Patterns of central nervous system disease and molecular landscape in epidermal growth factor receptor exon 20 insertion mutated non-small cell carcinoma

Introduction

While not the most common cancer, lung cancer continues to have the highest mortality rate throughout the world (1). Of these subtypes, non-small cell lung cancer (NSCLC) contributes to approximately 85% of the diagnoses, mainly consisting of adenocarcinoma (2). In the last two decades, the treatment landscape for NSCLC has radically changed with the implementation of targeted tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (2,3). EGFR activating mutations were the first to be effectively targeted by TKIs (2,4,5). Among EGFR-activating mutations, exon 19 deletions and point mutations in exon 21 (L858R) are by far the most common encompassing 85–90% of EGFR mutations (6).

After the initial success with EGFR mutations, it was later discovered that not all EGFR mutations confer the same sensitivity to TKIs. Mutations in exon 20, which include in-frame insertions or duplications of 3 to 21 base pairs, demonstrate innate resistance to EGFR TKIs including first generation erlotinib/gefitinib, second generation afatinib, third generation osimertinib (7,8). A previous retrospective analysis found EGFR ins20 mutations occurred at a rate of 9–12% in EGFR-mutated NSCLC (9,10). There is heterogeneity among EGFR ins20 with over 60 mutation subtypes identified to date (9). These studies also noted similar clinical characteristics of EGFR ins20 as traditional EGFR mutations, with a higher prevalence in non-smokers and among the Asian population, and a key difference in worse prognosis and clinical outcomes (9,10). The poor prognosis is in part due to the low response rate to EGFR TKIs, as mentioned above, with innate resistance due to an altered active site that greatly hinders TKI binding, severely limiting efficacy (11-13).

Advancements in treatment and the development of novel therapeutic agents have been attempted to overcome this barrier. Amivantamab, a bispecific antibody targeting both EGFR and MET, first showed promise in the EGFR ins20 mutated population in the phase I CHRYSALIS trial after which the Food and Drug Administration (FDA) granted accelerated approval (14,15). Amivantamab was later combined with chemotherapy with improvement in progression free survival and overall survival (OS) in the phase 3 PAPILLION trial (16). Another novel agent, mobocertinib, a TKI designed to target EGFR ins20 mutations, showed positive results in a phase 1/2 trial, but the drug did not meet its primary endpoint in the phase 3 EXCLAIM-2 trial, resulting in its removal from the market (17,18). More recently, a novel TKI, sunvozertinib showed promising results in a phase II trial with overall response rates (ORR) of 45.9% (97.5% CI: 33.6% to 58.5%) with 200mg dosing 47.2% (97.5% CI: 35.1% to 59.5%) with 300mg dosing with no new safety signals (19). A large phase III trial, WU-KONG28 the drug to platinum doublet in treatment naïve patients is on-going (NCT05668988). Additional investigations into other novel agents are currently underway.

While there is literature published regarding patterns of central nervous system (CNS) disease in EGFR canonical mutations, there is limited analysis on EGFR in20 specifically (20,21). We aimed to determine if patients with EGFR ins20 have higher rates of CNS disease at diagnosis, higher rates of progression in the CNS or higher rates of leptomeningeal disease compared to patients with EGFR canonical mutations and if this impacts OS, in a retrospective analysis of this patient population at a single institution. Secondary objectives included analysis of NGS testing to determine if any significance difference in co-mutations were observed in the EGFR in20 patient compared to known data in EGFR canonical mutations. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0104/rc).

Methods

Patient selection and oversight

For this retrospective analysis, electronic medical records were utilized to create a database of patients seen at City of Hope Comprehensive Cancer Center and network sites including the Chicago, Atlanta and Phoenix sites from 2014-2024 with NSCLC and EGFRins20 mutations detected through clinical somatic next-generation sequencing (NGS). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of City of Hope (IRB 24559), and individual consent for this retrospective analysis was waived.

To be included in the analysis, patients required documented NSCLC of the following most common pathologic subtypes; adenocarcinoma, adenosquamous, squamous, as well as next generation sequencing testing (liquid or tissue) with a known EGFR ins20 mutation (2). Pathological subtypes with neuroendocrine features, even if focal, were excluded. We excluded the rare neuroendocrine subtype only from the analysis given the unique pathogenesis, clinical characteristics, molecular profile and substantial difference treatment patterns (22,23).

