Osimertinib-Savolitinib in Advanced NSCLC after Progression during EGFR-TKI Therapy.

The third-generation EGFR-TKI osimertinib has significantly improved the prognosis of advanced EGFR-mutant NSCLC, but resistance is inevitable ^[2]. Acquired resistance mechanisms are highly heterogeneous, among which MET amplification and overexpression constitute an important EGFR-independent bypass activation pathway ^[1,4]. The earlier TATTON phase Ib study demonstrated antitumor activity of savolitinib combined with osimertinib in the MET-amplified population ^[5], but phase III randomized controlled evidence supporting it as a standard subsequent therapy was lacking.

The SAFFRON study (NCT05261399) provided pivotal phase III data for this population ^[6]. This was an international, open-label phase III trial that enrolled patients with locally advanced or metastatic EGFR-mutant NSCLC who had progressed on osimertinib and harbored MET overexpression (IHC 3+ ≥90%) or amplification (FISH ≥10 copies); patients were randomized 1:1 to receive osimertinib 80mg once daily combined with savolitinib 300mg twice daily, or intravenous platinum-pemetrexed chemotherapy, with the primary endpoint being progression-free survival assessed by blinded independent central review.

The results showed that the combination treatment group was significantly superior to the chemotherapy group: PFS hazard ratio 0.55 (95%CI 0.42-0.72, P<0.001), with a 12-month PFS rate of 36% versus 10%; final analysis OS hazard ratio 0.68 (95%CI 0.50-0.91, P=0.01), with a 12-month OS rate of 70% versus 53%. Regarding safety, the incidence of grade ≥3 adverse events in the combination group (64%) was similar to that in the chemotherapy group (63%); the most common treatment-related adverse events were peripheral edema at 49%, and anemia and diarrhea, each at 26%.

This study established a chemotherapy alternative for MET-driven resistant populations selected by biomarkers, elevating the combination strategy from phase Ib exploration ^[5] to the level of phase III evidence-based medicine. However, the study used an open-label design, and the MET determination criteria were relatively stringent; the acquired resistance mechanisms after combination therapy (such as the MET, EGFR, and KRAS alterations demonstrated in TATTON ^[5]) and the relative positioning versus newer therapies such as amivantamab combined with chemotherapy ^[3] remain to be clarified by future studies.