The phase II SAVANNAH study of savolitinib plus osimertinib demonstrated a clinically meaningful and durable response and may offer a chemotherapy-free treatment option in patients with EGFR-mutated and MET-overexpressed and/or MET-amplified advanced non-small cell lung cancer (NSCLC) progressing on osimertinib, said researcher Myung-Ju Ahn, MD, PhD, during the 2025 European Lung Cancer Conference (ELCC) in Paris.
Dr. Ahn also said the combination treatment was generally well tolerated and demonstrated a manageable safety profile. This oral combination is currently undergoing assessment versus platinum-pemetrexed chemotherapy in the ongoing phase III SAFFRON study.
Osimertinib is commonly used to treat EGFR-mutated NSCLC, but genetic alterations, such as MET amplification and MET overexpression, may arise during treatment with osimertinib and lead to disease progression, with the reported incidence of MET amplification after osimertinib varying from 7% to 50% across studies.1,2,3,4
Hypothesizing that combined EGFR and MET inhibition may improve outcomes for patients with MET-mediated acquired resistance, investigators examined the efficacy and safety of giving savolitinib—an oral agent designed to block the activity of the MET protein—in combination with osimertinib for patients with MET-overexpression and/or MET-amplification having progression while or after receiving osimertinib.
Dr. Ahn, from the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, said the study screened 1,064 patients, assigning 369 to treatment. The final protocol reflected refinements to the patient population and MET thresholds; it set the recommended phase II dose (RP2D) for savolitinib at 300 mg twice a day in combination with osimertinib 80 mg every day. In the final safety analysis, 101 patients received savolitinib 300 mg twice a day plus osimertinib. Among the 80 patients in the primary efficacy population were those whose disease had progressed on osimertinib and who had MET expression 90% or greater and/or positive FISH (> 10 copies per cell) status.
The primary endpoint of SAVANNAH was investigator-assessed objective response rate (ORR), with secondary end points including ORR by blinded independent central review (BICR), duration of response (DoR) and progression-free survival (PFS)—both by investigators and by BICR—as well as overall survival (OS) and safety.
For tumor response in the primary efficacy population, the investigator-assessed ORR was 56%; by BICR, it was 55% (Fig. 1).
The median investigator and BICR PFS times were 7.4 months and 7.5 months, respectively (Fig. 2).
In terms of safety, more than 50% of patients experienced peripheral edema (48% grade 1 to 2, 11% grade 3), 45% experienced nausea (43% grade 1 to 2, 2% grade 3), and 33% experienced diarrhea (30% grade 1 to 2, 3% grade 3). All other adverse event rates were below 25% incidence and included back pain, constipation, cough, and hypoalbuminemia.
References
- 1. Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737. doi:10.1038/s41416-019-0573-8
- 2. Piotrowska Z, Tan DS, Smit EF, et al. Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions. J Clin Oncol. 2023;41(26):4218-4225. doi:10.1200/JCO.23.00152
- 3. Chmielecki J, Gray JE, Cheng Y, et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer [published correction appears in Nat Commun. 2023 Jun 1;14(1):3179. doi: 10.1038/s41467-023-38999-0.]. Nat Commun. 2023;14(1):1070. Published 2023 Feb 27. doi:10.1038/s41467-023-35961-y
- 4. Maione P, Palma V, Pucillo G, Gridelli C. New Treatment Strategies in Advanced Epidermal Growth Factor Receptor-Driven Non-Small Cell Lung Cancer: Beyond Single Agent Osimertinib. Cancers (Basel). 2025;17(5):847. Published 2025 Feb 28. doi:10.3390/cancers17050847
