Dr Passaro on the Role of MET in Guiding Treatment Strategies After EGFR TKI Progression in NSCLC

"The most studied and influential biomarker as a resistance mechanism after osimertinib or an EGFR TKI is MET. The problem when we discuss MET is the understanding the way we test for it. There is no consensus at the present time [about] which [testing] method is the most effective here."

Antonio Passaro, MD, PhD, a medical oncologist in the Division of Thoracic Oncology at the European Institute of Oncology in Milan, Italy, discussed testing methodologies and clinical trials evaluating treatment strategies targeting MET following progression on EGFR TKIs in EGFR-mutated non–small cell lung cancer (NSCLC), based on his presentation during the 2025 Global Bridging the Gaps in Lung Cancer consensus meeting.

Passaro highlighted that the most influential and studied biomarker acting as a resistance mechanism following treatment with an EGFR TKI, such as osimertinib (Tagrisso), is MET. However, a significant challenge when addressing MET resistance involves standardizing the testing format.

Data confirm that MET status can be evaluated using several methods, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or next-generation sequencing analysis. Despite the availability of these techniques, Passaro noted that there is currently no consensus defining which method is the most effective. Additionally, there is uncertainty regarding the current cutoff values utilized by different testing methods, such as IHC or FISH, necessary to accurately identify patients who are highly sensitive and therefore candidates for potential MET inhibitors. Understanding these testing formats and corresponding cutoffs is crucial for optimizing post-progression treatment decisions, he said.

Despite these diagnostic ambiguities, Passaro confirmed that well-developed clinical trials are currently evaluating the efficacy of combining TKIs with MET inhibitors. The most well-known study is the phase 2 SAVANNAH trial (NCT03778229), which evaluated the combination of osimertinib and savolitinib in patients with EGFR-mutant/MET-positive NSCLC who had progressed after prior osimertinib. Furthermore, the phase 3 SAFFRON trial (NCT05261399) is now dedicated to determining if this same combination provides improved efficacy compared to standard doublet chemotherapy after osimertinib alone for those patients exhibiting high MET expression. This ongoing research is vital for establishing the optimal therapeutic strategy against this common mechanism of resistance, Passaro concluded.