NGS testing was not standardized, and multiple modalities were utilized as this was a retrospective study and depended on preferences and availability of testing from the patient’s primary clinical team. The following commercially available and our internal NGS platform were utilized; FoundationOne (Foundation Medicine, Cambridge, MA, USA), Onco48 (COH, Duarte, CA, USA), LabCorp (LabCorp, Burlington, NC, USA), Caris (Caris Life Sciences, Dallas, TX, USA), Hopeseq Lung (COH), Guardant 360 (Guardant Health, Redwood City, CA, USA), NeoGenomics Irvine (Irvine, CA, USA), Tempus (Chicago, IL, USA), Strada NGS (Ann Arbor, MI, USA), Lab Centre (Belfast, Ireland) and Pathline Emerge (Ramsey, NJ, USA). All molecular assays were performed by Clinical Laboratory Improvement Amendments (CLIA) certified assays reporting clinically pathogenic variants. Only pathogenic variants were reported, variants of uncertain significance were excluded. We have included a list of all EGFR ins20 mutation types in this cohort in the Table S1.

Further, availability of PET/CT and baseline MRI Brain imaging for complete staging was required for inclusion. Standardized protocols for PET/CT and MRI Brain imaging across institutions were not required for inclusion. Staging at diagnosis was performed using the International Association for the Study of Lung Cancer (IASLC) Lung TNM staging 9^th edition, based on PET/CT and MRI Brain imaging. CNS disease at diagnosis was defined by radiologic evidence from MRI of lesions in the brain parenchyma or surrounding meninges. Metastatic bone lesions in the skull or spine were not included as CNS disease. CNS progression was defined as radiologic evidence from MRI of new lesions in the brain parenchyma or surrounding meninges. Again, lesions in the bone of the skull or spine were not included in CNS progression.

A total of 80 patients met the inclusion criteria and were included in the analysis.

Statistical analysis

For statistical analysis, Fisher’s exact test was used to assess the association between mutations and clinical outcomes. All P values reported were two-sided, and a level of 0.05 was considered statistically significant. All statistical analyses were conducted using R Statistical Software, version 4.2.1. For survival outcomes, Cox multivariable regression modelling, hazard ratio, and Kaplan-Meier survival curves with log rank test were utilized. The images of locations of brain metastasis were created using software from Aria, which is utilized by Radiation Oncology for treatment planning. A board-certified and practicing Radiation Oncologist reviewed the images to ensure accuracy. To create the molecular heatmap, the co-mutations were identified from NGS panels as above and the oncoprinter from cBioPortal for cancer genomics was utilized for image creation.

Results

Patient demographics

In the 80 patient EGFR ins20 cohort, the patient demographics are consistent with previously reported data in EGFR mutated patients with high rates of females and never smokers (24,25) (Table 1). Of the 80 patients, 64 patients (80%) had EGFR ins20 mutations in the near loop, 9 patients (11.2%) had mutations in the far loop, 3 patients (3.75%) had mutations in the C-helix while 4 patients had unspecified EGFR ins20 mutations (Table S1) (26). Fifty-seven out of 80 patients were females (70.0%) versus 24 (30.0%) males. There was no significant difference in survival by gender. Most of the patients were never smokers (72.5%) but 27.5% were smokers. Smokers had an increased risk of death, but this effect was not significant with HR of 1.26 [95% confidence interval (CI): 0.67–2.38, P=0.47] (Figure 1A). Twenty-four patients were of Asian ethnicity (30.0%), 42 were Caucasian (52.5%), 8 were African American (10%), and 6 were Hispanic/Latino (7.5%). There was no significant change in survival according to race (Figure 1B). Of the NSCLC pathologic subtypes, the vast majority had adenocarcinoma, 77 patients (96.2%) and 3 patients (3.8%) had adenosquamous pathology. While squamous pathology was part of the inclusion criteria, as it is considered a subtype of NSCLC, no patient in the cohort had only squamous pathology.

Figure 1 Kaplan-Meier curves of overall survival by variable. (A) Smoking status (yes for former smokers, no for never smokers); (B) race; (C) stage at diagnosis.

Of the 80 patients, 51 (63.8%) had metastatic disease at the time of diagnosis. Eleven patients (13.8%) were stage I, 10 (12.5%) were stage II, and 8 (10.0%) were stage III. As expected, stage III disease was significantly associated with worse OS with HR =25.42 95% CI: 2.10–307.15, P=0.01). Stage IV disease showed an even stronger association with mortality (HR =92.84, 95% CI: 7.93–1087.45, P<0.01) (Figure 1C).

Treatment

As this patient cohort spanned across several years [2014–2024], several different treatment modalities were utilized including several clinical trials. Most of the patients received standard of care chemotherapy. As amivantamab was not included in the standard of care until recently, based on the CHRYSALIS trial as a single agent after progression on platinum chemotherapy and the PAPILLON trial in combination with platinum chemotherapy in the first line, only 13 out of the 80 patients received this treatment during the course of their disease (14,16). Given the small sample size, there was no statistically or clinically significant change in OS between patients who received amivantumab and those who did not (Figure 2). As mentioned previously, TKIs that are currently FDA approved and commercially available in the US have had limited efficacy in EGFR ins20 patients, but many patients (23 out of 80) in this cohort were treated with a TKI during the course of treatment either as single agent or in combination. The majority of patients received a TKI on a clinical trial, with mobocertinib being the most common agent utilized. Median OS in patients who had received a TKI was 65.7 months [95% CI: 39.3–not estimated (NE)] months compared to 43.0 (95% CI: 35.1–70.8) months in patients who never received TKIs but the survival outcomes did not reach statistical significance (HR =0.72, 95% CI: 0.37–1.42, P=0.346) (Figure 2). Again, this may be attributed to smaller sample size or other confounding factors.

