MA09.09 Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with EGFR-Mutant NSCLC and MET Dysregulation: 18-Month Follow-Up

Wu, Yi‐Long; Cheng, Ying; Zhou, Jianfeng; Lu, Shou‐En; Zhang, Y.; Zhao, Jing; Kim, D.; Soo, Ross A.; Kim, S.; Pan, Hongying; Chen, Y.; Chian, Chih-Feng; Liu, X.; Tan, Dengxu; Bruns, Rolf; Straub, Josef; Johne, Andreas; Scheele, J.; Park, K.; Yang, James Chih Hsin

doi:10.1016/j.jtho.2019.08.571

Cited by 8 publications

(8 citation statements)

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“…These data suggest that tepotinib warrants further investigation in cancer patients with MET dysregulation. Phase Ib/II trials of tepotinib 500 mg once daily in patients with MET-overexpressing hepatocellular carcinoma (NCT01988493 and NCT02115373) and non-small cell lung carcinoma (NSCLC) with MET alterations (NCT01982955 and NCT02864992) have confirmed both the tolerability of tepotinib and demonstrated clinical activity (22)(23)(24)(25). A pooled safety analysis of 260 patients who received tepotinib 500 mg in five phase Ib/II studies also showed the 500 mg dose to be generally well tolerated (26).…”

Section: Discussionmentioning

confidence: 95%

“…In patients with MET-amplified EGFRmutant NSCLC with resistance to EGFR tyrosine kinase inhibitors, treatment with tepotinib plus gefitinib greatly improved outcomes versus the chemotherapy control arm [PFS 16.6 vs. 4.2 months, HR 0.13 (90% confidence interval (CI), 0.04-0.43); overall survival 37.3 versus 13.1 months, HR 0.09 (90% CI, 0.01-0.54; ref. 23)]. Interim data from an ongoing study of patients with NSCLC harboring MET exon 14-skipping alterations reported an overall response rate of 45% to 55% (27).…”

Section: Discussionmentioning

confidence: 99%

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First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors

Falchook

Kurzrock

Amin

et al. 2020

Clinical Cancer Research

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Purpose: Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D). Patients and Methods: Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects. Results: One hundred and forty-nine patients received tepotinib (R1: n ¼ 42; R2: n ¼ 45; R3: n ¼ 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve !95% MET inhibition in !90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression. Conclusions: Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors

Falchook

Kurzrock

Amin

et al. 2020

Clinical Cancer Research

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“…For pediatric patients 12 years or older with NTRK gene fusion-positive solid tumors, the prescribing information provides dosage recommendations based on body surface area. Similarly, during the WCLC 2019, Paz-Ares et al 3 reported the intracranial activity of entrectinib in patients with NTRK-positive solid tumors (n ¼ 54) or ROS1þ NSCLC (n ¼ 53) with CNS disease at baseline (14). Time to CNS progression was 17.0 months (95% CI: 14.3eNE) for NTRK-positive solid tumor patients (and 20.9 months for those without brain metastases at baseline) and NE (95% CI: 15.1eNE) for ROS1þ NSCLC.…”

Section: Vape Pneumonitismentioning

confidence: 99%

“…Better outcomes were reported with tepotinib plus gefitinib versus chemotherapy in 19 patients with MET amplification (RR 67% vs. 43%, p<0.001; PFS 21.2 months vs. 4.2 months; HR 0.13 [90% CI 0.04e0.43], and OS, 37.3 months vs. 13.1 months, HR: 0.08 [0.01e0.51]), suggesting that personalised treatment with MET inhibitors improve the outcome compared with platinum-based chemotherapy in acquired MET-amplified tumors. (14) In 15 MET mutant exon 14 tumors treated with MET TKI and with paired tumor biopsies, the mechanisms of acquired resistance have been evaluated. The landscape of resistance mechanisms includes single and polyclonal secondary kinase domain mutations in one third-of cases and bypass track activation by amplification of key oncogenes involving the ErbB/HER family of tyrosine kinase receptors and the MAPK signaling pathway in almost 50% of cases.…”

Section: Wclc 2019mentioning

confidence: 99%

In This Issue/Research Watch/News-in-Brief/News from 002the IASLC Tobacco Control Committee

2019

Journal of Thoracic Oncology

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The epidermal stress response pathway is frequently dysregulated in NSCLC. However, the clinical relevance of these alterations remains unclear. To address this issue, the authors studied two of the genes involved in this pathway (kelch like ECH associated protein 1 gene [KEAP1] and nuclear factor erythroid 2 like 2 gene [NFE2L2]) in 88 advanced NSCLC patients by amplicon-based next-generation sequencing. Lung adenocarcinomas with mutations in the KEAP1-NFE2L2 pathway had a significantly shorter progression-free survival and overall survival when compared to wild-type tumors. This observation was further validated in two large independent cohorts (n¼1256 and n¼162, respectively). The authors also observed that the mutations in the KEAP1-NFE2L2 pathway and EGFR/anaplastic lymphoma kinase (ALK) alterations were mutually exclusive. The results of this study indicate that KEAP1/ NFE2L2 mutations may identify a subset of chemotherapy-resistant and rapidly progressing tumors among EGFR/ ALK-negative lung adenocarcinomas, whose outcome is already compromised due to the lack of targetable molecular alterations. Effective treatment options need to be identified for this subset of patients with extremely adverse outcome.

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“…Tepotinib alone or in combination has been shown to be active in various preclinical tumor models [8,[10][11][12][13][14][15][16]. It is currently being studied in clinical trials involving patients with hepatocellular carcinoma (NCT01988493, NCT02115373) [17,18] a n d N S C L C ( N C T 0 1 9 8 2 9 5 5 , N C T 0 2 8 6 4 9 9 2 , NCT03940703) [16,[19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

et al. 2020

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Tepotinib (MSC2156119J) is an oral, potent, highly selective MET inhibitor. This open-label, phase I study in healthy volunteers (EudraCT 2013-003226-86) investigated its mass balance (part A) and absolute bioavailability (part B). In part A, six participants received tepotinib orally (498 mg spiked with 2.67 MBq [ 14 C]-tepotinib). Blood, plasma, urine, and feces were collected up to day 25 or until excretion of radioactivity was <1% of the administered dose. In part B, six participants received 500 mg tepotinib orally as a film-coated tablet, followed by an intravenous [ 14 C]-tepotinib tracer dose (53-54 kBq) 4 h later. Blood samples were collected until day 14. In part A, a median of 92.5% (range, 87.1-96.9%) of the [ 14 C]-tepotinib dose was recovered in excreta. Radioactivity was mainly excreted via feces (median, 78.7%; range, 69.4-82.5%). Urinary excretion was a minor route of elimination (median, 14.4% [8.8-17.7%]). Parent compound was the main constituent in excreta (45% [feces] and 7% [urine] of the radioactive dose). M506 was the only major metabolite. In part B, absolute bioavailability was 72% (range, 62-81%) after oral administration of 500 mg tablets (the dose and formulation used in phase II trials). In conclusion, tepotinib and its metabolites are mainly excreted via feces; parent drug is the major eliminated constituent. Oral bioavailability of tepotinib is high, supporting the use of the current tablet formulation in clinical trials. Tepotinib was well tolerated in this study with healthy volunteers.

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MA09.09 Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with EGFR-Mutant NSCLC and MET Dysregulation: 18-Month Follow-Up

Cited by 8 publications

References 0 publications

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors

In This Issue/Research Watch/News-in-Brief/News from 002the IASLC Tobacco Control Committee

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

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