Savolitinib/Osimertinib Extends PFS in MET-Amplified EGFR-Mutated NSCLC

The combination of savolitinib (Orpathys) and osimertinib (Tagrisso) significantly improves progression-free survival (PFS) compared with platinum-based doublet chemotherapy in patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC) harboring MET amplification. Results from the phase 3 SACHI trial (NCT05015608), recently published in The Lancet, establish this all-oral regimen as a potent second-line strategy for patients whose disease progressed on prior EGFR tyrosine kinase inhibitor (TKI) therapy.^1,2

The SACHI study is the first randomized phase 3 trial to confirm the efficacy of MET inhibition in the setting of acquired MET amplification following EGFR-TKI treatment. Based on the strength of these data, the combination received regulatory approval in China in June 2025.

Primary Efficacy and Survival Outcomes

In the intention-to-treat (ITT) population, which included 211 randomized patients, the savolitinib and osimertinib combination demonstrated a statistically significant improvement in investigator-assessed PFS. Patients receiving the targeted combination achieved a median PFS of 8.2 months (95% CI, 6.9–11.2), compared with 4.5 months (95% CI, 3.0–5.4) for those receiving standard chemotherapy (HR, 0.34; 95% CI, 0.23–0.49; P <.0001). Independent review committee assessments mirrored these findings, reporting a median PFS of 7.2 months vs 4.2 months (HR, 0.40; P <.0001).

Overall survival (OS) data were immature at the time of the interim analysis (37%–43% maturity). However, early trends favored the combination arm, with a median OS of 22.9 months vs 17.7 months in the chemotherapy arm (HR, 0.84). Notably, the OS analysis was influenced by a 43% crossover rate from the chemotherapy arm to the savolitinib-osimertinib regimen upon progression. Sensitivity analyses adjusting for this crossover suggested a more pronounced OS benefit, with HRs ranging from 0.24 to 0.62.

Subgroup and Secondary End Point Performance

The study highlighted the combination’s utility across diverse prior treatment lines. In patients previously treated with first- or second-generation EGFR-TKIs (third-generation TKI-naive), the investigator-assessed median PFS was 9.8 months compared with 5.4 months in the control group (HR, 0.34). Importantly, clinical benefit was maintained in patients who had already failed a third-generation EGFR-TKI, such as osimertinib, with a median PFS of 6.9 months vs 3.0 months (HR, 0.32).

Secondary end points further underscored the efficacy of the dual inhibition:

• Objective Response Rate: 58% for the combination vs 34% for chemotherapy.
• Disease Control Rate: 89% vs 67%.
• Median Duration of Response: 8.4 months vs 3.2 months.

Safety Profile and Tolerability

The safety profile of the savolitinib and osimertinib combination was consistent with the known profiles of the individual agents, with no new safety signals identified. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 57% of patients in both the combination and chemotherapy arms.

While the frequency of high-grade events was similar, the nature of the toxicities differed. In the combination arm, common grade ≥3 TEAEs included decreased neutrophil count (14%) and decreased white blood cell count (7%). In contrast, the chemotherapy arm saw higher rates of grade ≥3 anemia (23%) and neutropenia (26%).

Clinical Context

MET amplification is a recognized resistance mechanism in approximately 15% to 50% of patients with EGFR-mutated NSCLC who progress on third-generation TKIs. Savolitinib, a potent and highly selective oral MET TKI, addresses this resistance by blocking the MET receptor tyrosine kinase pathway.

"The SACHI trial…provides compelling evidence that savolitinib combined with osimertinib can transform outcomes for patients with EGFR-mutated NSCLC with MET amplification," stated Professor Shun Lu, co-leading principal investigator of the trial, in a news release.² "This all-oral regimen offers a convenient and well-tolerated solution for an underserved population."

Ongoing global trials, including the phase 3 SAFFRON study (NCT05261399), are further evaluating this combination to support potential regulatory filings in the United States and other regions.

REFERENCES

1. Lu S, Wang J, Yang N, et al. Savolitinib plus osimertinib versus chemotherapy for advanced, EGFR mutation-positive, MET-amplified non-small-cell lung cancer in China (SACHI): interim analysis of a multicentre, open-label, phase 3 randomised controlled trial. Lancet. Published online ahead of print January 13, 2026. doi: 10.1016/S0140-6736(25)01811-2

2. HUTCHMED highlights publication of phase III SACHI results in The Lancet. News release. HUTCHMED Limited. January 13, 2026. Accessed January 14, 2026. https://tinyurl.com/2ev9t36x