Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration—A Narrative Review

SIMPLE SUMMARY: In this article, we outline updates on the clinical development of savolitinib, a novel, reversible c-MET kinase inhibitor conditionally approved in China for treatment of advanced non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping mutation (METex14). Savolitinib was developed as a monotherapy for NSCLC with MET alterations, and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who developed resistance to EGFR–TKIs because of MET alterations. Savolitinib showed anti-tumor activity in preclinical models. The early phase I trial established the recommended phase II dose to be 600 mg once-daily. Savolitinib plus osimertinib showed beneficial efficacy and safety in EGFR mutant patients with acquired resistance due to MET amplification and/or c-MET overexpression. Benefits were noted with savolitinib in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 mutation. Results from phase III trials are awaited to further confirm the beneficial effects from early phase trials. ABSTRACT: Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys(®)) is highly selective mesenchymal epithelial transition (MET)–tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR–TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR–TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.