Unlocking the central nervous system sanctuary in EGFR-mutant non-small cell lung cancer: molecular insights and therapeutic signals from amivantamab-lazertinib in leptomeningeal disease

The study by Chen et al., published in Journal of Thoracic Oncology, addresses a clinical challenge of growing magnitude (1). The prevalence of brain and leptomeningeal metastases (LMs) in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is increasing, with a cumulative leptomeningeal disease (LMD) prevalence of 11.1%, driven by prolonged survival with 3^rd-generation EGFR-tyrosine kinase inhibitors (TKIs) (2). The current study was a single-arm phase 2, USA investigator-initiated trial that enrolled 41 patients with EGFR-mutant NSCLC who had developed new or progressive central nervous system (CNS) metastases after prior systemic therapy, including patients with active LMD. Patients were enrolled into two parallel cohorts: cohort 1 included 20 patients with brain metastases (BMs); cohort 2 included 21 patients with LMD (with or without BMs). LMD required cytological confirmation or detectable circulating tumour cells (CTCs) in the cerebrospinal fluid (CSF).

Inclusion criteria were broad, with 10% of patients harboring uncommon EGFR mutations and 12% exon 20 insertions, a median of 2 prior lines of therapy (range, 1–7). All patients had prior osimertinib (except those with exon 20 insertions), and 61% of the population was non-Asian. Half of the cohort (n=22/41) had also received chemotherapy, 15% had prior immunotherapy and 14% had received more than four prior lines of therapy. Most of the cohort (n=29, 71%) did not receive prior brain radiation therapy. All patients received a combination of amivantamab [EGFR-mesenchymal-epithelial transition (MET) bispecific antibody; 1,050 mg intravenous (IV) (1,400 mg if ≥80 kg)] and lazertinib (CNS-penetrant, 3^rd-generation EGFR-TKI; 240 mg orally once daily). This was a chemotherapy-free regimen, combining antibody-mediated EGFR/MET targeting with TKI-mediated EGFR inhibition—a rationale designed to address both EGFR-dependent and MET-driven resistance mechanisms while leveraging lazertinib’s CNS penetrance. The primary endpoint was best overall response rate (ORR) using a combined assessment of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (for systemic disease) and Response Assessment in Neuro-Oncology (RANO)-BM or RANO-LM, depending on the cohort.

The composite objective response rate (ORR) was 50% [n=10/20; 95% confidence interval (CI): 27–73%] in the BMs cohort and 33% (n=7/21; 95% CI: 15–57%) in the LMD cohort. The intracranial ORR was 40% in the BMs cohort and 0% in the LMD cohort by RANO-LM. This striking discrepancy warrants careful interpretation rather than a dismissal of clinical activity. Response assessment in LMD remains one of the most challenging endeavors in neuro-oncology. Indeed, most leptomeningeal lesions are nonmeasurable; 20–30% of patients with confirmed LMD have normal magnetic resonance imaging (MRI) findings; and the heterogeneity of leptomeningeal enhancement patterns introduces substantial subjectivity (3). Median progression-free survival (PFS) was 5.8 months [95% CI: 3.6–not reached (NR)] for BMs and 7.8 months (95% CI: 4.2–12.2) for LMD, and median overall survival (OS) was 17.4 months (95% CI: 15.4–NR) for BMs and 14.4 months (95% CI: 8.9–NR) for LMD. The median time of treatment in the LMD cohort was 8.3 months (range, 1.1–25.3 months). These survival outcomes compare favorably with historical benchmarks and suggest that the 0% intracranial response rate by RANO-LM alone does not fully reflect the therapeutic benefit conferred by amivantamab plus lazertinib. Interestingly, the number of CSF CTCs decreased in 67% of evaluable patients in the LMD cohort (14/21).

This study is particularly notable for specifically enrolling patients with active, new, or progressing BMs and LMs, a population routinely excluded from clinical trials. To date, no treatment has been prospectively validated specifically for patients with active brain or leptomeningeal progression after 3^rd-generation EGFR-TKIs. Options after CNS failure on 3^rd-generation TKIs remain limited to local therapies such as stereotactic radiosurgery, high-dose osimertinib (160 mg), or intrathecal chemotherapy—none of which have been validated in randomized trials (Table 1).

A major strength of this study lies in its comprehensive molecular analyses. A striking finding is the marked heterogeneity in treatment response across EGFR mutation subtypes, with response rates of 60% for L858R, 35% for exon 19 deletions, 40% for exon 20 insertions, and 0% for uncommon mutations. The higher response rate observed in L858R compared with exon 19 deletions contrasts with the well-established efficacy profile of EGFR-TKIs. Whether this unexpected pattern reflects treatment-specific activity, the unique biology of LMD, or simply the limited sample size remains uncertain. To note, this combination demonstrated an ORR of 52% in uncommon EGFR mutations in the CHRYSALIS-2 study. The substantially higher response rate observed in MET-positive patients (77% vs. 26%) further emphasizes the importance of molecular profiling at progression and aligns with MET amplification as the predominant off-target resistance mechanism to osimertinib (4). Nevertheless, neither EGFR mutation subtype nor MET status was associated with OS, underscoring the continued lack of validated predictive biomarkers for durable clinical benefit.

