Savolitinib + osimertinib a potential option for Chinese patients with EGFR-mutated, MET-amplified NSCLC

Chinese patients with locally advanced or metastatic, EGFR-mutated, MET-amplified non-small-cell lung cancer (NSCLC) whose disease progressed on first-line (1L) EGFR tyrosine kinase inhibitor (TKI) therapy obtain progression-free survival (PFS) benefit from the all-oral combination of savolitinib plus osimertinib vs platinum-based doublet chemotherapy, interim results of the phase III SACHI trial have shown.

In addition to a 66 percent reduction in risk of disease progression or death, the savolitinib–osimertinib combination demonstrated a favourable tolerability profile vs chemotherapy, with no new safety signals observed. These results highlight savolitinib–osimertinib’s potential as a treatment option for the trial’s biomarker-selected population. [Lancet 2026;doi:10.1016/S0140-6736(25)01811-2]

Study design

SACHI was an open-label, randomized, active-controlled trial conducted across 68 hospitals in China. Eligible patients aged 18–75 years were randomized 1:1 to receive oral savolitinib (a highly selective MET TKI; 600 mg QD for body weight [BW] ≥50 kg, 400 mg QD for BW <50 kg) plus osimertinib (80 mg QD), or intravenous pemetrexed (500 mg/m²) plus either cisplatin (75 mg/m²) or carboplatin (target area under the plasma drug concentration–time curve, 5). Both regimens were given in 21-day cycles. Stratification was based on presence of asymptomatic brain metastases, previous exposure to third-generation EGFR TKIs, and EGFR mutation subtype (exon 19 deletion, L858R, or others).

The primary endpoint of investigator-assessed PFS was evaluated first in the population of patients naïve to third-generation EGFR TKIs and, if positive, in the intention-to-treat (ITT) population.

Improved PFS, higher response rates

As of data cut-off on 30 August 2024, 211 patients were enrolled, including 106 patients in the savolitinib–osimertinib group (median age, 59.4 years; female, 58 percent) and 105 patients in the chemotherapy group (median age, 61.9 years; female, 52 percent). A total of 137 patients (65 percent) were third-generation EGFR TKI–naïve (savolitinib–osimertinib group, n=69; chemotherapy group, n=68).

Median PFS as assessed by investigator was significantly prolonged with savolitinib–osimertinib vs chemotherapy in the third-generation EGFR TKI–naïve population (median, 9.8 vs 5.4 months; hazard ratio [HR], 0.34; 95 percent confidence interval [CI], 0.21–0.56; p<0.0001), as well as in the ITT population (median, 8.2 vs 4.5 months; HR, 0.34; 95 percent CI, 0.23–0.49; p<0.0001).

Similar PFS results were shown in independent review and prespecified subgroup analyses.

Overall survival (OS) data were immature. At data cut-off, median OS was 22.9 vs 17.7 months in the savolitinib–osimertinib vs chemotherapy group (HR, 0.84; 95 percent CI, 0.55–1.29). OS rates at 18 months were 59 vs 49 percent.

Objective response rates were higher with savolitinib–osimertinib vs chemotherapy (58 vs 34 percent), as were disease control rates (89 vs 67 percent). The median duration of response was 8.4 vs 3.2 months.

Favourable safety profile

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 57 percent of patients in each group. Frequently reported grade ≥3 TEAEs included decreased neutrophil count (14 vs 26 percent for savolitinib–osimertinib vs chemotherapy), decreased white blood cell count (7 vs 13 percent), and anaemia (4 vs 23 percent).

TEAEs led to discontinuation of ≥1 study drug in 8 percent of patients in each group.

A potential oral Tx option

“SACHI is the first randomized phase III trial to support the efficacy of MET inhibition in NSCLC patients with acquired MET amplification after progression on previous EGFR TKIs. Savolitinib–osimertinib has potential to provide an oral treatment option that directly targets MET amplification–mediated resistance, which occurs in about a fifth of patients with EGFR-mutated NSCLC treated with EGFR TKIs,” the investigators noted.