Spotlight on Tepotinib and Capmatinib for Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation

Brazel, Danielle; Zhang, Shannon; Nagasaka, Misako

doi:10.2147/lctt.s360574

Cited by 14 publications

(7 citation statements)

References 61 publications

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“…PSC is considered an aggressive subtype of lung cancer. Patients with PSCs generally show rapid progression, early metastasis, and dismal prognosis ( 28 ). The mOS of stage IV PSC patients was only 5.4 months in results from the National Cancer Database ( 29 ) and 2 months in those from the Surveillance, Epidemiology, and End Results (SEER) database ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study

Gow

Hsieh²,

Chen³

et al. 2023

Front. Oncol.

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IntroductionThe MET exon 14 skipping (METex14) mutation is an important oncogenic driver in lung cancer. We performed a retrospective analysis of clinical data from lung cancer patients with the METex14 mutation to analyze their survival outcomes and associated prognostic factors.MethodsA one-step reverse transcription-polymerase chain reaction to examine the presence of the METex14 mutation was performed using RNA samples from 1374 lung cancer patients with no detected EGFR and ALK mutations. Pathological features and immunohistochemistry (IHC) results for c-MET were analyzed in patients with METex14-positive tumors.ResultsMETex14 was identified in 69 patients with lung cancer, including 53 adenocarcinoma (ADC) and 16 non-ADC patients. In comparison with patients without the METex14 mutation, lung cancer patients harboring the METex14 mutation were generally elderly individuals, never-smokers, and had poor performance scores. A higher frequency of METex14 mutations was detected in pulmonary sarcomatoid carcinoma (PSC) patients (24.3%, n = 9/37). However, stage IV PSC patients with or without the METex14 mutations showed similarly poor overall survival (OS) (p = 0.429). For all 36 METex14-positive lung ADCs, multivariate analysis showed several poor prognostic factors, including strong c-MET IHC staining (p = 0.006), initial brain metastasis (p = 0.005), and administration of only supportive care (p < 0.001). After excluding seven patients who received only supportive care, we further analyzed 29 stage IV lung ADC patients with METex14 mutations who received anti-cancer treatment. Multivariate analysis showed that pemetrexed treatment (p = 0.003), lung radiotherapy (p = 0.020), initial brain metastasis (p = 0.005), and strong c-MET IHC staining (p = 0.012) were independent prognostic factors for OS in these patients.ConclusionsA higher frequency of METex14 mutations was detected in PSC patients. Stage IV PSC patients with or without the METex14 mutations had similarly poor overall survival. Pemetrexed-based chemotherapy, strong c-MET ICH staining, initial brain metastasis, and lung radiotherapy, may help predict survival outcomes in patients with advanced lung ADCs harboring the METex14 mutation.

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Section: Discussionmentioning

confidence: 99%

Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study

Gow

Hsieh²,

Chen³

et al. 2023

Front. Oncol.

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“…As for the MET exon 14 skipping mutation, more tyrosine kinase targeted agents were studied in the phase II trials, such as crizotinib, capmatinib, tepotinib and savolitinib, and those trials displayed positive results, with ORRs spanning from 32% to 68%, mPFS from 6.8 months to 9.7 months and mOS reaching up to 24.6 months [ 21 , 41 , 42 , 43 ]. Further trials are also needed to assess whether patients with cMET amplifications and overexpression will derive the same benefit as patients with the exon 14 skipping mutation, since initial signals show that responses are lower and survival is shorter when using MET TKIs [ 44 ]. A recent meta-analysis showed a clear benefit of MET TKIs when treating patients diagnosed with advanced NSCLC with the MET exon 14 skipping mutation, resulting in an ORR of 39% and DCR of 78%; when taken together with other MET alterations, the ORR and DCR were 28% and 69%, respectively [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Real-World Experience in Treatment of Patients with Non-Small-Cell Lung Cancer with BRAF or cMET Exon 14 Skipping Mutations

