Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose

Xiong, Wenyuan; Friese-Hamim, Manja; Johne, Andreas; Stroh, Christopher; Klevesath, Manfred; Hong, David S.; Girard, Pascal; Bawab, Samer El

doi:10.1002/psp4.12602

Cited by 24 publications

(19 citation statements)

References 41 publications

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“…Dose reductions, which can enable patients to continue benefiting from treatment, should be considered early to mitigate severity, and frequent short interruptions can also be considered. Data from a phase I study of tepotinib, and translational modelling approaches, indicate that ≥95% MET inhibition can be achieved at reduced doses of tepotinib (12,33). ILD-like events were uncommon, although lung function monitoring remains important in patients being treated for NSCLC.…”

Section: Discussionmentioning

confidence: 99%

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

Sakai

Felip³

et al. 2022

Clinical Cancer Research

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Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations. See related commentary by Rosner and Spira, p. 1055

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Section: Discussionmentioning

confidence: 99%

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

Sakai

Felip³

et al. 2022

Clinical Cancer Research

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“…MET is a proto-oncogene, and its abnormal signaling increases the proliferation, survival, invasion, and metastasis of tumor cells (Paik et al 2020 ). Tepotinib was approved for metastatic non-small cell lung cancer in adults following a priority review, and it was generally well tolerated (Xiong et al 2021 ). Sotorasib is the first-in-class drug targeting the G12C-mutated KIRSTEN RAT SARCOMA viral oncogene homologue (KRAS).…”

Section: Methodsmentioning

confidence: 99%

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

Kaykı-Mutlu

Aksoyalp

Wojnowski

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition (“first-in-indication”), (2) first drug using a novel molecular mechanism (“first-in-class”), and (3) “next-in-class”, i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indication drugs. By treatment area, the largest group is once again cancer drugs, many of which target specific genetic alterations. Every second drug approved in 2021 targets an orphan disease, half of them being cancers. Small molecules continue to dominate new drug approvals, followed by antibodies and non-antibody biopharmaceuticals. In 2021, the FDA continued to approve drugs without strong evidence of clinical effects, best exemplified by the aducanumab controversy.

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“…1 c). We expand these observations using additional Met inhibitors Crizotinib (0.1 µM) and Tepotinib (0.1 µM), currently used in the clinic with patients with advanced solid tumor [ 38 , 39 ] by studying phosphorylation of additional HER3–tyrosine residues (Y1222 and Y1289), known to participate in phosphatidylinositol-3 kinase signaling [ 12 ]. These results demonstrate that all three Met RTK inhibitors efficiently decrease HER3 phosphorylation on both tyrosine residues (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Met–HER3 crosstalk supports proliferation via MPZL3 in MET-amplified cancer cells

Stern

Al-Ghabkari

Monast

et al. 2022

Cell. Mol. Life Sci.

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Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3–tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in vitro and in vivo. Gene expression analysis of HER3-depleted cells identified MPZL3, encoding a single-pass transmembrane protein, as HER3-dependent effector in multiple MET-amplified cancer cell lines. MPZL3 interacts with HER3 and MPZL3 loss phenocopies HER3 loss in MET-amplified cells, while MPZL3 overexpression can partially rescue proliferation upon HER3 depletion. Together, these data support an oncogenic role for a HER3–MPZL3 axis in MET-amplified cancers.

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Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 24 publications

References 41 publications

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

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

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

Met–HER3 crosstalk supports proliferation via MPZL3 in MET-amplified cancer cells

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