Prolonged survival and response to tepotinib in a non-small-cell lung cancer patient with brain metastases harboring MET exon 14 mutation: a research report

Abstract

Tyrosine kinase inhibitors (TKIs) have transformed the standard of care in lung cancer. A number of TKIs have been discovered that specifically target oncogenes, including MET receptor tyrosine kinase. Second-generation MET TKIs are showing improved efficacy over first-generation TKIs. Herein, we report a case of a patient with metastatic lung adenocarcinoma harboring a MET exon 14 splice site mutation who has had prolonged disease control by a second-generation MET-TKI tepotinib. A 66-yr-old man was diagnosed with stage IV lung adenocarcinoma. He was started on carboplatin, paclitaxel, and bevacizumab, but had severe toxicity. He was switched to pembrolizumab as his tumor was PD-L1 70%, and molecular testing was not yet performed because of insufficient tissue. A bronchoscopy with endobronchial ultrasound was performed and a MET exon 14 splice site mutation was detected by next-generation sequencing. Upon progression, he was then enrolled in a clinical trial of tepotinib and continues with stable disease for more than 45 cycles and 31 mo. The MET receptor tyrosine kinase and the ligand hepatocyte growth factor (HGF) have been implicated as oncogenes and drivers of non-small-cell lung cancer (NSCLC). Newer MET TKIs including capmatinib and tepotinib more recently showed not only improved localized control and response, but early data suggests intracranial activity as compared to first-generation MET TKIs, both in the front-line and the refractory setting. This is a case report demonstrating an effective duration of response in a patient with widely metastatic lung adenocarcinoma harboring a MET exon 14 mutation.

Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

“…While VISION was not designed to assess the intracranial activity of tepotinib in patients with METex14 skipping NSCLC, an ad-hoc independent analysis using RANO-BM criteria demonstrated intracranial activity, with the caveat that most patients had received prior radiotherapy. Nonetheless, these data are in line with reported case studies (26,27), including the report of a patient in whom tepotinib achieved high cerebrospinal fluid concentrations and demonstrated efficacy against leptomeningeal metastasis (28). Post-hoc intracranial response analysis of capmatinib using RECIST v1.1 criteria showed that of 13 patients with brain metastases (six of whom received prior radiotherapy), seven had intracranial responses (22), and preliminary data also indicate savolitinib has antitumor activity in brain metastases (29).…”

Brain penetration and efficacy of tepotinib in orthotopic patient-derived xenograft models of MET-driven non-small cell lung cancer brain metastases

“…In the orthotopic experiments, tepotinib induced pronounced tumor regression, including complete or nearcomplete regressions, in both models tested. Together with clinical evidence of systemic and intracranial responses to tepotinib in patients with METex14 skipping NSCLC and brain metastases [9,10,[25][26][27][28], these data support the further prospective evaluation of the intracranial efficacy of tepotinib in patients with NSCLC with MET alterations.…”

“…Clinical evidence supporting the intracranial activity of tepotinib in patients with METex14 skipping NSCLC has recently been provided by several case reports [25][26][27][28], and an ad hoc analysis of intracranial responses in VISION patients who had brain metastases at baseline [10]. To complement such clinical data, preclinical experiments can provide important information regarding the potential for activity against brain lesions [24].…”

Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics

“…The VISION and INSIGHT trials, along with three separately published case reports, have also indicated that tepotinib has intracranial activity. [56][57][58][59][60] These findings prompted FDA accelerated approval for tepotinib for METex14 skipping NSCLC in February 2021. 61 Future studies evaluating genomic or other clinical determinants of response may help better differentiate the two promising drugs.…”