Global trends and research progress on immunotherapy for EGFR-mutant non-small cell lung cancer: a bibliometric analysis

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases (1). Recent epidemiological studies indicate that NSCLC has a 5-year survival rate of approximately 25%, while small cell lung cancer (SCLC), comprising about 15% of cases, shows more aggressive behavior with a 5-year survival rate of merely 7% (2). According to 2023 data, lung cancer was responsible for an estimated 1.9 million deaths globally, with approximately half of patients diagnosed at advanced stages where treatment options are primarily based on platinum chemotherapy (3). Despite advancements in treatment modalities, including the integration of chemotherapy with targeted therapies or other approaches, the average 5-year survival rate for advanced lung cancer remains around 6%, highlighting the urgent need for more effective therapeutic strategies (4).

The landscape of NSCLC treatment has been revolutionized by the discovery of oncogenic driver mutations, particularly those affecting the epidermal growth factor receptor (EGFR). EGFR mutations occur in 10–15% of Caucasian patients and 40–50% of Asian patients with NSCLC, highlighting significant ethnic variations in mutation prevalence (5). These mutations, predominantly exon 19 deletions and L858R point mutations in exon 21, lead to constitutive activation of the EGFR signaling pathway, promoting tumor cell proliferation, survival, and metastasis (6). The identification of EGFR mutations as key drivers in NSCLC has led to the development of targeted therapies, specifically EGFR tyrosine kinase inhibitors (TKIs). First-generation TKIs like erlotinib and gefitinib, second-generation agents such as afatinib, and third-generation inhibitors like osimertinib have demonstrated significant improvements in progression-free survival compared to traditional chemotherapy in EGFR-mutated NSCLC patients (7). This shift towards precision medicine has markedly improved outcomes for this subset of patients, with median overall survival now exceeding 3 years in some studies (8). Despite these advances, acquired resistance to EGFR-TKIs inevitably develops, typically within 9–14 months of treatment initiation (9). The mechanisms of resistance are diverse, including secondary EGFR mutations (e.g., T790M), activation of bypass signaling pathways, and histological transformation (10). This challenge has spurred research into novel treatment strategies, including next-generation TKIs and combination therapies.

Concurrently, the field of cancer immunotherapy has experienced unprecedented growth, particularly with the advent of immune checkpoint inhibitors (ICIs). These agents, which target programmed cell death protein 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have shown remarkable efficacy in various cancers, including NSCLC (11). In particular, pembrolizumab, nivolumab, and atezolizumab have demonstrated significant improvements in overall survival in advanced NSCLC patients, leading to their approval as first-line or subsequent therapies (12). However, the relationship between EGFR mutations and immunotherapy response is complex and often paradoxical. EGFR-mutated NSCLCs typically exhibit lower tumor mutational burden (TMB) and PD-L1 expression, both of which are associated with reduced immunotherapy efficacy (13). Several retrospective analyses and clinical trials have shown that patients with EGFR mutations derive less benefit from ICIs compared to those with wild-type EGFR (14). This observation has led to the exclusion of EGFR-mutated patients from some immunotherapy trials and has complicated treatment decisions in clinical practice. It is important to note that despite the extensive research activity, current international guidelines do not recommend ICIs as a standard of care for treatment-naïve patients with EGFR-mutant advanced NSCLC, primarily due to the lack of survival benefit and increased risk of toxicity observed in early clinical trials (15). The mechanisms underlying this reduced immunotherapy efficacy in EGFR-mutated NSCLC are multifaceted. EGFR signaling has been shown to upregulate PD-L1 expression through the activation of the JAK/STAT and PI3K/AKT pathways, potentially contributing to an immunosuppressive tumor microenvironment (16). Additionally, EGFR-mutated tumors often exhibit a lower density of tumor-infiltrating lymphocytes and a distinct immune contexture compared to EGFR wild-type tumors (17). Despite these challenges, recent research has focused on strategies to enhance immunotherapy efficacy in EGFR-mutated NSCLC. Approaches under investigation include combining EGFR-TKIs with immunotherapy, exploring novel immune checkpoint targets, and developing personalized neoantigen vaccines (18). Early-phase clinical trials combining osimertinib with durvalumab (anti-PD-L1) or gefitinib with pembrolizumab (anti-PD-1) have shown promising results, albeit with concerns about increased toxicity (19,20).

