Long-term survival with adaptive dual-targeted therapy in an epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patient with mesenchymal-epithelial transition (MET) amplification guided by minimal residual disease (MRD) assessments: a case report and literature review

Introduction

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line treatments for patients with EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) (1). However, despite high response rates, patients eventually develop resistance to EGFR-TKI therapy via several mechanisms (2). Resistance to EGFR-TKIs in NSCLC is broadly categorized into EGFR-dependent and EGFR-independent mechanisms. EGFR-dependent mechanisms include secondary mutations (e.g., T790M, C797S) that impair drug binding and primary resistance mutations (e.g., exon 20 insertions) that reduce TKI sensitivity. EGFR-independent mechanisms include bypass pathway activation: mesenchymal-epidermal transition (MET)/human epidermal growth factor receptor 2 (HER2) amplification, RAS-MAPK/PI3K pathway upregulation; histologic transformation: e.g., epithelial-to-mesenchymal transition (EMT) or small cell lung cancer (SCLC) conversion; MET amplification is a dominant EGFR-independent mechanism, accounting for 15–22% of resistance to first-/second-generation EGFR-TKIs and 5–15% to third-generation agents like osimertinib (3).

MET amplification is a pivotal bypass resistance mechanism in patients with acquired resistance to first- and second-generation EGFR-TKIs (4), paralleling the T790M mutation (5) as a major contributor to therapeutic failure, which is a different mechanism of acquired resistance and is less frequent than the T790M acquired resistance. While some therapies such as chemotherapy and immunotherapy have limited clinical efficacy, several phase 1 clinical studies on MET-TKI combined with EGFR-TKI have shown promising therapeutic potential for EGFRm/MET-amplified NSCLC patients who experience disease progression on EGFR inhibitors, the overall response rate (ORR) was 48% and median duration of response (DOR) was 9.5 months in osimertinib and savolitinib combination, positioning this combination as a viable therapeutic avenue for overcoming resistance (6-9).

Savolitinib (AZD6094, HMPL-504, and volitinib) is an oral and highly selective MET inhibitor (10), has clinically validated the therapeutic strategy of dual EGFR/MET inhibition for patients acquiring MET amplification-driven resistance following EGFR-TKI treatment. However, the safety profile of such combination regimens requires careful consideration due to the potential for cumulative toxicities, particularly in the context of prolonged treatment duration.

In a single-arm, multi-cohort, multi-center, open-label, phase 3b confirmatory study in China, savolitinib monotherapy demonstrated promising efficacy in treatment-naïve NSCLC patients harboring MET exon 14 skipping mutations. The most common reported grade ≥3 adverse events (AEs) were increased aspartate aminotransferase (14%), increased alanine aminotransferase (16%), other abnormal liver function (22%), and peripheral oedema (8%). Of the 87 patients in the study, treatment-related adverse events (TEAEs) leading to treatment interruption and dose reduction were reported in 29 (33%) and 63 (72%) patients, respectively (11).

A combination regimen of savolitinib and osimertinib in MET-amplified NSCLC patients was evaluated in a phase Ib TATTON study, in which 79 (57%) of 138 patients in the expansion cohort part B experienced grade ≥3 AEs, 115 (83%) patients experienced AEs possibly related to savolitinib, and 62 (45%) patients experienced serious AEs. AEs that were possibly related to the study treatment led to interruption and dose reduction of savolitinib in 38 (28%) and 46 (33%) of the 138 patients, respectively. While AEs that were possibly related to the study treatment led to the interruption and dose reduction of osimertinib in 14 (10%) patients and 8 (6%) of the 138 patients, respectively (6).

In a phase Ib trial of savolitinib plus gefitinib in patients with EGFRm, MET-amplified advanced NSCLC, no dose-limiting toxicities were observed in the 13 patients enrolled in the safety run-in phase or in the 51 patients enrolled in the expansion phase. However, in the safety run-in and expansion phases, grade ≥3 AEs were reported in 21 (37%) of 57 patients. The most frequently reported AEs (all grades) were vomiting (46%), nausea (40%), and increased aspartate aminotransferase (39%). The ORRs of the EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively (7).

