Challenges and Limitations of Sequential MET-TKI Therapy in METex14- Positive NSCLC With a Focus on Non-ILD...

Nonsmall cell lung cancer (NSCLC) with mesenchymal-epithelial transition exon 14 skipping mutation (METex14) represents a distinct molecular subtype with limited therapeutic options. Selective MET tyrosine kinase inhibitors (MET-TKIs) such as tepotinib, capmatinib, and gumarontinib have improved outcomes, but toxicities frequently limit their use. Previous case reports have described sequential rechallenge with two MET-TKIs and, in rare cases, with three agents including an investigational drug. To our knowledge, this is the first reported case worldwide of sequential treatment with all three MET-TKIs currently approved in Japan-tepotinib, capmatinib, and gumarontinib.

We report a 72-year-old man with METex14-positive NSCLC who underwent surgery and adjuvant chemotherapy, later developing pleural dissemination. Tepotinib was discontinued after 2 months due to Grade 3 interstitial lung disease (ILD). Following chemotherapy and immune checkpoint inhibitors, capmatinib was introduced but stopped within 10 days for fever, mucositis, and possible ILD. Gumarontinib was subsequently initiated, but treatment was interrupted on Day 36 due to Grade 2 hepatotoxicity before resumption at a reduced dose.

Although all three MET-TKIs share similar mechanisms of action, they exhibit differing toxicity profiles. In this case, treatment discontinuation was not due to ILD recurrence but rather to distinct non-ILD adverse events. Furthermore, the toxicities experienced by the patient varied between agents, suggesting that rechallenge may remain a viable strategy depending on individual tolerance. Careful toxicity monitoring and personalized risk assessment are essential when considering sequential MET-TKI therapy.