onartuzumab (RG3638) / Roche - LARVOL DELTA

Light-Induced Synthesis and Radiotheranostic Treatment of Gastric Cancer with 161Tb-Labeled Monoclonal Antibodies. (PubMed, JACS Au) - "Collectively, the new complexation and chemoselective photoconjugation chemistries overcome some of the limitations in traditional labeling approaches. Photoradiosynthesis represents an excellent platform for building future antibody-based radiotracers for applications in diagnostic and therapeutic medicine."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • MET

Photoradiolabeling of onartuzumab with 99mTc and 188Re-tricarbonyl for radiotheranostics of gastric cancer. (PubMed, Chem Sci) - "Here, we report the synthesis and characterization of 99mTc- and 188Re-onartuzumab by labeling of the cancer-specific mAb onartuzumab (MetMAb) with the corresponding metal-tricarbonyl complexes derived from a novel photoactivatable ligand...Overall, the experiments demonstrated that photoradiosynthesis can be employed to develop a variety of rhenium based radioimmunoconjugates for future applications in tumor targeted radioimmunotherapy. Furthermore, these results underline the high potential of rhenium and technetium radioconjugates as theranostic platforms."

IO biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • MET

Systematic Literature Review (SLR) of Randomized Controlled Trials (RCTs) of Treatments for First-Line (1L) Gastric Cancer/Gastroesophageal Junction Adenocarcinoma (GC/GEJ) in Adult Patients (ISPOR-EU 2024) - "Among trials of PD-1/PD-L1 inhibitors (tislelizumab, nivolumab, pembrolizumab, sugemalimab, sintilimab), improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were observed for PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone at median follow-up times ranging from 11.6 to 54.3 months, with median OS, median PFS, and ORR ranging from 12.5 to 17.45 months, 6.9 to 10.94 months, and 47.3% to 68.6%, respectively...Among other targeted therapies, response and survival benefits compared to chemotherapy were mixed; improvements in response and survival were seen with the CLDN18.2 inhibitor zolbetuximab and the FGFR inhibitor bemarituzumab, while benefits compared to chemotherapy were not seen with cetuximab, ramucirumab, andecaliximab, onartuzumab, rilotumumab, pazopanib, or ipatasertib... PD-1/PD-L1 inhibitors showed improved efficacy compared to chemotherapy for the treatment of 1L GC/GEJ; while other..."

Clinical • IO biomarker • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CLDN18 • CTLA4 • HER-2

Randomized phase II study of FOLFOX +/- MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC) (ASCO-GI 2015) - Abstract #2; P2, N=123; “The addition of O to mFOLFOX6 in metastatic GEC did not improve PFS in either an unselected population or in MET-positive patients as defined by IHC.”

P2 data • Oncology

TARGETED THERAPY OF MET, TYROSINE KINASE RECEPTOR, IN PEDIATRIC HIGH-GRADE OSTEOSARCOMAS : A NEW WAY TO TREAT PATIENTS ? (CTOS 2024) - "We demonstrated mostly with a selective-MET gene inhibitor a significant antiproliferative effect and a stop of invasive OS cell capacities based on cell-cell interaction pathways associated to a metabolic maintenance of nutrient dependencies."

Clinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • HGF

Erratum: Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O6-Methylguanine-DNA Methyltransferase Biomarker Analyses. (PubMed, J Clin Oncol) - No abstract available

Biomarker • Clinical • Journal • P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • HGF

Synthesis and Evaluation of a Novel c-Met-Targeting Cyclic Peptide as a Potential Diagnostic Agent for Colorectal Cancer. (PubMed, Mol Pharm) - "In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC."

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

HNODThia: A Promising Chelator for the Development of Cu Radiopharmaceuticals. (PubMed, Inorg Chem) - "One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [Cu]Cu-7-azepin-HSA and [Cu]Cu-7-azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable Cu-radiopharmaceuticals by using aza-heterocyclic tacn-based chelators, and the method can easily be extended to the development of Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy."

Journal • Renal Cell Carcinoma

Clinicopathological characteristics of Non-Small Cell Lung Cancer (NSCLC) patients with c-MET exon 14 skipping mutation, MET overexpression and amplification. (PubMed, BMC Pulm Med) - "Together, these findings indicated a significant correlation between MET overexpression and MET amplification in NSCLC patients but no correlation to prognosis."

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

Preclinical evaluation of MCLA-129, a bispecific antibody targeting EGFR and c-MET on solid tumor cells, in comparison with amivantamab (AACR 2023) - "A phase 1/2 clinical trial of MCLA-129 in solid tumors is ongoing. These data support the further clinical development of MCLA-129 in patients with NSCLC and other solid tumors."

