Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial

Wu, Yi‐Long; Cheng, Ying; Zhou, Jianying; Lü, Shun; Zhang, Yiping; Zhao, Jun; Kim, Dong-Wan; Soo, Ross A.; Kim, Sang‐We; Pan, Hongming; Chen, Yuh‐Min; Chian, Chih-Feng; Liu, Xiaoqing; Tan, Daniel S.W.; Bruns, Rolf; Straub, Josef; Johne, Andreas; Scheele, J.; Park, Keunchil; Yang, James Chih‐Hsin; Liu, Zhe; Chen, Xi; Wang, Mengzhao; Yu, Shiying; Zhang, Helong; Fang, Jian; Li, Wei; Yang, Chih-Hsin; Chang, Gee‐Chen; Hsia, Te‐Chun; Yang, Cheng‐Ta; Wang, Chin‐Chou; Cho, Byoung Chul; Lee, Ki Hyeong; Kim, Young‐Chul; An, Ho Jung; Woo, In Sook; Cho, Jae Yong; Shin, Sang Won; Lee, Jong-Seok; Kim, Joo-Hang; Yoo, Seung Soo; Kato, Terufumi; Shinagawa, Naofumi; Tan, Shao Weng Daniel; Ngo, L.; Ratnavelu, Kananathan; Ahmad, Azura Rozila; Liam, Chong Kin; Marinis, Filippo de; Tassone, Pierfrancesco; Mollá, A. Insa; Calles, Antonio; Quintela, Martín Emilio Lázaro; Font, E. Felip; Dingemans, Anne‐Marie C.; Bui, Lynne A.

doi:10.1016/s2213-2600(20)30154-5

Cited by 199 publications

(177 citation statements)

References 23 publications

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“…Several phase I/II trials of tepotinib are ongoing (NCT01988493, NCT02115373, NCT01982955, and NCT02864992), and initial phase Ib data have shown that tepotinib 500 mg once daily is well-tolerated. [37][38][39] This dose has been used in the phase II parts of these trials both as a single agent and combined with other anticancer agents. [40][41][42] There is now evidence that the 500 mg once daily dose of tepotinib is associated with tumor responses in patients with MET-positive, EGFR-mutation positive NSCLC after EGFR TKI relapse.…”

Section: Discussionmentioning

confidence: 99%

“…[40][41][42] There is now evidence that the 500 mg once daily dose of tepotinib is associated with tumor responses in patients with MET-positive, EGFR-mutation positive NSCLC after EGFR TKI relapse. 39 In addition, tepotinib also showed efficacy in MET exon 14-altered NSCLC 42 and 500 mg once daily tepotinib has been approved in this setting in Japan. Together, these data indicate that the human dose prediction from the translational modeling process was successful.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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

Xiong

Friese-Hamim

Johne

et al. 2021

CPT Pharmacom & Syst Pharma

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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

Xiong

Friese-Hamim

Johne

et al. 2021

CPT Pharmacom & Syst Pharma

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“…MET amplification correlates with the degree of MET expression in most cases. Importantly, tepotinib plus gefitinib was generally well tolerated (104). The trial highlights the need for tailored therapy, and that MET amplification could be a feasible predictive biomarker in this subset of patients, as the combination of tepotinib and gefitinib was ineffectual in patients with low MET expression (IHC2+ or less) (105).…”

Section: Tepotinibmentioning

confidence: 88%

“…Tepotinib has also demonstrated activity in the setting of acquired resistance to EGFR TKIs. Results from the randomized, phase II part of the INSIGHT trial in patients with EGFR-mutant NSCLC T790M-negative, with MET overexpression and/ or MET amplification, and resistance to prior EGFR TKI, have been reported (104,105). Tepotinib in combination with gefitinib showed an ORR of 45.2% versus 33.3% for the chemotherapy groups (Table 3).…”

Section: Tepotinibmentioning

confidence: 99%

A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations

Santarpía¹,

Massafra²,

Gebbia³

et al. 2021

Transl Lung Cancer Res

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Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment.However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.

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Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

et al. 2020

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MET inhibitors have shown activity in non-small cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect and thus response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with Next Generation Sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with METΔex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally co-exist with other drivers. For METΔex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies.

show abstract

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial

Cited by 199 publications

References 23 publications

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

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

A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations

Multiplex RNA‐based detection of clinically relevant MET alterations in advanced non‐small cell lung cancer

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