ArticleCPT: pharmacometrics & systems pharmacology2021
Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose.
Article in CPT: pharmacometrics & systems pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.Nature medicine · 2026Trial
- Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Trial
- Preclinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-Wild-type Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Biomimetic Tumour Model Systems for Pancreatic Ductal Adenocarcinoma in Relation to Photodynamic Therapy.International journal of molecular sciences · 2025Review
- Sensitivity of Tepotinib to Inhibitors or Inducers of CYP3A4 and P-Gp: Drug Interaction Studies and Physiologically-Based Pharmacokinetic Analysis.Clinical and translational science · 2025Article
- Model-Based Evaluation of HangAmDan-B1 and Afatinib Combination Therapy in HCC827 Xenograft Mice with Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Model-Informed Selection of the Recommended Phase 2 Dosage for Anti-TIGIT Immunotherapy Leveraging co-Expressed PD-1 Inhibitor Target Engagement.Clinical pharmacology and therapeutics · 2025Article
- Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.Cancer discovery · 2024Article
- Moving the needle for oncology dose optimization: A call for action.Clinical and translational science · 2024Article
- Moving the needle for oncology dose optimization: A call for action.CPT: pharmacometrics & systems pharmacology · 2024Article
- Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development.CPT: pharmacometrics & systems pharmacology · 2024Review
- Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.GigaScience · 2024Article
- Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates.Investigational new drugs · 2023Article
- The Preclinical Pharmacology of Tepotinib-A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations.Molecular cancer therapeutics · 2023Review
- Model-based assessment of combination therapies - ranking of radiosensitizing agents in oncology.BMC cancer · 2023Article
- A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021.Naunyn-Schmiedeberg's archives of pharmacology · 2022Review
- Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management.Clinical lung cancer · 2022Article
- Population pharmacokinetic analysis of tepotinib, an oral MET kinase inhibitor, including data from the VISION study.Cancer chemotherapy and pharmacology · 2022Article
- Met-HER3 crosstalk supports proliferation via MPZL3 in MET-amplified cancer cells.Cellular and molecular life sciences : CMLS · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first-in-human (FIH) trial, an efficacy-driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP-4 pancreatic cell-line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP-4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near-to-complete (>95%) phospho-MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose-dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy-driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non-small cell lung cancer harboring MET exon 14 skipping.
Indexed as
Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.