Highlights
The interim analysis of the SACHI trial has revealed several critical findings for the management of advanced non-small-cell lung cancer (NSCLC):
- The combination of savolitinib and osimertinib achieved a 66% reduction in the risk of disease progression or death compared to standard platinum-based chemotherapy in both the third-generation TKI-naive and intention-to-treat populations.
- Median progression-free survival (PFS) was nearly doubled in the third-generation TKI-naive group (9.8 months vs. 5.4 months) and significantly improved in the overall population (8.2 months vs. 4.5 months).
- The safety profile of the oral combination was comparable to chemotherapy in terms of Grade 3 or higher adverse events, offering a more convenient treatment modality for patients.
- These results establish the savolitinib-osimertinib regimen as a potential new standard of care for patients with EGFR-mutated, MET-amplified NSCLC following TKI failure.
Background: The Challenge of MET-Mediated Resistance
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of NSCLC patients with sensitizing EGFR mutations. However, the emergence of resistance remains an inevitable clinical hurdle. Among the various mechanisms of acquired resistance, mesenchymal-epithelial transition (MET) gene amplification is one of the most frequent, occurring in approximately 15% to 25% of patients who progress on third-generation EGFR TKIs like osimertinib.
MET amplification acts as a bypass signaling pathway, allowing the tumor to survive despite continued EGFR inhibition. Historically, patients who develop MET-driven resistance have been transitioned to platinum-based doublet chemotherapy, which offers limited durability and significant toxicity. There has been an urgent unmet need for targeted, biomarker-driven strategies that simultaneously inhibit both the primary EGFR driver and the secondary MET resistance mechanism. Savolitinib, a highly selective MET TKI, combined with the potent EGFR inhibitor osimertinib, was hypothesized to overcome this resistance.
Study Design: The SACHI Trial Framework
SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 hospitals in China. The trial targeted a highly specific patient population: adults with locally advanced or metastatic EGFR mutation-positive NSCLC who had developed MET amplification (centrally confirmed) following progression on previous EGFR TKI therapy.
A total of 211 patients were randomly assigned (1:1) to receive either the combination of oral savolitinib (600 mg or 400 mg once daily based on body weight) plus osimertinib (80 mg once daily) or standard-of-care intravenous chemotherapy (pemetrexed plus cisplatin or carboplatin). Randomization was stratified by the presence of brain metastases, previous third-generation EGFR TKI use, and EGFR mutation subtype (Exon 19 deletion vs. L858R).
The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST v1.1. A hierarchical testing procedure was employed, focusing first on the population who had not previously received third-generation EGFR TKIs (3G TKI-naive), followed by the intention-to-treat (ITT) population.
Key Findings: Superior Progression-Free Survival
The interim analysis, with a data cutoff of August 30, 2024, demonstrated a clear and statistically significant advantage for the targeted combination over chemotherapy.
Efficacy in the Third-Generation TKI-Naive Population
In the 137 patients who had not previously received a third-generation TKI, the median PFS was 9.8 months (95% CI 6.9–12.5) for the savolitinib-osimertinib group, compared to 5.4 months (95% CI 4.2–6.0) for the chemotherapy group. This translated to a hazard ratio (HR) of 0.34 (95% CI 0.21–0.56; p<0.0001), representing a profound clinical benefit.
Efficacy in the Intention-to-Treat Population
The benefit extended to the entire ITT population (n=211), which included patients who had previously failed third-generation TKIs. In this group, the median PFS was 8.2 months (95% CI 6.9–11.2) with the combination therapy versus 4.5 months (95% CI 3.0–5.4) with chemotherapy. The hazard ratio remained consistent at 0.34 (95% CI 0.23–0.49; p<0.0001). These data suggest that the combination is effective regardless of the generation of the prior TKI used, though the absolute duration of benefit may be slightly higher in 3G TKI-naive patients.
Secondary Endpoints and Subgroup Consistency
While overall survival data were still maturing at the time of the interim analysis, early trends and secondary endpoints such as objective response rate (ORR) and duration of response (DoR) also favored the savolitinib-osimertinib arm. Subgroup analyses indicated that the benefit was consistent across key clinical variables, including the presence of stable brain metastases and the specific type of EGFR mutation.
Safety and Tolerability Profile
One of the most encouraging aspects of the SACHI trial was the safety profile of the savolitinib-osimertinib combination. Grade 3 or worse treatment-emergent adverse events (TEAEs) occurred in 57% of patients in the combination group and 57% of patients in the chemotherapy group. While the frequency of high-grade events was identical, the nature of the toxicities differed.
Common AEs associated with the targeted combination included peripheral edema, nausea, and rash, which are characteristic of MET and EGFR inhibition. In contrast, the chemotherapy group experienced more hematological toxicities, such as leukopenia and anemia, as well as fatigue. Discontinuation rates due to AEs were manageable in the combination arm, suggesting that the regimen is well-tolerated for long-term use compared to the cumulative toxicity often seen with cytotoxic chemotherapy.
Expert Commentary: A Shift in the Treatment Paradigm
The SACHI trial results represent a landmark in the transition toward “precision medicine for resistance.” For years, the oncology community has sought ways to delay or replace chemotherapy in the second-line setting. By identifying MET amplification as the driver of resistance, clinicians can now offer a targeted oral alternative that is both more effective and generally more palatable to patients than IV chemotherapy.
However, some considerations remain. The trial was conducted exclusively in a Chinese population, which, while highly relevant given the prevalence of EGFR mutations in Asian populations, necessitates further validation in Western cohorts to ensure global generalizability. Furthermore, the optimal timing for MET testing—whether at the first sign of progression or through liquid biopsy monitoring—remains a topic of clinical discussion. The use of central MET confirmation in this trial underscores the necessity of robust biomarker testing infrastructure in clinical practice.
Biologically, the success of this combination reinforces the “dual-blockade” theory: when a bypass track (MET) is activated, simply switching to a different TKI is insufficient; one must inhibit both the original driver (EGFR) and the new escape route (MET) simultaneously to achieve meaningful tumor control.
Conclusion
The interim analysis of the SACHI trial provides high-level evidence that savolitinib plus osimertinib is superior to chemotherapy for patients with EGFR mutation-positive, MET-amplified NSCLC who have progressed on prior TKI therapy. With a 66% reduction in the risk of progression and a favorable safety profile, this oral regimen offers a compelling alternative to traditional platinum-based doublets. As we move forward, integrating routine MET testing into the post-progression diagnostic workup will be essential to identify those patients who stand to benefit most from this innovative combination.
Funding and ClinicalTrials.gov
The SACHI trial was funded by HUTCHMED and AstraZeneca. The study is registered with ClinicalTrials.gov under the identifier NCT05015608.
References
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. 2026;407(10526):375-387. doi:10.1016/S0140-6736(25)01811-2.