Preclinical • Tumor cell • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

Development of a MET-targeted single-chain antibody fragment as an anti-oncogene targeted therapy for breast cancer. (PubMed, Invest New Drugs) - "Histopathology and immunohistochemical assessments revealed higher rate of response to therapy. In our study, we designed and synthetized a novel anti-MET scFv which could effectively suppress MET-overexpressing breast cancer tumors."

Journal • Breast Cancer • Oncology • Solid Tumor

MET-Lung: A Phase III Trial of Onartuzumab (METMab) Plus Erlotinib vs Erlotinib in Previously Treated Stage IIIB or IV NSCLC (WCLC 2017) - "Alternative design strategies such as a randomized Phase II/III design that can better balance benefit and risk for our patients and still achieve the goal should be considered. Criteria should be established to help investigators select the appropriate design"

Biomarker • Retrospective data • Non Small Cell Lung Cancer

Dissecting Gastric Cancer biology and how and when to use immunotherapy (ESMO 2018) - P2, P3; "... We explored 2 randomized MetMAb trials (Ph3 Study 1 YO28322 and Ph2 Study 2 YO28252) in combination with mFOLFOX6 in metastatic HER2-negative and MET-positive GC... Although GC has been challenging to treat, it may be possible to increase the success of immunotherapy with carefully tailored combination therapies in the Stage IV setting with molecules that inhibit pathways such as Notch, Wnt and TGFb. Furthermore, it may make a lot of sense to take immunotherapies into Stage I, II and III GC where the immune and Teff gene prognosis is good and the disease is less convoluted."

IO biomarker • MSi-H Biomarker • PD(L)-1 Biomarker • Gastric Cancer • Lung Cancer

Engaging c-MET (mesenchymal-epithelial transition factor) Axis to Enhance the Safety and Antitumor Function of HER2-CAR T-Cells in Sarcoma (TCT-ASTCT-CIBMTR 2023) - "Methods : We developed a HER2-CAR/5D5-T, a T-cell co-expressing a first generation HER2-CAR and a c-MET antibody receptor derived from Onartuzumab (MetMAb; OA-5D5), linked to a 4-1BB co-stimulatory domain...However, the pattern of pro-inflammatory cytokine production (e.g., IL6, TNFα, GMCSF) in conditions with variable densities of target antigen HER2 was moderate, density dependent and distinct from 2 nd generation HER2-CART (Figure 1d-g). Conclusion : Our studies suggest a more favorable functional profile of HER2-CAR/5D5-T and support further testing of strategies to combine c-MET inhibition with CART targeting HER2 or other tumor-associated antigens in sarcoma."

CAR T-Cell Therapy • Clinical • IO biomarker • Immune Modulation • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • HER-2 • IFNG • IL2 • IL6 • MET • TNFA

A rotaxane-based platform for tailoring the pharmacokinetics of cancer-targeted radiotracers. (PubMed, Chem Sci) - "Head-to-head comparison of the biodistribution and excretion profile of [Zr]ZrFe-2versus two control compounds, alongside characterisation of two potential metabolites, showed that the rotaxane-radiotracer has an improved clearance profile with higher tumour-to-tissue contrast ratios and reduced radiation exposure to critical (dose-limiting) organs including liver, spleen, and kidneys. Collectively, the experimental results suggested that non-covalent mechanical bonds between the radionuclide and mAb can be used to fine-tune the pharmacokinetic profile of supramolecular radiopharmaceuticals in ways that are simply not accessible when using traditional covalent design."

IO biomarker • Journal • PK/PD data • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Immunology • Oncology • Solid Tumor • MET

Heptadentate chelates for Zr-radiolabelling of monoclonal antibodies. (PubMed, Inorg Chem Front) - "One-pot Zr-photoradiosynthesis produced [Zr]Zr-2-onartuzumab directly from the formulated, clinical-grade sample MetMAb™, without pre-purifying the monoclonal antibody (mAb) component, with an isolated decay-corrected radiochemical yield of 36.4 ± 2.4%. PET imaging and biodistribution studies were performed in female athymic nude mice bearing subcutaneous xenografts derived from the MKN-45 human gastric cancer cell line to assess the pharmacokinetic profile and tumour binding of [Zr]Zr-2-onartuzumab. Specific tumour uptake of [Zr]Zr-2-onartuzumab was confirmed by using competitive inhibition (blocking) studies and bone uptake was significantly reduced compared to the parent DFO analogue."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases. (PubMed, Molecules) - "The aim of current study is the comparison of therapeutic combinations of the currently applied in clinical practice: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, and Satraplatin...The very important strategy for the improvement of the antitumor effect against different cancers is synergistic combination of Cisplatin derivatives with: (1) anticancer agents-Fluorouracil, Gemcitabine, Cytarabine, Fludarabine, Pemetrexed, Ifosfamide, Irinotecan, Topotecan, Etoposide, Amrubicin, Doxorubicin, Epirubicin, Vinorelbine, Docetaxel, Paclitaxel, Nab-Paclitaxel; (2) modulators of resistant mechanisms; (3) signaling protein inhibitors-Erlotinib; Bortezomib; Everolimus; (4) and immunotherapeutic drugs-Atezolizumab, Avelumab, Bevacizumab, Cemiplimab, Cetuximab, Durvalumab, Erlotinib, Imatinib, Necitumumab, Nimotuzumab, Nivolumab, Onartuzumab, Panitumumab, Pembrolizumab, Rilotumumab, Trastuzumab, Tremelimumab, and Sintilimab. An important approach for..."

