Dossier — MET

In the phase 2 VISION trial, patients were prospectively selected for MET exon 14 skipping using tissue RNA or plasma cfDNA/NGS. Tepotinib produced objective responses in approximately half of patients, and matched liquid-biopsy analysis showed a molecular cfDNA response in 67% of evaluable patients, supporting…

VISION investigators defined molecular response as complete disappearance or >75% depletion of the METex14 alteration in cfDNA. Molecular response was observed in 67% of patients with matched baseline/on-treatment samples and was associated with radiographic tumor response, providing clinical evidence of…

In a phase I biomarker-enrichment study, response rate was 47% among patients with MET gene copy number ≥6, and all four evaluable patients with METex14-altered NSCLC had tumor shrinkage. The investigators concluded that MET GCN ≥6 and/or METex14 were useful predictive biomarkers, whereas MET IHC overexpression alone…

Among 499 MET-IHC-selected patients with advanced NSCLC, onartuzumab plus erlotinib produced no improvement in overall survival (6.8 vs 9.1 months; HR 1.27; P=.067) or progression-free survival (2.7 vs 2.6 months; HR 0.99; P=.92). Exploratory MET FISH and gene-expression analyses also showed no benefit.

A fit-for-clinic immunoassay study developed and validated assays measuring phosphorylated MET, including pY1235-MET, and used pMET:MET ratios to quantify MET inhibitor pharmacodynamics, molecular target engagement, and duration of effect. This supports pMET suppression as the most direct target-engagement biomarker,…

In a study of 120 nonsquamous NSCLC cases, MET-IHC positivity changed by up to 40% across tumor areas and MET amplification classification varied by 25–50%; the authors concluded that MET heterogeneity hinders adequate selection for MET-targeted therapy. MET copy-number gains also correlated poorly with total MET…

In the final phase 2 GEOMETRY mono-1 analysis, capmatinib produced objective responses in 68% of 60 treatment-naive patients and 44% of 100 previously treated patients with MET exon 14–skipping NSCLC; median follow-up was 46.4 and 66.9 months, respectively. The investigators concluded that the results support METex14…

FDA converted tepotinib's accelerated approval to traditional approval on February 15, 2024. In the VISION evidence base, blinded independent review showed an objective response rate of 57% among 164 treatment-naive patients and 45% among 149 previously treated patients; 40% and 36% of responders, respectively, had a…

The FDA prescribing information specifies capmatinib for adults with metastatic NSCLC whose tumors harbor a mutation that leads to MET exon 14 skipping, detected by an FDA-approved test, establishing clinical validity of the METex14 biomarker-treatment relationship in routine practice.

FDA granted accelerated approval to telisotuzumab vedotin-tllv on May 14, 2025 for previously treated, locally advanced or metastatic nonsquamous NSCLC with high c-MET protein overexpression, defined as at least 50% of tumor cells with strong 3+ staining by an FDA-approved test.

The study evaluated telisotuzumab vedotin in previously treated, locally advanced or metastatic nonsquamous EGFR-wild-type NSCLC selected for c-Met protein overexpression, using an immunohistochemical threshold of at least 25% of tumor cells with 3+ staining and a high-expression subgroup defined as at least 50% 3+…

In GEOMETRY mono-1, capmatinib response rates were only 7% to 12% in previously treated tumors with MET copy number below 10, leading those cohorts to close for futility. High-level amplification with gene copy number at least 10 showed higher activity, but response remained below the prespecified threshold for…

In GEOMETRY mono-1, objective response was 68% in treatment-naive patients and 41% in previously treated patients, with median response durations of 12.6 and 9.7 months, respectively. Among patients with brain metastases, intracranial responses occurred in 7 of 13 evaluable patients, including complete resolution in 4.

