Tepmetko (tepotinib)

P1, N=0, Withdrawn, M.D. Anderson Cancer Center | N=60 --> 0 | Trial completion date: Dec 2025 --> Apr 2024 | Active, not recruiting --> Withdrawn | Trial primary completion date: Dec 2025 --> Apr 2024

Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation...Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1...Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC.

There are three currently active sub-studies and one soon to be activated sub-study studying amivantamab-vmjw in MET amplification positive NSCLC (S1900J). Current sub-studies: S1900E (KRAS) activated on April 2, 2021 and is studying sotorasib (AMG 510) in non-squamous NSCLC...S1900G (EGFR and MET) activated on April 3, 2023 and is studying capmatinib and osimertinib with or without ramucirumab in NSCLC. S1900K (MET exon 14 skipping) activated on December 18, 2023 and is studying tepotinib with or without ramucirumab in NSCLC...One hundred seventy (7%) were submitted with the classification of "Other". The most common reasons included: no sub studies available, patient chose hospice, and patient transferred to different hospital.

P1, N=60, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Phase classification: P1a/1b --> P1 | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.

While c-MET inhibitors such as crizotinib, capmatinib, tepotinib and cabozantinib have garnered FDA approval for non-small cell lung cancer (NSCLC), their potential within breast cancer therapy is still undetermined...Furthermore, we highlight the pivotal role of c-MET-targeted therapies in breast cancer, offering a clinical perspective on this promising avenue of intervention. In this pursuit, we strive to unravel the potential of c-MET as a beacon of hope in the fight against breast cancer, unveiling new horizons for therapeutic innovation.

Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.

High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.

Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added...The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

These in vitro findings suggest that compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibits the growth of c-MET-positive GC cells, cells lacking MET amplification but containing phosphorylated MET, and cells containing MET mutations. Clinical studies are required to confirm the therapeutic effects of these regimens.

Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines...Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.

The side effects from sacituzumab govitecan could generally be managed well by doctors. Although there were more side effects with sacituzumab govitecan than with chemotherapy, they were generally mild to moderate.

Thus, the results of our present investigation offer valuable insights into the interaction between TPT and ctDNA. It is evident that TPT, as an anti-cancer medication, binds to the minor groove of ctDNA.

P2, N=120, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Sep 2023 --> May 2024

No abstract available

Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992).

We corroborated these data with target engagement studies by fluorescence cross-correlation spectroscopy using KD constructs in cell lysates or full-length receptors from solubilized cellular membranes as wildtype or activated mutants (Y1235D and Y1234E/1235E). Collectively, our results provide further insight into the MET A-loop structural determinants that affect the binding of the selective inhibitor tepotinib.

No abstract available

Importantly, compared with the combination of Larotrectinib and Tepotinib, 1D228 monotherapy in MKN45 xenograft tumor models showed stronger antitumor activity and lower toxicity. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for cancer patients with abnormal expressions of c-Met or NTRK, or simultaneous of them.

MET exon 14 (METex14) skipping mutation is noted in approximately 4% of NSCLC cases and is targetable with the recently approved tyrosine kinase inhibitors capmatinib and tepotinib. We highlight some ongoing capmatinib clinical trials that expand their role to other subsets of patients, especially those with EGFR mutations, who develop MET alterations as a resistance pathway. We further provide our perspective on the management of METex14 NSCLC, strategies for sequencing agents, and toxicity management.

P2, N=47, Not yet recruiting, Samsung Medical Center

Accrual Goals The accrual goal is 56 participants to achieve 50 eligible participants. Accrual will be placed on hold during the interim safety assessment of the first 10 toxicity-evaluable participants enrolled to the tepotinib/ramucirumab arm.

P1/2, N=2, Terminated, Criterium, Inc. | N=65 --> 2 | Trial completion date: Jul 2027 --> Jun 2023 | Recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Jun 2023; Study was terminated due to lack of lack of enrollment and difficult patient population.

P1/2, N=60, Not yet recruiting, M.D. Anderson Cancer Center

No abstract available

Improvements with tepotinib vs comparators were also seen in VISION pts overall and pts in Asia, regardless of T+ status. Conclusions Based on available evidence (with limited capmatinib subgroup size), the MAICs show no clinically relevant differences in ORR and trends for longer PFS and/or OS with tepotinib vs savolitinib, gumarontinib, or capmatinib in pts in Asia in 1L and 2L+.

Conclusions TEP+OSI was generally well tolerated in patients in Asia, comparable to the overall population. Most AEs were considered manageable with TEP and/or OSI dose modifications.

P2, N=32, Active, not recruiting, The University of Sydney | Recruiting --> Active, not recruiting

Although the introduction of IO has led to a step change in non-oncogenic NSCLC, in patients with METex14 skipping NSCLC, consistent with published observational data, we find time-to-event outcomes to be shorter. Despite limited patient numbers, the evidence presented suggests similarly patterns for IO+chemo. Estimated PFS is longer with tepotinib, while evidence on overall survival remains uncertain and confounded by subsequent treatment use, but does suggest a differential outcome for any treatment in isolation.

MET inhibitors are investigated in open-label, single-arm trials in patients with METex14 skipping aNSCLC, such as the VISION trial investigating tepotinib... MOMENT is designed to collect high-quality RWD from a rare patient population with METex14 skipping aNSCLC and enable further studies which can inform optimal care of these patients.

All methods demonstrated a progression-free QALY and survival benefit of tepotinib versus C+IO providing evidence of superiority. The greatest differences are driven by post-progression survival which is likely due to the different data sources used, as only method 1 uses the correct METex14 skipping population, whereas methods 2 and 3 rely on the wider NSCLC data, which is a major limitation of these approaches.

In comparisons using both TOGETHER and published studies, tepotinib provided longer PFS than chemotherapy, with OS differences seemingly reduced by subsequent therapy use. Although cross-study comparisons can be complex, using a combination of individual and aggregate level data, hypotheses (such as the impact of subsequent therapies) can be tested, overcoming the limitations of a single data source.

P2; Trial completion date: Aug 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

No abstract available

The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine appears elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization...Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted.

No abstract available