Figure 2 Kaplan-Meier curve of overall survival by type of treatment received (yes for received treatment versus No for never received treatment). (A) Amivantamab; (B) any TKI. TKI, tyrosine kinase inhibitor.

CNS disease

While disease of the central nervous system is not uncommon among lung cancer patients, there have been varying reported rates of brain metastasis among the lung cancer subtypes, including EGFR mutations, with rates as high as 25% (20,21,24-27). In the EGFR ins20 patient population included in our analysis, 19 (23.7%) patients had CNS disease at diagnosis, defined as above while 29 (36.25%) patients developed CNS progression, defined as above. Additionally, 6 (7.5%) patients developed leptomeningeal disease. In survival analysis, patients with CNS progression had a similar median OS of 45.3 months (31.6–78.5 months) compared to patients without progression, who had a median OS of 47.8 (36.8–NE) and an HR of 1.21 (95% CI: 0.66–158 2.23, P=0.54) (Figure 3).

Figure 3 Kaplan-Meier curve by patients who had progression in the CNS (yes) versus patient who did not (no). CNS, central nervous system.

To analyze the patterns of CNS diseases in depth, we utilized MRI imaging from the time of diagnosis and MRI imaging from progression in a smaller cohort of patients from the City of Hope (COH) California sites. Of the 13 patients with CNS disease at diagnosis, 4 patients received upfront whole brain radiation, 6 patients received upfront stereotactic radiosurgery (SRS), and in 3 patients CNS radiation was deferred and the patients only received systemic treatment. At diagnosis, 6 of 13 patients (46.2%) had ≥6 brain lesions, including 4 (30.8%) with >10 lesions. The most common locations of metastases within the brain were the cerebellum (61.5%) and the frontal lobes (61.5%). 37.5% patients in the COH California cohort were found to have disease progression in the CNS on MRI after the diagnosis. Of these 21 patients with progression, 12 patients received SRS (6 on progression and 6 upfront), 2 received whole brain (1 upfront and 1 on progression) and the remaining 7 patients received systemic treatment. Of the patients with CNS progression, 13 (61.9%) had ≥6 brain lesions, including 7 (33.3%) with >10 lesions. On the brain MRIs at the time of progression, the most common locations of metastases within the brain were the frontal lobe (71.4%) and the cerebellum (66.6%). The size of the largest brain lesions ranged from 0.4 to 2.5 cm in diameter, measured on axial T1-weighted post-contrast MR images. The degree of edema, assessed on axial FLAIR MR images, was generally mild, with two cases of moderate edema.

Using MRI data from the patients in our cohort, we created a heat map to visually represent the various locations of the brain lesions at two time points: time of diagnosis and time of progression in the CNS. There was minimal overlap of brain lesions across patients with CNS disease at diagnosis and patients with CNS disease at progression (Videos 1,2), indicating a widespread pattern of metastasis rather than a common focal pattern (Figure 4).

Figure 4 Patterns of brain lesions at the time of diagnosis (A-D) and at the time of progression on treatment (E-H).

Co-mutations

As a secondary analysis, we investigated the mutational landscape of our EGFR ins20 cohort. In the EGFR ins20 cohort, TP53 mutations were the most common co-mutations, with 23 patients (28.8%). EGFR amplifications were the next most common, with 13 patients (16.2%), followed by RAC1 amplification in 5 patients (6.2%) and CDK4 amplification in 5 patients (6.2%) (Figure 5). Of all the mutations analyzed only TP53 mutation was associated with a decreased median OS of 31.6 months compared to 47.8 months HR 1.79 (0.89–3.60, P=0.105) (Figure 5A). Among patients with CDK4 amplifications prolonged median OS of 78.5 months was observed compared to 45.3 months, HR 1.20 (95% CI: 0.37–3.91, P=0.757), but not statistically significant (Figure 5B).

Figure 5 Kaplan-Meier curve of overall survival by presence (yes) or absence (no) of co-mutation. (A) TP53 mutation; (B) CDK4 mutation; (C) Heat map depicting the most common mutations in the total cohort.

We also conducted a multivariable Cox proportional hazards regression analysis to evaluate factors associated with OS in the 80-patient cohort (Table 2). The adjusted HR from the multivariable Cox model for co-mutation withTP53 was associated with worse OS (HR =6.07, 95% CI: 2.20–16.76, P=0.001). Further, co-mutations CDK4 showed a HR of 7.54 (95% CI: 0.86–66.29, P=0.069) in the multivariable Cox model.