Janžič

Shalata

Szymczak

et al. 2023

IJMS

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BRAF and cMET exon 14 skipping are rare mutations of NSCLC. The treatment sequence in these cases for the first and second line is not clear. An international registry was created for patients with advanced NSCLC harboring BRAF or cMET exon 14 skipping mutations, diagnosed from January 2017 to June 2022. Clinicopathological and molecular data and treatment patterns were recorded. Data on 58 patients, from eight centers across five countries, were included in the final analysis. We found that 40 patients had the cMET exon 14 skipping mutation and 18 had the BRAF V600E mutation. In total, 53 and 28 patients received first- and second-line treatments, respectively, among which 52.8% received targeted therapy (TT) in the first line and 53.5% in the second line. The overall response rate (ORR) and disease control rate (DCR) for first-line treatment with TT vs. other treatment such as immune checkpoint inhibitors ± chemotherapy (IO ± CT) were 55.6% vs. 21.7% (p = 0.0084) and 66.7% vs. 39.1% (p = 0.04), respectively. The type of treatment in first-line TT vs. other affected time to treatment discontinuation (TTD) was 11.6 m vs. 4.6 m (p= 0.006). The overall survival for the whole group was 15.4 m and was not statistically affected by the type of treatment (19.2 m vs. 13.5 m; p = 0.83).

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“…The discrepancy in efficacy may be due to the difference in types of MET-TKIs. Crizotinib is a type Ia inhibitor, blocking ATP binding to prevent phosphorylation/activation of the receptor, whereas tepotinib is a type Ib inhibitor, blocking MET more specifically than type Ia inhibitors ( 8 ). According to preclinical work by Suzuwa et al ( 7 ), cell viability assays using an EGFR-mutant NSCLC cell model transfected with a lentiviral vector expressing MET ex14del revealed that MET ex14del reduced sensitivity to osimertinib, and MET ex14del expression correlated with upregulation of phosphorylated EGFR .…”

Section: Discussionmentioning

confidence: 99%

Case report: Success of tepotinib therapy in overcoming resistance to osimertinib in a patient with EGFR-mutant lung adenocarcinoma with a potential acquired MET exon 14 skipping mutation

et al. 2022

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Osimertinib is a standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor gene (EGFR) mutations, but most patients with EGFR-mutant NSCLC develop secondary resistance to osimertinib. Mesenchymal-epithelial transition gene (MET) alterations and oncogene fusions have been identified as the most common mechanisms of resistance to osimertinib. However, MET exon 14 skipping mutation (METex14del) as an acquired resistance to osimertinib has rarely been reported. A non-smoking 76-year-old woman was diagnosed with lung adenocarcinoma in the right lower lobe (cT2bN2M1c [pulmonary and bone metastases], cStage IVB). The primary tumor was submitted to cobas® EGFR Mutation Test v2 (Roche Diagnostics Ltd.), next generation sequencing (Oncomine Comprehensive Assay v3; Thermo Fisher Scientific), the AmoyDx® Essential NGS panel (Amoy Diagnostics, Xiamen, China), all of which were positive for EGFR L858R and de novo T790M. We administered daily osimertinib (80 mg/day), and achieved a partial response. However, after 14.0 months, computed tomography showed progression of the primary tumor and lung metastases. Re-biopsy of the primary tumor was conducted, and the specimen was submitted to Archer®MET companion diagnostic for detection of METex14del. Although the primary tumor was negative for METex14del, the re-biopsy specimen was positive for METex14del. We validated that the biopsy specimen of the primary tumor at diagnosis before osimertinib administration was negative for METex14del using local reverse transcription PCR. We administered daily tepotinib (500 mg/day) to the patient as a further-line treatment, and achieved a partial response (tumor shrinkage rate: 34.5%) after 2.0 months, who responded to tepotinib therapy for 8.0 months. We described a patient with lung adenocarcinoma harboring METex14del as a potential acquired resistance to osimertinib, who responded to subsequent tepotinib therapy. Re-biopsy and re-analysis of genetic profiles should be considered in NSCLC patients who develop osimertinib resistance.

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Spotlight on Tepotinib and Capmatinib for Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation

Cited by 14 publications

References 61 publications

Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study

Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study

Real-World Experience in Treatment of Patients with Non-Small-Cell Lung Cancer with BRAF or cMET Exon 14 Skipping Mutations

Case report: Success of tepotinib therapy in overcoming resistance to osimertinib in a patient with EGFR-mutant lung adenocarcinoma with a potential acquired MET exon 14 skipping mutation

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