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A Retrospective, Multicenter Analysis Within the National Network Genomic Medicine Lung Cancer in Germany to Detect RET Fusions as a Possible Mechanism of Resistance in Patients With EGFR Mutations

Kropf-Sanchen C, Frost N, Kuon J, Wermke M, Krüger S, Fuchs F, Wiesweg M, Christopoulos P, Thomas M, Gaisa NT, Josten M, Wenzel C, Buth J, Glanemann F, Stenzinger A, Froelich MF, Janning M, Colienne M, Haselmann V, Loges S (2026)

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Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1016/j.cllc.2026.03.005

Abstract

Background Resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib remains a major challenge in the treatment of EGFR -mutated non-small cell lung cancer (NSCLC). While on-target and bypass mechanisms such as MET amplification are well-characterized, oncogenic fusions—particularly RET fusions—are emerging as relevant resistance mechanisms in a subset of patients. The feasibility of dual inhibition strategies and personalized monitoring through liquid biopsy remains underexplored in real-world clinical practice. Materials and Methods This retrospective, multicenter study within the German national Network Genomic Medicine (nNGM) Lung Cancer identified patients with advanced EGFR -mutated NSCLC and co-occurring RET fusions between 2018 and 2024. Clinicopathological data, treatment history, progression-free survival (PFS), and overall survival (OS) were analyzed. RET alterations were either present at diagnosis or acquired under EGFR-TKI therapy. In 2 patients, a personalized droplet digital PCR (ddPCR) assay was developed to monitor EGFR and RET alterations longitudinally using liquid biopsy. Results Nine patients met the inclusion criteria (median age: 54 years). RET fusions were detected at diagnosis in 2 patients and acquired in 7 patients during EGFR-TKI treatment, with a median time to detection of 11.4 months. RET fusion partners included CCDC6 ( n = 4), KIF5B ( n = 2), NCOA4 ( n = 2), and one case with an unknown partner. The most common EGFR mutation was exon 19 deletion ( n = 6), followed by L858R mutation ( n = 1), with 2 patients harboring exon 20 insertions. First-line treatment consisted of RET inhibition with pralsetinib in the 2 patients with atypical EGFR mutations, third-generation EGFR-TKIs in 6 patients (median PFS: 13.5 ± 9.2 months), and a second-generation EGFR-TKI (afatinib) in one patient (PFS: 8.7 months). Following progression, all patients underwent re-biopsy, confirming persistence of the EGFR mutation and presence of RET fusions. Second-line therapies varied, including chemo-immunotherapy ( n = 4, mPFS: 6.5 ± 2.5 months), chemotherapy ( n = 1, PFS: 0.3 months), and best supportive care ( n = 1). Three patients received the combined EGFR-TKI osimertinib and RET-TKI pralsetinib either in second- or third-line, with PFS ranging from 3.9 to 10.5 months. Median OS for the cohort was 27 months (range: 7 to >30 months), with 4 patients still alive at last follow-up. In 2 patients, a personalized ddPCR assay enabled non-invasive, longitudinal monitoring of EGFR and RET alterations, closely reflecting the clinical course of disease. In 1 patient, molecular recurrence in liquid biopsy preceded clinical and radiologic progression, underscoring the potential of this approach for early detection of therapeutic resistance. Conclusion RET fusions represent a rare mechanism of acquired resistance in EGFR -mutant NSCLC. Combined RET and EGFR inhibition may offer clinical benefit, particularly in patients with co-occurring alterations. Personalized ddPCR-based liquid biopsy is a promising tool for real-time, non-invasive monitoring of treatment response and resistance evolution.

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APA:

Kropf-Sanchen, C., Frost, N., Kuon, J., Wermke, M., Krüger, S., Fuchs, F.,... Loges, S. (2026). A Retrospective, Multicenter Analysis Within the National Network Genomic Medicine Lung Cancer in Germany to Detect RET Fusions as a Possible Mechanism of Resistance in Patients With EGFR Mutations. Clinical Lung Cancer. https://doi.org/10.1016/j.cllc.2026.03.005

MLA:

Kropf-Sanchen, Cornelia, et al. "A Retrospective, Multicenter Analysis Within the National Network Genomic Medicine Lung Cancer in Germany to Detect RET Fusions as a Possible Mechanism of Resistance in Patients With EGFR Mutations." Clinical Lung Cancer (2026).

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