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Osimertinib with or without savolitinib as first-line treatment for MET-aberrant, EGFR-mutant NSCLC: randomized phase

Anna Li1, Wei-Neng Feng2, Juan Li3

  • 1Division 1 of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.

Nature Communications
|January 13, 2026
PubMed

Insights

The combination of osimertinib and savolitinib demonstrated superior efficacy in treating advanced non-small cell lung cancer (NSCLC) with EGFR mutations and MET aberrations compared to osimertinib alone. This combination therapy showed a higher objective response rate and manageable safety.

Area of Science:

  • Oncology
  • Pharmacology
  • Genetics

Background:

  • Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide.
  • Epidermal growth factor receptor (EGFR) mutations are common drivers in NSCLC, and MET aberrations can confer resistance to targeted therapies.
  • De novo MET aberrations, including amplification or overexpression, present a specific challenge in NSCLC treatment.

Purpose of the Study:

  • To evaluate the efficacy and safety of combining osimertinib with savolitinib in treatment-naïve patients with advanced NSCLC.
  • To compare the outcomes of combination therapy against osimertinib monotherapy in patients with EGFR mutations and de novo MET aberrations.
  • To determine the confirmed objective response rate (ORR) as the primary endpoint for this phase 2 study.

Main Methods:

  • A randomized, multicenter, open-label, phase 2 study (NCT05163249) was conducted.
  • Treatment-naïve patients with advanced NSCLC, EGFR mutations, and de novo MET aberrations were randomized into two cohorts.
  • Cohort 1 received osimertinib monotherapy (80 mg daily), while Cohort 2 received combination therapy (osimertinib 80 mg daily + savolitinib 300 mg twice daily).

Main Results:

  • The confirmed objective response rate (ORR) was significantly higher in the combination arm (90.5%) compared to osimertinib monotherapy (60.9%).
  • Disease control rates were also higher with combination therapy (95.2%) versus monotherapy (87%).
  • Grade 3 or higher treatment-related adverse events were more frequent in the combination arm (57.1%) than in the monotherapy arm (8.7%), but were considered manageable.

Conclusions:

  • The combination of osimertinib and savolitinib demonstrates promising antitumor activity in patients with advanced NSCLC harboring EGFR mutations and de novo MET aberrations.
  • This combination therapy offers a significant improvement in objective response rates compared to osimertinib monotherapy.
  • While the combination therapy is associated with increased adverse events, its safety profile appears manageable, warranting further investigation.

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