As mentioned above, MET inhibitors are associated with a distinct spectrum of AEs, including but not limited to grade 3/4 toxicities, which often necessitate dose reductions or treatment interruptions. Notably, combining MET inhibitors with EGFR-TKIs may increase the incidence of AEs, potentially compromising long-term treatment adherence. Therefore, striking an optimal balance between efficacy and safety is crucial for patients undergoing prolonged therapy duration. A potential strategy is needed to evaluate whether dose reduction can maintain therapeutic efficacy while reducing AEs.

Several studies have already shown the predictive and prognostic value of measuring circulating tumor DNA (ctDNA) concentration in the blood, enabling real-time monitoring of the molecular disease burden, the early identification of resistance, and the dynamic adjustment of therapeutic strategies (12-14). The integration of comprehensive genomic profiling and minimal residual disease (MRD) testing strengthens treatment decision making.

In this article, we report the case of a patient with MET amplification-mediated resistance to EGFR-TKIs, in which an adaptive treatment regimen with optimize management was guided by the occurrence of AEs, and dynamic ctDNA monitoring achieved durable disease control. Specifically, combination therapy with savolitinib and gefitinib was personalized to achieve sustained clinical benefit while minimizing toxicity. Our findings align with emerging evidence suggesting that adaptive treatment strategies, such as dose de-escalation or precision dosing adjustments, can significantly improve outcomes in selected patients with driver-gene-driven resistance (15). We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-850/rc).

Case presentation

The patient was a 65-year-old female, never-smoker, who developed a cough with white sputum and an absence of hemoptysis in October 2015. A chest computed tomography (CT) performed in December 2015 revealed a mass in the right upper lobe of the lung and enlarged mediastinal lymph nodes, leading to a diagnosis of metastatic lung adenocarcinoma (LUAD) (Figure 1). No diagnostic challenges arose for this patient. Based on positron emission tomography-CT (PET-CT), CT, and pathological findings, stage IIIB (T4N2M0) LUAD was confirmed. Next-generation sequencing (NGS) of the lung biopsy specimen indicated an EGFR exon 19 p.E746_A750 deletion mutation (NGS detection turnaround time 5 days).

Figure 1 Baseline chest CT scans. CT, computed tomography.

The patient received frontline treatment with first-generation EGFR-TKI gefitinib (250 mg daily) and achieved a partial response (PR) after two cycles of treatment delivered every 21 days as evaluated by CT (Figure 2).

Figure 2 Chest CT during first-generation EGFR-TKI gefitinib treatment. (A,C) Chest CT results before EGFR-TKI initiation. (B,D) Chest CT results after EGFR-TKI initiation. The red circles represent the lung tumor lesion. CT, computed tomography; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor.

However, at the end of August 2016, the patient developed a headache. Chest CT revealed disease progression, and brain magnetic resonance imaging (MRI) showed right parietal osteolytic bone destruction (Figure 3). The first-line treatment progression-free survival (PFS) was 8 months. The patient, who had stage IV (T4N2M1) disease, then received parietal bone and chest radiotherapy at a dose of 45 Gy in 15 fractions and 50 Gy in 10 fractions. At the same time, she was treated with gefitinib 250 mg daily as droplet digital polymerase chain reaction (PCR) of peripheral blood reveal an EGFR exon19 deletion mutation and EGFR T790M mutation negative.

Figure 3 Brain MRI showing tumor progression after gefitinib treatment. The red circles represent the osteolytic bone lesion. MRI, magnetic resonance imaging.

After radiotherapy, a CT scan revealed progressive disease with left adrenal gland metastasis, and the brain lesion was assessed as stable disease (SD) on October 2016. The patient received left adrenalectomy in November 2016 (Figure 4A). Her immunohistochemistry results showed immunophenotypic changes in pulmonary tumors. Fluorescence in situ hybridization (FISH) of the adrenal gland specimen indicated MET amplification [MET/centromeric enumeration probe 7 (CEP7) =6.46]. NGS of the biopsy specimen revealed the patient carried MET amplification together with EGFR exon 19 deletion mutation. DNA sequencing indicated an EGFR exon 19 deletion mutation (13.8%), TP53 mutation (18.4%), ATM mutation (5.3%), MET amplification copy number 3.48, ERBB2 amplification copy number 2.11; the results were negative for the homologous recombination deficiency (HRD) mutation. The tumor burden mutation related to the immune checkpoint blockade was low, and microsatellite stability was detected. The RNA transcriptome analysis did not identify any gene rearrangement. The patient then received four cycles of chemotherapy with pemetrexed and combined with gefitinib. In February 2017, the disease was stable in the chest, brain and bone, but the adrenal gland metastasis became enlarged (2.6 cm) (Figure 4B). The biopsy result revealed MET amplification [MET/centromere specific probe 7 (CSP7) >2.2] and EGFR exon 19 deletion mutation.