Discussion

After the initial discovery of EGFR mutations in NSCLC, the subsequent identification of mutation subgroups has greatly advanced our understanding of EGFR diversity. EGFR ins20 mutation had stood out as a particular subgroup of interest in part due to differing responses to treatment. In our analysis, we sought to characterize this patient population further by including the patterns of CNS disease, as the rate of CNS disease could impact treatment selection. There was a high rate of CNS disease at diagnosis as well as progression in the CNS in this patient population. This is consistent with previous studies in patients with generalized EGFR mutations, which reported a high rate of brain metastasis from 29.4% to 60.3% over 3 years (28,29). Prior data on patients with EGFR ins20 reported rates of brain metastasis of 23% to 39% at diagnosis, which is consistent with our data (30).

Given the limited study size, 80 patients, there were no statistically significant differences in survival between patients with CNS progression and those with stable CNS disease. Further the median OS in months was similar and this may be clinically relevant. With this data and data from previous studies, it remains important for treatments of EGFR-mutated lung cancer, EGFR ins20 especially, to be able to penetrate the blood-brain barrier and have CNS activity. This has been demonstrated clinically with the success and widespread use of amivantamab in EGFRins20 with good control of intracranial disease versus the discontinuation of mobocertinib with a high rate of intracranial progression (31,32).

Furthermore, the rates of leptomeningeal disease, while rare, appear to be on the rise, estimated at 3–5% in driver-mutated NSCLC (33,34). It should be noted there is some variation in method to detect leptomeningeal disease with MR imaging of the brain/spine as the standard imaging modality for diagnosis according to guidelines, but cytologic confirmation with cerebral spinal fluid (CSF) testing is also utilized (35,36). Recent advances have shown some clinical utility in circulation tumor DNA testing from CSF (36,37). In addition, the location of the brain lesions in our cohort was widespread, with minimal overlap between the time points (Video 2). In canonical EGFR mutations, different patterns of brain metastasis have been reported (21). While not directly investigated in this study, the widespread pattern of metastasis could influence CNS targeted radiation treatment, such as considering whole brain radiation versus SRS.

The co-mutational status of patients is important to consider as the mutational profile of a patient may play a larger role in the treatment response than we know. Prior studies have documented common co-mutations in EGFR mutated NSCLC; TP53, phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PIK3CA), retinoblastoma (Rb1) and catenin beta 1-(CTNNB1) (38). Apart from TP53, the mutational landscape of EGFR ins20 appears to differ with EGFR amplifications, CDK4 amplifications and RAC1 amplifications as the most common in this study and from an earlier study of EGFR ins20, the most common non-EGFR mutations included TP53, CKDN2A, CDKN2B, and NKX2-1 (9). There is data on the clinical impact of certain co-mutations in EGFR mutated NSCLC, such as negative impact of TP53, decreased response to chemotherapy with CDKN2A/B and association with de novo EGFR TKI resistance with CDK4 amplifications (39-41). In comparison, data regarding the prognostic impact of co-mutations in EGFR ins20 specifically, is limited. In this study population, the significance of co-mutations was difficult to assess apart from the common negative prognostic TP53 mutation, due to the small patient cohort. However, in a larger patient population across multiple institutions, co-mutational status and the interaction between co-mutations may be better evaluated. Given the unique properties of EGFR ins20, interactions with other co-mutations may be distinct from those of common EGFR mutations.

Conclusions

While progression in the central nervous system did not impact clinical outcomes in this patient population, the high rate of disease in the central nervous system does warrant consideration and tailoring treatment with central nervous system penetration and consideration for modalities that target widespread disease. Co-mutation status continues to play an essential role in NSCLC and should be further evaluated among EGFR ins20 patients given the potential difference from the general EGFR mutated population. Additional studies into this diverse subgroup of patients are warranted to better inform treatment decisions and drug development with a goal of improving treatment response and OS.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0104/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0104/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0104/prf

Funding: This work was supported by the National Cancer Institute of the National Institutes of Health under award (No. P30CA033572).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0104/coif). A.R. participated in two events in an advisory role for Johnson and Johnson and received compensation for her time. D.N. has received research funding in various forms from the following pharmaceutical companies or entities: Pfizer/Seagen, Novartis, Taiho Therapeutics, Johnson and Johnson, Blueprint Medicines, Elevation Oncology, Takeda and Black Diamond Therapeutics. D.N. also received funding from a grant, ‘Kure It’ and participated on the Board for Johnson and Johnson and City of Hope (Data Safety Monitoring). 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional/regional/national approved by the Institutional Review Board of City of Hope (IRB 24559), and individual consent for this retrospective analysis was waived.

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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