The FDA’s traditional-approval review of VISION reported an objective response rate of 57% in treatment-naive patients and 45% in previously treated patients, with median durations of response of 9.1 and 8.4 months, respectively. The approved regimen is 450 mg orally once daily; the dataset included 313 patients with…

FDA review materials state that chemotherapy and immunotherapy remain background options for METex14-positive NSCLC, but there is no indication that METex14-positive tumors have higher response rates to platinum chemotherapy or immunotherapy than the general NSCLC population. This supports biomarker-selected MET…

In GEOMETRY mono-1, capmatinib efficacy in MET-amplified NSCLC was higher in tumors with high gene copy number than in tumors with low gene copy number, whereas METex14-skipping disease showed the clearest and most reproducible activity. This supports prioritizing METex14 over nonspecific MET amplification for…

A 2025 Nature Reviews Clinical Oncology review states that capmatinib, tepotinib, and savolitinib are approved for advanced METex14-mutant NSCLC, while additional agents including crizotinib, gumarontinib, bozitinib, and ensartinib have also been tested. This crowded class may limit differentiation for any individual…

The FDA granted accelerated approval on May 14, 2025, to the c-Met-directed antibody-drug conjugate telisotuzumab vedotin for previously treated nonsquamous NSCLC with high c-Met protein overexpression. Its approval expands competition beyond METex14-directed TKIs and produced a 35% ORR with a 7.2-month median…

METex14 skipping and focal amplification are recurrent drivers, though the allelic series is narrower.

In 230 resected lung adenocarcinomas, DNA/RNA profiling identified MET exon 14 skipping in 4% of tumors; 10 tumors had MET exon 14 skipping in RNA, and 9 of these carried a MET splice-site mutation or deletion. The study concluded that cis-acting splice-site mutations activate MET by exon 14 skipping.

Comprehensive genomic profiling of 38,028 tumors identified 221 MET exon 14 alterations, including 126 distinct sequence variants. METex14 occurred in 3% of lung adenocarcinomas and 2.3% of other lung neoplasms; functional studies showed constitutive MET activation and oncogenic transformation, while clinical cases…

Among 11,205 lung cancers, 298 (2.7%) harbored alterations predicted to cause MET exon 14 skipping. Frequencies included 2.9% in adenocarcinoma, 2.1% in squamous carcinoma, and 7.7% in sarcomatoid carcinoma; 15% of METex14 tumors also had MET amplification.

In a cfDNA cohort of 289 advanced METex14 NSCLCs, RAS–MAPK alterations were detected before treatment and were more frequent than in an independent EGFR-mutant comparison cohort; the clinical and preclinical analyses indicated that these alterations can promote primary resistance or reduce the magnitude and duration…

In a clinical series, four patients with stage IV lung adenocarcinoma harboring MET exon 14 splice acceptor or donor mutations experienced responses to crizotinib or cabozantinib. The alterations cause exon 14 skipping, remove the CBL-binding juxtamembrane region, and reduce turnover of the aberrant MET protein.

A systematic review and meta-analysis of 18,464 NSCLCs estimated MET exon 14 mutation prevalence at approximately 3% and found an association with worse survival (HR 1.82, 95% CI 1.04–3.19). This limits the generalizability of MET as a broad human-genetic disease mechanism and indicates clinically heterogeneous…

Aberrant MET signalling via the HGF axis is well characterised mechanistically.

In lung cancer, somatic intronic MET mutations produced an alternatively spliced receptor lacking the juxtamembrane domain and CBL E3-ligase binding site. The mutant receptor showed decreased ubiquitination, delayed down-regulation, increased MET expression, and sustained phospho-MET and downstream MAPK activation…

The FDA mechanism-of-action description states that MET phosphorylation can be triggered by hepatocyte growth factor or MET amplification, leading to phosphorylation of downstream signaling proteins and proliferation and survival of MET-dependent cancer cells. It also identifies exon 14 skipping as a loss of negative…

In EGFR-mutant NSCLC models that acquired gefitinib resistance, focal MET amplification restored downstream signaling through ERBB3/HER3-dependent PI3K activation. MET inhibition restored gefitinib sensitivity, and MET amplification was detected in 4 of 18 clinical specimens with acquired gefitinib or erlotinib…

In EGFR-mutant lung-cancer models, MET amplification activated ERBB3/PI3K/AKT signaling, whereas HGF-mediated MET activation induced resistance through GAB1 signaling. Combined EGFR and MET inhibition overcame resistance caused by either mechanism in vivo.