Figure 4 CT showing changes of adrenal gland metastasis. (A) CT scan after left adrenalectomy. (B) CT scan showing progressive disease with left adrenal gland metastasis. (C) CT scan showing a PR after dual-targeted therapy. The red circles represent the adrenal gland tumor lesion. CT, computed tomography; PR, partial response.

In March 2017, the patient was enrolled in an early access clinical trial program, receiving savolitinib 600 mg daily in combination with gefitinib 250 mg daily, this combination regimen was under investigation in China. This regimen resulted in a PR (Figure 4C). The patient remained on this treatment for more than 60 months. However, patient reported grade 1–2 peripheral edema in early 2022. This was initially managed with lifestyle modifications (specifically, a low-sodium diet and limb elevation) and physical therapy, which provided symptomatic relief. Consequently, no drug dosage adjustments were made at that time. From April 2022, the edema progressed in severity. Diuretic therapy was initiated but failed to improve symptoms. Then plasma ctDNA MRD detection by NGS was then performed to monitor her molecular disease status after treatment. The results showed she was negative for ctDNA.

Initially, the physician adopted a personalized adaptive treatment approach for this patient, leading to a dose reduction of savolitinib to 400 mg daily and gefinitib dose remained unchanged, resulting in reduction of edema to grade 1. She continued to receive combination therapy, and showed an ongoing response and no evidence of disease progression. Her CT scans showed SD, and she continued to test negative for ctDNA in September 2023 and January 2025 (Figures 5-7). The patient’s quality of life improved significantly, allowing her to return to normal daily activities, as reported through patient self-reported outcomes. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 5 Clinical history of the patient. AE, adverse event; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; MET, mesenchymal-epithelial transition; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 6 Chest CT follow-up during treatment. The green lines in images indicate the measured diameter of the tumor lesion. CT, computed tomography.

Figure 7 Abdomen CT follow-up during treatment. CT, computed tomography.

Discussion

Previous clinical trials have shown the efficacy and safety of dual-target therapy. The INSIGHT study compared the efficacy and safety of tepotinib plus gefitinib with chemotherapy in patients with MET-altered EGFR-mutant NSCLC. In 19 patients with the MET amplification subgroup, the median PFS of the dual-target arm was 19.3 months [90% confidence interval (CI): 5.6–22.1] while that of the chemotherapy arm was 4.2 months (90% CI: 1.4–7.0) [unstratified hazard ratio (HR) =0.16; 90% CI: 0.05–0.52] and the longest PFS was 22 months. A remarkable improvement was also observed in the median overall survival (OS) of the dual-target arm (37.3 months; 90% CI: 21.1–52.1) compared to the chemotherapy arm (13.1 months, 90% CI: 3.3–22.6) and the longest OS was 52.1 months (unstratified HR =0.10; 90% CI: 0.02–0.36) (9,16). Moreover, the INSIGHT2 study showed that the tepotinib plus osimertinib therapy in patients with EGFRm NSCLC and MET amplification had promising anti-tumor activity and acceptable safety, 140 patients were enrolled and the confirmed ORR was 50%, median PFS was 5.6 months (95% CI: 4.2–8.1), with event-free rates of 48% (95% CI: 37–58%) at 6 months and 30% (95% CI: 20–40%) at 9 months, median OS was 17.8 months [95% CI: 11.1–not estimable (NE)], with event-free rates of 81% (95% CI: 72–88%) at 6 months and 71% (95% CI: 60–79%) at 9 months (17). This study is ongoing. Real-world case series have shown that tepotinib plus an EGFR-TKI has promising efficacy, 28 cases of patients with EGFRm NSCLC and MET alterations were analyzed, 25/28 patients (89%) had clinical benefit, 16 of whom (57%) were considered to have a PR (18). Additionally, an ORR of 47% was reported in EGFRm, MET-dysregulated (amplified/overexpressing) NSCLC in patients with a MET gene copy number ≥6, who received capmatinib plus gefitinib therapy (8).

