Managing MET-driven resistance after first-line osimertinib with insights from the ORCHARD study

Despite the recent expansion of frontline therapeutic strategies for advanced EGFR-mutated non-small cell lung cancer (NSCLC), including osimertinib plus platinum-based chemotherapy in FLAURA2 and amivantamab plus lazertinib in MARIPOSA, osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), remains a central component of first-line management for this disease (1-3). However, even with its substantial clinical benefit, most patients eventually develop acquired resistance and experience disease progression, underscoring the need for effective post-osimertinib treatment approaches. Mechanisms of resistance to osimertinib are heterogeneous and are broadly categorized into on-target resistance, involving secondary EGFR mutations, and off-target resistance, in which tumor cells bypass EGFR inhibition through alternative signaling pathways. MET amplification is a representative off-target mechanism, occurring in approximately 5–24% of patients after progression on first-line osimertinib, and has emerged as an important therapeutic target in this setting (4).

In this context, the ORCHARD study was designed to identify resistance mechanisms that emerge after first-line osimertinib and to guide subsequent therapy based on molecular profiling (5). The present report focuses on the cohort with MET amplification and evaluates the efficacy of osimertinib plus savolitinib in patients whose post-progression tumor biopsy confirmed MET amplification. Because the study required mandatory biopsy and next-generation sequencing (NGS) at progression, it is possible that patients with relatively indolent disease who could wait for molecular results were preferentially enrolled. The sample size was also modest (n=32). Nevertheless, the combination demonstrated clinically meaningful activity, with a confirmed objective response rate (ORR) of 47%, a median duration of response of 14.5 months, a median progression-free survival (PFS) of 7.6 months, and a median overall survival of 20.7 months. Exploratory analyses further suggested that higher MET gene copy number (GCN) may be associated with improved response: the ORR was 53% in patients with MET GCN ≥10 (n=19) compared with 25% in those with MET GCN <10 (n=8).

These findings are broadly consistent with results from other studies evaluating dual EGFR-MET inhibition. In the SAVANNAH trial, osimertinib plus savolitinib achieved an ORR of 56.3% and a median PFS of 7.4 months in patients with high MET overexpression and/or amplification after progression on osimertinib (6). Similarly, the INSIGHT 2 study demonstrated an ORR of 50.0% and a median PFS of 5.6 months with the combination of tepotinib and osimertinib in patients with MET amplification (7). Furthermore, the SACHI trial showed that osimertinib plus savolitinib significantly prolonged median PFS compared with platinum-based chemotherapy (8.2 vs. 4.5 months) in the intention-to-treat population (8). Collectively, these data support the therapeutic relevance of dual EGFR and MET inhibition in EGFR-TKI-resistant NSCLC with MET amplification or overexpression.

However, a major challenge in translating MET-targeted strategies into routine clinical practice is the lack of consensus on how MET alterations should be defined. It remains unclear which specific MET alterations most reliably predict therapeutic benefit and what cut-off values should be used to designate clinically meaningful MET positivity. MET overexpression is assessed by immunohistochemistry (IHC), whereas MET amplification is evaluated by fluorescence in situ hybridization (FISH), using MET GCN or MET/CEP7 ratio, or by NGS-based copy number analysis. It is still uncertain which method most accurately reflects MET dependency, or whether a combination of assays is preferable. Even within a single assay, the optimal threshold for defining MET positivity has not been standardized.

Definitions of MET positivity varied substantially across the ORCHARD, SAVANNAH, INSIGHT 2, and SACHI trials. ORCHARD defined MET amplification as a MET copy number exceeding tumor ploidy by at least four copies on NGS (5). SAVANNAH initially used MET IHC 3+ in ≥50% of tumor cells and/or FISH5+, but later restricted enrollment to a high-MET subgroup (IHC 3+ in ≥90% or FISH10+) based on preliminary efficacy signals (6). INSIGHT 2 applied multiple criteria, including MET GCN ≥5 or MET/CEP7 ≥2 by tissue FISH, or plasma MET GCN ≥2.3 by liquid biopsy NGS (7). In SACHI, MET amplification was assessed by FISH, with thresholds dependent on prior EGFR-TKI exposure: MET GCN ≥5 or MET/CEP7 ≥2 after first- or second-generation TKIs, and MET GCN ≥10 after third-generation TKIs such as osimertinib (8). These inconsistencies highlight the need for robust biomarkers and standardized cut-offs to identify tumors with true MET dependency.

Meanwhile, amivantamab plus chemotherapy has recently emerged as a new standard option after resistance to osimertinib. In the MARIPOSA-2 trial, amivantamab plus chemotherapy improved median PFS (6.3 vs. 4.2 months) and ORR (64% vs. 36%) compared with chemotherapy alone (9). Because this trial enrolled patients irrespective of MET alteration status, it remains unclear which patients should preferentially receive EGFR-MET dual inhibition versus amivantamab-based therapy.

Against this backdrop, the MET pathway remains a compelling therapeutic target in EGFR-mutated NSCLC after resistance to osimertinib. Future research should prioritize developing robust, clinically validated methods to identify tumors with true MET dependency and to clarify the optimal positioning of EGFR-MET dual inhibition relative to amivantamab plus chemotherapy and other emerging post-osimertinib strategies. Together, these efforts will be essential for refining personalized therapy and improving outcomes for patients with EGFR-mutated NSCLC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Shanghai Chest. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2026-0023/coif). K.Y. serves as an advisor or consultant for Boehringer Ingelheim, AbbVie, and GlaxoSmithKline. K.Y. has also received grants from Chugai, Eli Lilly, AstraZeneca, Boehringer Ingelheim, AbbVie, Taiho, Daiichi Sankyo, Takeda, MSD, and ArriVent and personal fees from Chugai, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Taiho, Daiichi Sankyo, Takeda, MSD, Ono, Bristol-Myers Squibb, Kyowa Kirin, Janssen, and Amgen. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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