Another innovative aspect of the study is the integration of CSF cell-free RNA (cfRNA) analysis using a lung adenocarcinoma-specific enrichment score. Its association with LMD, CSF CTC burden, and poorer clinical outcomes reinforces the concept of molecular compartmentalization within the CNS and highlights the potential of multimodal CSF liquid biopsy, while future integration of DNA methylation and fragmentomics analyses may further expand its diagnostic and prognostic potential (5). CSF molecular profiling appears to provide a more faithful representation of intracranial disease than plasma circulating tumor DNA (ctDNA) analysis. Although ctDNA remains the reference liquid biopsy for monitoring tumor evolution and treatment resistance, plasma-based analyses may underestimate isolated CNS progression because of the blood-brain barrier (5).

The study provides important insights into acquired resistance. Only one patient acquired an EGFR T790M mutation, whereas resistance was mainly driven by off-target emergence. Patient B28 illustrates this evolutionary process, with sequential expansion of an NRAS-mutant clone during osimertinib and subsequent amivantamab-lazertinib treatment, supporting clonal selection rather than de novo resistance (6). Overall, these findings suggest an evolutionary shift from EGFR dependency toward RAS/RAF/MAPK pathway activation under therapeutic pressure. Interestingly, long-term MARIPOSA resistance analysis showed that amivantamab-lazertinib significantly reduced MET amplifications (3.4% vs. 13.1%, P=0.002) and secondary EGFR mutations (1.4% vs. 7.6%, P=0.01) compared to osimertinib, without significant increases in other known resistance pathways (7). The resistance profile observed in the Chen et al. study—where patients had already progressed on osimertinib before receiving amivantamab-lazertinib—may represent a further evolutionary step beyond what is seen in the first-line MARIPOSA setting.

Another strength of this work is the application of whole-genome sequencing (WGS) to CNS metastases, revealing biallelic CDKN2A loss together with homologous recombination deficiency signatures associated with BRCA2 or PALB2 alterations. Furthermore, the identification of extrachromosomal DNA harboring MDM2 and CDK4 amplifications in rapidly progressing tumors highlights the ability of WGS to uncover genomic drivers of aggressive disease and therapeutic resistance that would remain undetected using conventional molecular profiling.

Importantly, the toxicity profile of amivantamab-lazertinib remains a significant concern. Treatment-related adverse events were similar to previous reports, with half of patients required a dose interruption (due to rash, oedema, or hypoproteinemia), and 17% required dose reductions. Quality-of-life data are particularly relevant in this population, where median OS remains limited and where the primary therapeutic goal should arguably prioritize preservation of neurological function and quality of life alongside disease control.

In conclusion, the study by Chen et al. demonstrates that conducting dedicated clinical trials in patients with active BMs and LMD is both feasible and critically needed. The signal of efficacy observed with amivantamab plus lazertinib is encouraging and should be evaluated with more patients. Perhaps most importantly, the comprehensive molecular profiling performed in this study represents a major effort to decipher the mechanisms of resistance operating within the CNS sanctuary. Understanding the unique evolutionary trajectories of tumors in this compartment will be essential to inform rational, biomarker-driven therapeutic strategies and ultimately improve outcomes for patients with EGFR-mutant NSCLC and CNS involvement.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0920/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0920/coif). E.P.T. received consulting fees from AstraZeneca, Amgen, BMS, Roche, Takeda, Sanofi, J&J, and Daiichi Sankyo. The other authors have 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/.

References

1. Chen MF, Lee JJ, Choudhury NJ, et al. Phase 2 Study of Amivantamab Plus Lazertinib in Previously Treated Patients With EGFR-Mutant Lung Cancers With Brain and Leptomeningeal Metastases. J Thorac Oncol 2026;21:103505. [Crossref] [PubMed]
2. Zheng MM, Xia Y, Pan K, et al. The evolving landscape of leptomeningeal metastases from NSCLC: an international, contemporary, multicenter cohort study. Ann Oncol 2026;37:104-16. [Crossref] [PubMed]
3. Le Rhun E, Devos P, Boulanger T, et al. The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal. Neuro Oncol 2019;21:648-58. [Crossref] [PubMed]
4. Piotrowska Z, Ahn MJ, Voon PJ, et al. ELIOS: A Multicenter, Molecular Profiling Study of Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer Treated with First-Line Osimertinib. Cancer Discov 2026;16:1074-86. [Crossref] [PubMed]
5. Sankar BS, Johnson D, Boasiako PA, et al. Cerebrospinal fluid ctDNA as a prognostic and disease-activity biomarker in leptomeningeal metastases: systematic review, meta-analysis, and implications for CSF-guided care. J Neurooncol 2026;177:75. [Crossref] [PubMed]
6. Zhou X, Zeng L, Huang Z, et al. Strategies Beyond 3rd EGFR-TKI Acquired Resistance: Opportunities and Challenges. Cancer Med 2025;14:e70921. [Crossref] [PubMed]
7. Hayashi H, Cho BC, Spigel DR, et al. Long-Term Impact of First-Line Amivantamab Plus Lazertinib Versus Osimertinib on Mechanisms of Acquired Resistance in MARIPOSA: A Brief Report. J Thorac Oncol 2026;103894. [Crossref] [PubMed]