A chemotherapy-free second-line option for MET-amplified EGFR-mutant NSCLC

In the phase 3 SACHI study, the combination of savolitinib and osimertinib demonstrated clinically meaningful improvements in progression-free survival and response rates compared with chemotherapy in participants with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who had progressed on first-line EGFR tyrosine kinase inhibitors (TKI).

Acquired mesenchymal-epidermal transition (MET) amplification is a key resistance mechanism in pretreated EGFR-mutant NSCLC and is associated with a poor prognosis. Savolitinib is a highly selective, oral MET TKI that has shown encouraging activity in combination with osimertinib in NSCLC participants in both phase 1 and 2 trials [1,2]. To further evaluate this combination, the phase 3 SACHI study (NCT05015608), presented by Prof. Shun Lu (Shanghai Chest Hospital, China), compared its efficacy and safety with standard platinum-based doublet chemotherapy in participants with locally advanced or metastatic EGFR-mutant NSCLC who had acquired MET amplification following progression on first-line EGFR TKI therapy [3].

The SACHI trial randomised 211 participants 1:1 to receive either savolitinib plus osimertinib or platinum-based chemotherapy until disease progression or intolerable toxicity. Cross-over to the combination therapy was permitted for participants in the chemotherapy arm upon progression. “At the data cut-off, 43% of participants initially assigned to chemotherapy had crossed over to receive the combination,” reported Prof. Lu.

The median progression-free survival, the study’s primary endpoint, was significantly prolonged in the combination arm compared with chemotherapy: 7.2 months versus 4.2 months (HR 0.40; 95% CI 0.28–0.59; P<0.0001). This benefit was consistent across all pre-specified subgroups, including age, sex, smoking status, prior use of third-generation EGFR TKI, EGFR mutation subtype, and metastatic burden or location. The objective response rate was higher in the savolitinib-osimertinib arm than in the chemotherapy arm (58% vs 34%). Additionally, the disease control rate favoured the combination (89% vs 67%), as did median duration of response (8.4 vs 3.2 months). A longer follow-up is, however, needed to assess overall survival outcomes fully. Grade ≥3 adverse events occurred at similar rates in both arms (57% vs 57%), indicating comparable safety.

Prof. Lu concluded: “The savolitinib-osimertinib combination may offer a new chemotherapy-free treatment option for patients with EGFR-mutated NSCLC and acquired MET amplification following progression on first-line therapy.”

Several trials are ongoing in this clinical setting, including the randomised, global phase III SAFFRON trial (NCT05261399), which compares savolitinib plus osimertinib to chemotherapy in the second-line setting for EGFR-mutant NSCLC participants who have failed osimertinib and have MET amplification or overexpression.

1. Hartmaier RJ, et al. Cancer Discover. 2023;13(1):98–113.
2. Ahn M-J, et al. J Thorac Oncol. 2025;20(3):S4-5.
3. Lu S, et al. Savolitinib combined with osimertinib versus chemotherapy in EGFR-mutant and MET-amplified advanced NSCLC after disease progression on EGFR tyrosine kinase inhibitor: results from a randomized phase 3 SACHI study. Abstract LBA8505, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.

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Posted on 30 July 2025