Patients with epidermal growth factor receptor (EGFR)-mutant lung cancer face higher rates of central nervous system (CNS) metastases and—in this era of targeted therapy—subsequent treatment resistance. A 2025 study reported a five-year cumulative incidence of brain metastases (BrM) and leptomeningeal disease (LMD) of 54% and 12%, respectively.1
Patients with active CNS disease—particularly those with LMD—are often excluded from clinical trials, despite the high burden of this condition. Consequently, therapeutic options are limited, and significant evidence gaps remain.
Inspired by this unmet clinical need, Mark Jeng, MD, PhD, and colleagues initiated a phase 2, single-institution study to evaluate amivantamab plus lazertinib in previously treated patients with EGFR-mutant non-small cell lung cancer (NSCLC) and new or progressive CNS metastases.2
The combination had not yet been approved at the time of the study, and its CNS activity was largely undefined in patients with CNS disease—particularly those with progressive disease. However, the treatment landscape for EGFR-mutant lung cancer has evolved significantly since the study was initiated. Patients now have access to highly effective combination therapies in the frontline setting, including amivantamab plus lazertinib, supported by the phase 3 MARIPOSA study, and osimertinib combined with chemotherapy, based on the phase 3 FLAURA2 trial.3,4
Given these advances, the results of the study by Dr. Jeng and his colleagues can be considered in a new light. Because patients enrolled in the study had previously progressed on standard-of-care therapies, clinicians may want to consider initiating the amivantamab plus lazertinib combination earlier as a preferred strategy for patients with CNS involvement or LMD, rather than waiting for disease progression, Dr. Jeng said.
“There is a strong rationale for using the most effective therapies earlier in the disease course, particularly for patients at high risk of CNS progression,” he said. “The observed CNS activity of amivantamab and lazertinib supports their use as part of earlier-line treatment strategies, especially in patients with known CNS involvement or high-risk features.”
The study also revealed implications for overcoming specific resistance pathways, such as in patients who achieve disease control with osimertinib but still develop CNS progression.
In patients with EGFR-mutant lung cancer who progress on osimertinib, one of the most common acquired resistance mechanisms is MET overexpression or amplification. In this study, nearly all patients (90%) had previously been treated with osimertinib, and one-third were MET-positive. Although the sample size was small, these patients had a higher response rate than patients who were MET-negative (77% vs 26%), suggesting that dual targeting of EGFR and MET may be particularly effective in this subgroup.
Given that amivantamab simultaneously inhibits both pathways, it may overcome bypass signaling that drives resistance to EGFR-directed therapy alone, Dr. Jeng said.
Patients who were eligible had EGFR-mutant NSCLC with CNS involvement and disease progression, either intracranially or extracranially. The patients were enrolled in two parallel cohorts: BrM (n = 20) and LMD (n = 21). To ensure that patients could safely tolerate systemic therapy, the trial excluded individuals with poor functional status and those with uncontrolled or worsening neurological symptoms requiring escalating doses of corticosteroids.
The primary end point was the best overall response rate (ORR), defined as a confirmed complete or partial response, using a composite assessment that incorporated both systemic and CNS disease. An encouraging ORR was observed in both the BrM cohort (50%) and the LMD cohort (33%), Dr. Jeng said. Considering that the patient population was heavily pretreated—with more than half having received two or more prior lines of therapy and 90% having progressed on osimertinib—these results are especially noteworthy, he said.
Additionally, the trial yielded clinically meaningful survival outcomes. Patients with BrM demonstrated a median overall survival (OS) of 17.4 months, while those in the LMD cohort reported a median OS of 14.4 months. By comparison, studies have shown that patients who stop targeted therapy and forego further lines of systemic treatment following progression have a median OS of less than five months.5
Standard LMD assessment typically relies on neurologic examinations, MRI scans of the brain and spine, and cerebrospinal fluid (CSF) cytology. However, these methods are often insensitive and may not fully capture disease burden or accurately reflect treatment response.
Dr. Jeng and colleagues aimed to address these limitations by incorporating correlative analyses, including CSF circulating tumor cells (CTCs) and comprehensive genomic profiling of paired pre- and post-treatment samples. Notably, CSF CTCs offer a quantitative and potentially more sensitive measure of disease burden compared with traditional cytology.
Using the standard Response Assessment in Neuro-Oncology Leptomeningeal Metastases (RANO-LM) criteria for LMD, no patients met the formal response criteria. However, when examining CSF CTCs, 67% of patients demonstrated a reduction in tumor burden, compared with only 38% who achieved cytologic clearance. Dr. Jeng said this suggests that conventional metrics may underestimate treatment benefits and reveals a need for more sensitive, quantitative biomarkers in LMD.
Looking ahead, Dr. Jeng said he hopes future trials will allow broader inclusion criteria and CNS-specific end points to generate more representative and clinically actionable data for this population.
References
1. Wilcox JA, Jeng MY, Tischfield S, et al. Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases. Ann Oncol. 2025;36(10):1142-1153. doi:10.1016/j.annonc.2025.06.001
2. 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(3):103505. doi:10.1016/j.jtho.2025.10.012
3. Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
5. Song Z, Zhang Y. Treatment and prognosis after progression in long-term responders to EGFR-tyrosine kinase inhibitor in advanced non-small cell lung cancer. Arch Med Sci. 2016;12(1):107-111. doi:10.5114/aoms.2016.57586
