Orpathys (savolitinib)

Savolitinib demonstrated robust and durable efficacy in patients with METex14-mutated, locally advanced NSCLC with manageable safety, supporting savolitinib as a treatment option in this disease setting. HUTCHMED, AstraZeneca.

CALYPSO (NCT02819596) was a prospective, multi-arm trial that evaluated durvalumab alone or in combination with tremelimumab or savolitinib in metastatic ccRCC and pRCC. Also, an increase in KIM-1 during therapy was linked to worse progression-free survival (HR 1.7; 95% CI, 1.13-2.58; p = 0.01) and OS (HR 1.95; 95% CI, 1.23-3.08; p = 0.004) in ccRCC. This exploratory analysis supports the utility of KIM-1 in advanced ccRCC and pRCC.

The SACHI trial demonstrated that savolitinib plus osimertinib nearly doubled progression-free survival (PFS) compared with chemotherapy (9.8 vs. 5.4 months; hazard ratio 0.34) in patients with EGFR-mutated, MET-amplified non-small-cell lung cancer (NSCLC) after EGFR tyrosine kinase inhibitor (TKI) failure-the first phase 3 evidence for dual EGFR/MET inhibition in this setting.1.

P2, N=367, Active, not recruiting, AstraZeneca | Trial completion date: May 2025 --> Dec 2026

P1, N=344, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Dec 2026

Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC.

Molecular docking revealed high-affinity binding between tepotiniband all six hub targets (Vina scores: -8.0 to -10.6 kcal/mol), providing a structural basis for the postulated mechanistic link to AKI. These findings not only highlight the necessity for enhanced renal monitoring in tepotinib-treated patients but, more broadly, establish the FAERS-NetDock Pipeline as a reusable, generalizable and hypothesis-generating framework for evaluating tyrosine kinase inhibitors (TKIs)-induced nephrotoxicity; this framework is immediately applicable to profiling the safety of other TKIs (e.g. crizotinib, capmatinib, savolitinib, afatinib and osimertinib) and is readily adaptable for de-risking a wider spectrum of targeted therapies.

P3, N=60, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Dec 2026

P2, N=47, Active, not recruiting, AstraZeneca | Trial completion date: Aug 2025 --> Jan 2027 | Trial primary completion date: Aug 2025 --> Jan 2027

P2, N=25, Recruiting, Jeeyun Lee | Trial completion date: Dec 2026 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population.

Treatment-related adverse events of grade 3 or higher occurred in 2 patients (8.7%) in cohort 1 and 12 patients (57.1%) in cohort 2. Osimertinib plus savolitinib showed promising antitumor activity and manageable safety.