The ORCHARD study (NCT03944772) is a phase II study of patients with advanced NSCLC who showed disease progression after first-line osimertinib therapy. The interim analysis showed preliminary activity in patients with MET amplification after first-line osimertinib, and seven patients achieved an ORR of 41%. The safety was acceptable and consistent with known profiles of osimertinib and savolitinib (19).

Clinical trials are ongoing to test the combination of osimertinib and MET-TKI, including savolitinib and tepotinib. Based on the promising findings of the TATTON study, the SAVANNAH study (NCT03778229) observed disease progression in patients with EGFRm NSCLC with MET overexpression and/or amplification following osimertinib therapy, confirming the necessity for appropriate MET biomarker-based patient selection in this population (20). A randomized phase III study (SACHI, NCT05015608) compared the efficacy and safety of savolitinib plus osimertinib versus pemetrexed plus platinum in patients with MET amplification following EGFR-TKIs treatment failure. Results showed that among patients previously treated with first/second-generation EGFR-TKIs, the investigator-assessed median PFS in the savolitinib plus osimertinib group was 9.8 months. In the intention-to-treat (ITT) population, the investigator-assessed median PFS for the combination group was 8.2 months. In terms of tumor response, the ORR was 58% in the savolitinib plus osimertinib group versus 34% in the control group, with an odds ratio (OR) of 2.74 (P=0.0004). Regarding safety, the savolitinib plus osimertinib regimen demonstrated tolerable safety with no new safety signals observed. These findings further enrich precision treatment strategies for EGFRm NSCLC patients with MET amplification after progression on EGFR-TKI therapy. Savolitinib combined with osimertinib has been approved in China for the treatment of locally advanced or metastatic non-squamous NSCLC patients with EGFRm and MET amplification who progressed after EGFR-TKI therapy (21).

This is the first reported case of a patient with MET amplification with a PFS time of over 8 years. Interestingly, the INSIGHT study also reported survival beyond 5 years in two cases (16). We believe that MET amplification plays a key role in driving disease progression after EGFR-TKI resistance and the combination of an EGFR-TKI with a MET-TKI may lead to improved outcomes.

ctDNA was found to carry cancer-specific molecular alterations in blood plasma and other body fluid, serving as a sensitive biomarker for MRD monitoring. In recent studies, ctDNA has emerged as a prognostic and diagnostic biomarker in lung cancer (22-25). During follow-up, MRD diagnosis may detect relapse much earlier than conventional diagnosis. Further, ctDNA can provide critical information as to whether and how intensively therapy should be administered. This case report showed the utility of ctDNA-guided TKI de-escalation and the importance of adopting a personalized adaptive approach in the management of NSCLC patients.

Conclusions

We are the first to report on a patient with LUAD harboring both MET amplification and an EGFR exon 19 deletion mutation, who achieved a durable response and prolonged survival following combination treatment with savolitinib and gefitinib. Identifying driver oncogene alterations is crucial for patients with advanced NSCLC, particularly after disease progression. This case paradigmatically illustrates the transformative potential of precision oncology, where real-time molecular diagnostics and adaptive treatment converge to redefine aggressive driver-mutant cancers as manageable chronic conditions, thereby optimizing both the survival outcomes and quality of life of patients. Based on our observations, further research should be conducted to determine the optimal treatment combinations for patients with NSCLC harboring MET amplification and EGFR mutations. Additionally, more studies are needed to elucidate the roles of these genetic alterations and their effects on the efficacy of TKIs.

Acknowledgments

We would like to thank the patient for permitting us to discuss her case and present her images.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-850/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-850/prf

Funding: This work was supported by grants from the National Natural Science Foundation of China (Nos. 82473171, 82272669, and 82203010) and the HUI LAN Public Foundation (No. HL-HS2020-123).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-850/coif). All authors report that this work was supported by grants from the National Natural Science Foundation of China (Nos. 82473171, 82272669, and 82203010) and the HUI LAN Public Foundation (No. HL-HS2020-123). The authors have no other 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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(English Language Editor: L. Huleatt)