMed, Biomed Res Int) - "In the network meta-analysis for OS, gemcitabine + cisplatin (GemCis) + cediranib (HR, 0.11; 95% CI, 0.00-2.88), GemCis+durvalumab (HR, 0.27; 95% CI, 0.06-1.29), and GemCis + merestinib (HR, 0.37; 95% CI, 0.03-4.36) showed the trend of OS benefit over standard treatment (GemCis), although there was no significant difference. GemCis+durvalumab might be the most promising regimen for advanced BTC when considering OS and PFS. GemOxa and GemS1 could be alternative options for advanced BTC patients with nontolerance to GemCis."

Journal • Retrospective data • Review • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer (clinicaltrials.gov) - P2 | N=309 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Merestinib In Non-Small Cell Lung Cancer And Solid Tumors (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial primary completion date: Oct 2020 ➔ Oct 2021

Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • MET • NTRK • NTRK1

Proposal of Foretinib as Second-Line TKI after Capmatinib/Tepotinib Treatment Failure in NSCLC with MET Exon 14 Mutation (IASLC-WCLC 2022) - " Initial screening (300 drugs, including 33 MET-TKIs) was performed using Ba/F3 cells carrying METex14 plus MET D1228A/Y because anecdotal case reports suggested that D1228X mutations were more refractory to second-line MET-TKIs than Y1230X mutations.This screening found four candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). We then performed further growth inhibitory assays using these four candidates plus other four MET-TKIs (type Ib; capmatinib and tepotinib, type II; cabozantinib and merestinib) in Ba/F3 cells carrying METex14 plus one of MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations... The type II MET-TKI foretinib may be an appropriate second-line MET-TKI for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at D1228 or Y1230 residues.212"

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

Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. (PubMed, J Hematol Oncol) - "The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230."

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