METex14 skipping NSCLC and tepotinib
Mutations in the mesenchymal–epithelial transition (MET) gene drive the growth of some subtypes of non-small cell lung cancer (NSCLC). MET encodes a tyrosine kinase receptor for hepatocyte growth factor. Internalization and degradation of the receptor involves binding of a key intracellular region encoded by exon 14. METex14 skipping splice site mutations cause loss of this region, resulting in accumulation of MET and oncogenic downstream signaling.1
METex14 skipping occurs in 3–4% of patients with NSCLC, including 1–4% of Asian patients with lung adenocarcinoma.1–7 Several selective MET inhibitors have demonstrated clinical activity in patients with METex14 skipping NSCLC,2 including tepotinib.8,9 This oral, once-daily, highly selective, potent MET inhibitor is currently approved for treating advanced or metastatic METex14 skipping NSCLC in many countries in Europe, North America, South America, and Asia, and is the first MET inhibitor with full approval in China. The US FDA granted full approval, in place of the previous accelerated approval, in February 2024.10
Detection of METex14 skipping
METex14 skipping can be detected via the complementary approaches of tumor tissue biopsy (TBx) or liquid biopsy (LBx).11 TBx is the more established technique and involves detection of DNA or RNA in tumor biopsy samples. LBx offers several advantages over TBx, including being more convenient and less invasive. LBx measures levels of circulating tumor DNA in plasma and its use is increasing, particularly when TBx samples are inadequate or unavailable.11–13 The dynamics of consecutive LBx measurement may also be used to monitor response and progression to treatment in NSCLC.9,11,14,15
VISION trial of tepotinib
The basis for regulatory approval of tepotinib was the Phase II VISION study (NCT02864992), which included two cohorts, A and C, of patients with METex14 skipping advanced/metastatic NSCLC as detected by TBx and/or LBx.9,16 In these combined groups (totaling 313 patients, 62% white and 34% Asian), robust and durable clinical activity of tepotinib was demonstrated in long-term follow-up (median 32.6 months [range: 0.3–71.9]; data cut-off: November 20, 2022), with an objective response rate (ORR) of 51.4% (95% confidence interval [CI]: 45.8, 57.1), median duration of response (DOR) of 18.0 months (95% CI: 12.4, 46.4), and median progression-free survival (PFS) of 11.2 months (95% CI: 9.5, 13.8).17
Asian patients in VISION
Genetic or environmental factors, including regional differences in clinical practice, have been proposed to influence the performance of anticancer drugs between patients from different ethnic groups.18 For NSCLC, differences in epidemiology, clinicopathologic characteristics, and prognosis have been reported between Asian and non-Asian populations.19
Our analysis included the 106 Asian patients from the METex14 cohorts in VISION who were treated with tepotinib and had at least 18 months of follow-up. The group constitutes the largest population of Asian patients with METex14 skipping NSCLC in a MET inhibitor trial to date, comprising 38 patients from Japan, 20 from South Korea, 12 from Taiwan, 30 from China, and six enrolled from outside Asia. Almost half (47.2%) had received no previous treatment while the rest had up to two previous treatments (patients previously treated with MET inhibitors were not eligible).
Outcomes in Asian patients in VISION
Efficacy of tepotinib was similar for Asian patients as for the global study population, with an ORR of 56.6% (95% CI: 46.6, 66.2). As might be expected, ORR was higher in patients with no prior treatment (64.0% [95% CI: 49.2, 77.1]) than in previously treated patients (ORR 50.0% [95% CI: 36.3, 63.7]). Nonetheless, these robust efficacy data from Asian patients in VISION support the use of tepotinib in first or subsequent lines of therapy in patients with METex14 skipping metastatic NSCLC, which is in line with recently published consensus from the Asian Thoracic Oncology Research Group (ATORG).12
The most common treatment-related adverse events (TRAEs) in the Asian population in the VISION study were peripheral edema (a MET inhibitor class effect), creatinine increase, and diarrhea. Tepotinib was generally well tolerated in Asian patients, with a low proportion of TRAEs leading to discontinuation. Health-related quality of life (HRQoL) remained stable during treatment, the first time HRQoL has been examined in Asian patients with METex14 skipping NSCLC treated with a MET inhibitor.
Other MET inhibitors besides tepotinib include capmatinib and savolitinib (in China), which are included in the ATORG consensus recommendations,12 and gumarontinib, which has also demonstrated efficacy in Asian patients with METex14 skipping NSCLC.20–22 As we discuss in our paper, available data support the use of MET inhibitors in this population, and our findings compare favorably with those of these other agents.
Use of LBx in VISION
In VISION, 83 Asian patients were enrolled by TBx, and 48 by LBx. Results were similar for those identified via either method, with ORR of 59.0% (95% CI: 47.7, 69.7) in the TBx group and 58.3% (95% CI: 43.2, 72.4) for LBx. Despite this consistency, there were trends in the LBx group to shorter median PFS in previously treated patients and shorter median OS irrespective of prior treatment. These findings were concordant with the overall study, and may reflect a poorer prognosis of the LBx subgroup due to a greater baseline disease burden.23 Tumor size correlates with shedding of circulating tumor DNA,24 so LBx may preferentially identify patients with higher tumor load. Overall, TBx and LBx both seem to be appropriate methods for identifying patients likely to benefit with tepotinib.
Summary
Our analysis confirms effiacy and safety of tepotinib in Asian patients with METex14 skipping NSCLC, with stability of HRQoL. Whether patients are identified via LBx or TBx, these data support use of tepotinib in first or subsequent lines of therapy to improve clinical outcomes.
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