Combination therapy • IO biomarker • Journal • Review • Oncology

Efficacy and safety of bevacizumab combined with other therapeutic regimens for treatment of recurrent glioblastoma: A network meta-analysis. (PubMed, World Neurosurg) - "Both Bev + CCNU and Bev + rindopepimut could be considered as effective therapies for treating the recurrent glioblastoma according to the network meta-analysis results. Among them, Bev + rindopepimut therapy seems to be safer and more effective. Moreover, we found that Bev + Iri also appeared to be an effective therapy in a retrospective study."

Journal • Retrospective data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Comparative efficacy and safety of anti-HGF/MET pathway agents plus chemotherapy versus chemotherapy alone as first-line treatment in advanced gastric cancer: a protocol for a systematic review and meta-analysis. (PubMed, BMJ Open) - "Randomised controlled trials (RCTs) were undertaken assessing whether the addition of anti-HGF/MET agent (rilotumumab or onartuzumab) to chemotherapy improves survival outcomes of advanced GC, but conflict conclusions were reached...It is anticipated that the dissemination of results will take place at conferences and through publication in a peer-review journal, any adjustments from the protocol will be clearly documented and explained in its final report. CRD42020177404."

Journal • Retrospective data • Review • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • HGF

The Significance of MET Expression and Strategies of Targeting MET Treatment in Advanced Gastric Cancer. (PubMed, Front Oncol) - "MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • MET

Changes in plasma genomic abnormalities at chromosome 8 and 20 predict treatment response and monitor disease progression in advanced gastric cancer (AACR 2018) - P2; "...Using low-pass whole-genome sequencing (LP-WGS) data from 329 blood plasma samples collected from 63 1L metastatic (mGC) patients enrolled in phase II trial NCT01590719, receiving either onartuzumab or placebo in combination with mFOLFOX6, we evaluated the global percent genome change (%GC) and copy number (CN) gain at baseline and throughout the course of treatment...Monitoring %GC pre- and post-treatment demonstrates the ability to assess the depth of the treatment and early detection of disease progression. Findings from this study suggest that plasma genomic abnormality monitoring may be used for treatment decision-making in mGC and should be evaluated further in clinical trials."

Gastric Cancer

"Capmatinib? Tivantinib? Emibetuzumab ? Onartuzumab?" (@EnriquedeAlava)

Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer. (PubMed, Crit Rev Oncol Hematol) - "Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping...Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients."

Journal • Review • Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

The efficacy and safety of onartuzumab in patients with solid cancers: A meta-analysis of randomized trials. (PubMed, Indian J Cancer) - "With respect to AEs, onartuzumab increased the incidence of hypoalbuminemia (odds ratio (OR) = 14.8 [95% CI, 3.49-62.71], P < 0.001), peripheral edema (OR = 6.52 [95% CI, 3.60-11.81], P < 0.001), neutropenia (OR = 1.36 [95% CI, 1.03-1.79], P = 0.03), thrombocytopenia (OR = 1.98 [95% CI, 1.03-3.81], P = 0.04), and venous thrombotic events (OR = 3.05 [95% CI, 1.39-6.71], P = 0.006). This meta-analysis indicates that the addition of onartuzumab to the standard treatments had no definite survival benefit with increased severe toxicities in patients with solid cancer."

Journal • Retrospective data • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia • Venous Thromboembolism

OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models (AACR 2018) - "In an EGFR inhibitor resistant PDX having MET amplification, single agent OMO-1 caused tumour stasis whereas MetMab/erlotinib only led to tumor growth delay. The potent preclinical activity we have observed, supports ongoing clinical development of OMO-1 in patients with MET pathway-driven tumors."

Monotherapy • Preclinical • Gastric Cancer • Non Small Cell Lung Cancer