A Phase II, Open Label, Single-Arm Study on the Efficacy of Cabozantinib in Patients With Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring MET Exon 14 Alterations who Developed Acquired Resistance to Tepotinib or Capmatinib (CAPTURE Trial)

Abstract

Background: MET gene exon 14 skipping was identified as a potential driver mutation that occurs in approximately 3%-4% of patients with nonsmall cell lung cancer (NSCLC), typically in the absence of other driver mutations. Capmatinib and tepotinib were the first MET- tyrosine kinase inhibitors (MET-TKIs) approved by the FDA and PMDA, specifically for patients with metastatic NSCLC. Several studies have reported acquired resistance after MET-TKI treatment for MET mutation-positive NSCLC. Sequencing of the MET kinase region of resistant cell lines revealed secondary mutations at residues D1228 and Y1230 that were sensitive to type II MET-TKIs, such as cabozantinib. This suggested that sequential administration of other MET-TKIs may overcome the development of secondary mutations after acquired resistance in MET exon 14 mutation-positive NSCLC.

Methods: We designed the single arm phase II study CAPTURE Trial to assess the efficacy of cabozantinib in patients with advanced/metastatic NSCLC with activating MET exon 14 alterations who developed acquired resistance to tepotinib or capmatinib, as well as after 2 prior chemotherapy regimens that included platinum and docetaxel. The primary endpoint was objective response rate by independent review committees. The sample size (n = 30) is calculated by assuming a threshold response rate of 5% and an expected response rate of 25%. Recruitment began in August 2024.

Results: This ongoing study aimed to evaluate the safety and efficacy of cabozantinib after acquired resistance to tepotinib or capmatinib.

Keywords: Acquired resistance; Clinical trial; Driver mutation; MET; MET-TKI.