In 499 patients with MET-positive NSCLC selected by immunohistochemistry, onartuzumab plus erlotinib did not improve progression-free survival or overall survival; median overall survival was shorter with onartuzumab than with erlotinib alone (6.8 vs 9.1 months; HR 1.27). Exploratory analyses using MET FISH and…

The ATTENTION trial enrolled 307 Asian patients with previously treated, EGFR-wild-type, nonsquamous NSCLC. The trial did not demonstrate a significant overall-survival benefit for tivantinib plus erlotinib, providing negative clinical evidence for broad MET-pathway inhibition outside a tightly defined MET-dependent…

In a panel of nine lung cancer cell lines, EBC-1 and H1993 harbored significant MET amplification, constitutive MET phosphorylation, and high MET expression. shRNA-mediated MET knockdown caused significant growth inhibition, G1–S arrest, and apoptosis in these MET-amplified lines, while having little or no effect in…

In MET-amplified NSCLC cell lines and six MET-amplified lung-cancer patient-derived xenograft models, MET tyrosine-kinase inhibition with crizotinib was associated with inhibition of MET survival signaling and antitumor responses. MET–GRB2 complexes were identified in MET-driven models, and their presence correlated…

The study established six patient-derived EGFR-mutant, MET-amplified lung-cancer models. All six showed downstream signaling governed by MET activation and sensitivity to single-agent MET inhibition; adding an EGFR inhibitor produced no greater efficacy than MET inhibition alone in vitro or in vivo.

In a nine-cell-line NSCLC panel, shRNA-mediated MET knockdown caused strong growth inhibition, G1–S arrest and apoptosis in the two MET-amplified lines, but had little or no effect in the other seven non-amplified lines. This weakens a broad MET-dependency claim and supports biomarker-restricted activity.

Genetic ablation of MET in A549 cells produced growth rates and tumor-cell proliferation comparable to wild-type cells, while impairing HGF-driven anchorage-independent growth, invasion, anoikis resistance and lung colonization. Thus, MET perturbation affected metastatic behavior more clearly than baseline tumor-cell…

Across A549, H3122, PC9, HCC827, resistant derivatives and MET-amplified H1993/EBC-1 cells, tivantinib showed broader anti-proliferative activity than selective MET TKIs. The study concluded that tivantinib efficacy was independent of MET inhibition, indicating that pharmacologic results with this agent cannot be used…

A generally manageable on-target profile (peripheral oedema) gives an acceptable window.

In the phase 2 GEOMETRY mono-1 trial, capmatinib produced objective responses in 41% of previously treated patients and 68% of treatment-naive patients with MET exon 14 skipping NSCLC; median response durations were 9.7 and 12.6 months, respectively.

In GEOMETRY mono-1, capmatinib activity was limited in previously treated tumors with low-level MET amplification below 10 gene copies, with responses in only 7–12% of patients, whereas responses were higher in MET exon 14–altered disease and high-level amplification.

The current TABRECTA label reports serious adverse reactions in 53% of 373 treated patients, fatal adverse reactions in 0.5%, permanent discontinuation for adverse reactions in 17%, and common adverse reactions including edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite.…

In the phase 2 VISION study, tepotinib produced a 46% independently assessed response rate with a median response duration of 11.1 months; grade 3 or higher treatment-related adverse events occurred in 28% of patients, peripheral edema was the main grade ≥3 toxicity, and 11% discontinued treatment because of adverse…

The FDA label reports interstitial lung disease/pneumonitis in 2% of treated patients, including one fatal Grade ≥3 event; 1% discontinued treatment because of ILD/pneumonitis.

