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Clinical Trial
. 2026 Jan;27(1):38-46.
doi: 10.1016/j.cllc.2025.10.018. Epub 2025 Oct 22.

Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial

James Chih-Hsin Yang  1 , Yuh-Min Chen  2 , Ullas Batra  3 , Kien Hung Do  4 , Piyada Sitthideatphaiboon  5 , Pongwut Danchaivijitr  6 , Kang-Yun Lee  7 , Jarin Chindaprasirt  8 , Cheng-Ta Yang  9 , Gee-Chen Chang  10 , Chaiyut Charoentum  11 , Teerapat Ungtrakul  12 , Juan Ignacio Hernandez Moran  13 , Ryan Hartmaier  14 , Ike Igwegbe  15 , Alexander Gont  16 , Matthew Haskins  17 , Wanning Xu  18 , Jonathan W Riess  19
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Free article
Clinical Trial

Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial

James Chih-Hsin Yang et al. Clin Lung Cancer. 2026 Jan.
Free article

Abstract

Background: MET amplification is the most common resistance mechanism to first-line osimertinib. We report safety and efficacy data from a phase II study assessing savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated, MET-amplified, advanced non-small cell lung cancer (NSCLC).

Patients and methods: Patients with EGFR-mutated, MET-amplified (MET gene copy number ≥ 5 or MET:CEP7 ratio ≥ 2), advanced NSCLC post-osimertinib were enrolled. Patients received savolitinib 300 mg once daily (QD) plus osimertinib 80 mg QD or savolitinib plus placebo. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory analysis included retrospective efficacy assessment by higher MET cutoffs (immunohistochemistry 3+ staining ≥ 90% tumor cells and / or MET gene copy number ≥ 10).

Results: Thirty patients were randomized (14 savolitinib-osimertinib; 16 savolitinib-placebo). Among all patients, ORR (95% confidence interval [CI]) was 57% (29-82) versus 13% (2-38); median PFS (95% CI) was 7.4 months (5.6-not calculable [NC]) versus 1.6 months (1.3-4.1) for savolitinib-osimertinib and savolitinib-placebo, respectively. In patients with higher MET cutoffs, ORR was 63% (24-91) and 29% (4-71); median PFS was 8.2 months (4.1-NC) and 4.0 months (1.3-NC) for savolitinib-osimertinib (n = 8) and savolitinib-placebo (n = 7), respectively. There were no new safety signals. This study was terminated early and the contribution of osimertinib to savolitinib is being assessed further in SAVANNAH (NCT03778229) in patients with higher MET biomarker cutoffs.

Conclusions: Savolitinib plus osimertinib demonstrated numerically higher clinical activity versus savolitinib plus placebo in all patients and patients with higher MET biomarker cutoffs.

Keywords: Contribution of components; EGFR-TKI; MET amplification; MET-TKI.

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Conflict of interest statement

Disclosure JCHY reports advisory or consulting for AbbVie, Amgen, Arrivent, AstraZeneca, Daiichi-Sankyo, Daiichi-Sankyo/AstraZeneca, Janssen, Lilly, MSD, and Takeda (all to institution); honoraria from Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi-Sankyo/AstraZeneca, MSD, Pfizer, Roche/Genentech, and Takeda (all to institution); researching funding from AstraZeneca (to institution); and travel funding from AstraZeneca, Dizal Pharmaceutical, and Takeda. Y-MC reports advisory council and consulting fees with Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eli Lilly, MSD, and Ono Pharmaceutical. C-TY reports advisory council with AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis, Ono Pharmaceutical, and Roche; advisory role with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck, Ono Pharmaceutical; and invited speaker with AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Ono Pharmaceutical, Pfizer, and Roche; local PI with AstraZeneca, Boehringer Ingelheim, and Pfizer; and speaker, consultant, advisor with AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Roche. G-CC reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Roche, MSD, Novartis, and Pfizer. CC reports employment at Chiang Mai University and grants or funds from AstraZeneca, Daiichi-Sankyo, Exelixis, MSD, Novartis, and Roche. RH reports employment and stocks/shares with AstraZeneca and inventor on issued patent US201902186118A1 (assigned to Foundation Medicine, Genentech). II reports employment and stocks/shares with AstraZeneca. AG reports employment at AstraZeneca. MH reports employment at AstraZeneca. WX reports employment (at the time of study) and stocks/shares with AstraZeneca. JWR reports advisory council with Amgen, Bicycle Pharmaceuticals, Bristol Myers Squibb, Catalyst, Janssen, Merck, Merus NV, Oncohost, Pfizer, Roche/Genentech, Regeneron, and Sanofi; consulting fee from Daiichi-Sankyo; grants or funds from AstraZeneca/MedImmune, Arrivent, Avistone, Boehringer Ingelheim, IO Biotech, Merck, Novartis, Nuvalent, Pfizer, Revolution Medicines, Summit (all to institution); travel funding from AstraZeneca and IO Biotech. No other disclosures were reported.

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