SACHI: Savolitinib Plus Osimertinib Prolongs PFS Versus Chemotherapy in MET-Driven EGFR-Mutated NSCLC

Savolitinib plus osimertinib “significantly improved” progression-free survival (PFS) compared with chemotherapy in patients with MET-amplification (METamp) EGFR-mutated advanced non–small cell lung cancer (NSCLC) after disease progression during treatment with an EGFR tyrosine kinase inhibitor (TKI), according to the primary results of the prespecified interim analysis of SACHI.

Lu Shun, MD, PhD, of the Shanghai Chest Hospital, and colleagues conducted the study and presented the results of the interim analysis at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

The study compared the safety and efficacy of savolitinib, as a “highly selective” MET-TKI, combined with osimertinib versus chemotherapy. The investigators identified 250 patients with EGFR-mutated METamp advanced NSCLC after disease progression during treatment with first-line EGFR-TKIs for the randomized, open-label, phase 3 study and required that those patients have no T790M EGFR mutations after disease progression during treatment with first- or second-generation EGFR-TKIs.

Patients who met the eligibility criteria were randomized 1:1 to receive 400 or 600 mg of savolitinib once daily, with the dose depending on body weight, plus 80 mg of osimertinib once daily or chemotherapy consisting of pemetrexed plus carboplatin or cisplatin. Patients were stratified by brain metastases, prior treatment with a third-generation EGFR-TKI, and type of EGFR mutation.

The researchers noted that they allowed patient crossover from the chemotherapy group to the savolitinib plus osimertinib group if immune-related criteria for progression occurred. The primary end point of the study was PFS by investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), which was “hierarchically tested via a stratified log-rank test in 3G [third generation] EGFR-TKI treatment naïve set,” then tested in the intention-to-treat set as well.

Data were collected from October 15, 2021, to August 30, 2024, among 211 patients. A total of 106 patients were in the savolitinib plus osimertinib cohort, and 105 patients comprised the chemotherapy cohort. According to the results, “baseline characteristics were well balanced.”

The findings revealed that modified PFS, as evaluated by investigators, was “significantly longer” in the savolitinib plus osimertinib group compared with the chemotherapy group in both the third-generation EGFR-TKI treatment-naive set and the intention-to-treat set (P<0.0001 in both sets). Furthermore, modified PFS was “significantly prolonged” in patients receiving savolitinib plus osimertinib versus chemotherapy (6.9 months vs 3.0 months, HR [hazard ratio], 0.32; P<0.0001).

In addition, PFS benefits evaluated through immune-related criteria were “consistent.” The researchers also reported on adverse event data, noting that grade 3 and higher treatment-related adverse events were observed in 56.6% of patients receiving savolitinib plus osimertinib and in 57.3% of patients receiving chemotherapy. Savolitinib plus osimertinib also “had lower rates of hematologic events” compared with chemotherapy.

In reflecting on the results, the investigators deemed the drug combination safe and well tolerated. “Savo + osi [Savolitinib plus osimertinib] is a potential new treatment option for this genomically defined population,” they concluded.