The FDA label reports ALT/AST increases in 18%, Grade 3–4 ALT/AST increases in 4.7%, one fatal hepatic-failure event, amylase/lipase increases in 13%, and teratogenicity in rabbits at exposures below the human clinical exposure.

In a treatment-naive cohort of 687 NSCLCs, moderate-to-strong MET protein expression by tumor-cell immunohistochemistry was detected in 33.5% of cases. MET IHC positivity was reported in 49.7% of adenocarcinomas, 42.9% of adenosquamous carcinomas, 40.9% of pleomorphic/sarcomatoid carcinomas, and 5.6% of squamous cell…

In 300 surgically resected NSCLCs, including 93 with matched nodal metastases, MET protein was assessed by IHC and MET gene copy number by FISH. Primary tumors were MET-IHC positive in 10.3% of cases, whereas MET protein expression was present in 21.3% of nodal metastases; high MET gene copy number was also more…

Among 687 NSCLCs, moderate-to-strong MET protein expression was detected in 33.5% overall, but rates varied substantially by histology: 49.7% in adenocarcinoma, 42.9% in adenosquamous carcinoma, 40.9% in pleomorphic/sarcomatoid carcinoma, 15.6% in large-cell carcinoma, and 5.6% in squamous cell carcinoma;…

In a tri-institutional cohort of 181 metastatic lung adenocarcinomas, 39% were MET-IHC positive, but only 2% were MET-amplified and 1% harbored MET exon 14 mutations; only 1% of IHC-positive cases were amplified and 3% carried METex14, indicating substantial discordance between tissue protein staining and actionable…

Among 81 resected lung sarcomatoid carcinomas, IHC sensitivity was 50% for MET amplification and 20% for MET exon 14 mutation, with positive predictive values of 21.4% and 7%, respectively; the authors concluded that IHC was not a relevant screening tool for MET abnormalities.

In a cohort of 168 MET exon 14-altered NSCLCs, MET expression was undetectable in tumors with DNA- and RNA-confirmed exon 14 skipping, and the study reported heterogeneous MET protein expression in both early-stage and metastatic disease; tumors without detectable MET expression did not respond to MET inhibition in…

Approved MET TKIs confirm small-molecule tractability.

The FDA granted regular approval to capmatinib (Tabrecta), a MET kinase inhibitor, on August 10, 2022, for adults with metastatic NSCLC whose tumors harbor a mutation leading to MET exon 14 skipping, as detected by an FDA-approved test.

In the phase 2 GEOMETRY mono-1 study, overall response was 68% in previously untreated patients and 41% in patients who had received one or two prior lines; median response duration was 12.6 and 9.7 months, respectively.

The FDA granted traditional approval to tepotinib (Tepmetko) on February 15, 2024, based on the VISION study; objective response rates were 57% in treatment-naive patients and 45% in previously treated patients, with durable responses in both groups.

The FDA granted accelerated approval to telisotuzumab vedotin-tllv (Emrelis), a c-Met-directed antibody conjugated to a microtubule inhibitor, for previously treated locally advanced or metastatic nonsquamous NSCLC with high c-Met expression defined as at least 50% of tumor cells showing strong 3+ staining.

In the phase 2 LUMINOSITY trial, telisotuzumab vedotin was evaluated using immunohistochemical c-Met expression selection; the publication reports durable antitumor activity and supports c-Met protein overexpression as a tractability biomarker for an ADC approach.

In GEOMETRY mono-1, capmatinib activity was limited in previously treated tumors with MET amplification and gene copy number below 10, whereas response rates were higher in tumors with gene copy number of at least 10; this supports a modality strategy that is strongly dependent on the specific MET alteration and its…