For MET exon 14+ NSCLC, globally approved MET TKIs like TABRECTA, TEPMETKO, and HAIYITAN are standard, while ORPATHYS (savolitinib) is specifically approved in China. Savolitinib is currently an emerging therapy for EGFRm+ and MET+, locally advanced or metastatic NSCLC who have progressed following treatment with TAGRISSO in the US.

Savolitinib is integral to AstraZeneca’s TAGRISSO life cycle strategy, with the combination receiving FDA Fast Track designation for 2/3L TAGRISSO-refractory MET+ NSCLC.  AstraZeneca brought results of the Phase II SAVANNAH trial at ASCO 2025. 

The combination of savolitinib and TAGRISSO showed significantly better clinical outcomes than savolitinib plus placebo, with a Blinded Independent Central Review (BICR) ORR of 58% vs. 16%, and investigator-assessed ORR of 54% vs. 24%. The median duration of response was longer in the combination group, as was Progression-free Survival (PFS) by BICR and investigator assessment. These results highlight the benefit of dual EGFR and MET inhibition in overcoming MET-driven resistance. Additionally, the combination demonstrated CNS protective effects, with fewer CNS progression events in patients with brain metastases and no new CNS lesions in patients without baseline metastases, compared to the placebo group, underscoring its potential as a targeted therapy in this population.

KOL insights

“Savolitinib 300 mg twice daily plus osimertinib may offer a new chemotherapy-free treatment option in patients with EGFR-mutant, MET-overexpressed, and/or amplified advanced non-small cell lung cancer who have progressed on osimertinib .” – Expert Opinion

Conclusion

For NSCLC without oncogenic drivers, first-line treatment typically involves platinum-based chemotherapy or immune checkpoint inhibitors (ICIs), depending on PD-L1 expression and patient condition, with ICIs used in second-line if not previously administered. In oncogene-driven NSCLC, targeted therapies are preferred due to limited response to standard treatments. TEPMETKO received full FDA approval in February 2024 for MET exon 14 skipping metastatic NSCLC and TABRECTA, approved in August 2022. HAIYITAN, an oral MET inhibitor by Haihe Biopharma, was launched in Japan in October 2024 for advanced NSCLC with MET exon 14 skipping, with plans for expansion into Southeast Asia and Australia and ongoing Phase III trials in MET-overexpressing NSCLC. Emerging therapies in the MET space include Telisotuzumab Vedotin, Savolitinib plus TAGRISSO, MCLA-129, and Vebreltinib, reflecting a dynamic and evolving treatment landscape.

Savolitinib, a selective MET inhibitor, is approved in China for NSCLC with MET exon 14 skipping mutations in patients who have progressed after prior treatment or cannot receive chemotherapy. HUTCHMED plans to broaden its patient base in China over the next two years and is aiming for global approval in NSCLC. The SAVANNAH Phase II/III trial, which completed enrollment in February 2024, could lead to a potential NDA filing in 2025, depending on the results. Combining savolitinib with osimertinib led to higher response rates, prolonged benefit duration, better progression-free survival, and reduced CNS relapse compared to MET inhibition alone. This dataset is one of the largest randomized studies evaluating an oral MET-TKI in this resistance context and serves as an important basis for ongoing Phase III trials like SAFFRON, which will further investigate the combination’s role in a broader patient population.