The rapid evolution of research in this field necessitates a comprehensive analysis of the current literature landscape. Bibliometric analysis offers a powerful tool to map research trends, identify key players, and highlight emerging areas of focus. This approach has been successfully applied to various fields in oncology, providing valuable insights into research patterns and collaborative networks (21). Previous bibliometric analyses have failed to identify critical research gaps, particularly regarding optimal integration timing of immunotherapy with EGFR-TKIs and the development of predictive biomarkers for immunotherapy response in this patient population (22). Additionally, there is insufficient attention to emerging resistance mechanisms beyond T790M mutation and their relationship with the tumor immune microenvironment (22). Prior bibliometric analyses have examined research trends in lung cancer and the tumor microenvironment (23) and immunotherapy applications across various cancer types (24). However, these studies either focused broadly on lung cancer without specific attention to EGFR-mutant subtypes or examined immunotherapy across multiple malignancies without depth in NSCLC. Bibliometric analysis offers distinct advantages over systematic reviews or meta-analyses in this context, as it not only synthesizes findings but also visualizes global research patterns, identifies influential stakeholders, and reveals emerging research fronts through objective, data-driven approaches. This study aims to fill this gap by providing a comprehensive bibliometric analysis of global research trends and hotspots in immunotherapy for EGFR-mutant NSCLC. By systematically analyzing publication patterns, collaborative networks, and keyword trends, we seek to offer valuable insights into the current state of research, identify knowledge gaps, and guide future investigations in this critical area of oncology. Our findings may inform research priorities, facilitate collaborations, and ultimately contribute to improving outcomes for patients with EGFR-mutated NSCLC. We present this article in accordance with the BIBLIO reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2242/rc).

Methods

Search strategies and data collection

The literature search was conducted using the Web of Science Core Collection (WoSCC) database, an authoritative source for scientific literature retrieval. The search was performed on July 18, 2024. The search strategy employed was: TS = (((Lung Cancer OR Lung Carcinoma) AND “non Small Cell”) OR NSCLC) AND TS = (Epidermal Growth Factor Receptor OR EGFR) AND TS = (Mutant OR Mutation) AND TS = (immun* AND (therapy OR treatment)). The wildcard “*” was used to include variations of terms. Primary inclusion criteria were English-language articles and reviews. Other document types (e.g., conference papers, editorial materials) and non-English publications were excluded. Bibliographic data were exported using the “Full record and cited references” format in “plain text” file type. Extracted information included publication counts, citation, authors, institutions, geographical distribution, keywords, and journal names.

Statistical analysis

Relevant data were extracted from the retrieved literature records, and Microsoft Excel was used to identify and calculate bibliometric indicators. These indicators include annual publication volume, citation frequency, average citation frequency, journal name and impact factor, as well as the country/region, publishing institution and author. We applied a minimum threshold of ≥1 publications for author/institution inclusion and ≥10 citations for document significance evaluation.

For the statistical analysis and visualization of bibliometric data, we employed three specialized software tools: VOSviewer (version 1.6.20), CiteSpace (version 6.3.R1), and “bibliometrix” package of R (version 4.3.3). VOSviewer was utilized for visualizing and exploring bibliometric networks, particularly for mapping institutional and author collaborations, co-authorship networks, citation analyses, and co-citation analyses (25). In VOSviewer, the size of nodes represents the number of publications or citations, the thickness of lines indicates the strength of connections between nodes, and different colors are used to distinguish clusters or time periods. CiteSpace was employed to detect emerging trends and research hotspots (26). “bibliometrix” package of R was used for additional analyses, including annual publication trends, country/region contributions, and journal impact evaluations (25).

To quantify academic impact, we employed several indices. The H-index measures both the productivity and impact of a researcher, where a researcher has an H-index of H if they have published H papers that have each been cited at least H times (27). The G-index, proposed by Egghe, aims to give more weight to highly cited articles (27). The M-index is calculated as the H-index divided by the number of years since the researcher’s first publication, allowing for comparison between academics with different career lengths (27). Additionally, we considered the journal impact factor (IF) (IF 2023), a measure reflecting the yearly average number of citations to recent articles published in that journal, and the Journal Citation Reports (JCR) (JCR 2023) Quartile, a ranking system that divides journals into four quartiles based on their IF within their subject category (28).

Results

An overview of publications in research of immunotherapy for EGFR-mutant NSCLC

The literature screening process and selection criteria are illustrated in Figure 1. The initial search yielded 2,065 publications. After screening, 1,537 publications were included in the final analysis. The overview of publication trends in the field of EGFR-mutated NSCLC and immunotherapy is presented in Figure 2A. The bibliometric analysis covers research in EGFR-mutated NSCLC and immunotherapy from 1995 to 2024. The dataset comprises 1,537 documents published in 352 different journals. The field shows an annual growth rate of 12.69% in publications. A total of 12,131 authors contributed to these documents, with an average of 10.9 co-authors per paper. The dataset included 12 single-authored documents. International collaboration is evident in 20.36% of the publications. The documents contain 2,498 unique author keywords and cite a total of 30,767 references. The average age of the documents in the dataset is 5.68 years.

Figure 1 Flow chart of the literature screening process. The sum of records removed by category (n=562) is greater than the total number of unique records excluded because some records met multiple exclusion criteria. EGFR, epidermal growth factor receptor.

Figure 2 Bibliometric analysis overview of publication trends. (A) Search overview. (B) Annual number of publications.

Publication trends

The annual publication output in immunotherapy for EGFR-mutant NSCLC from 1995 to 2024 is illustrated in Figure 2B. The field showed minimal activity from 1995 to 2000, with fewer than five publications per year. A notable increase began in 2005, with 12 publications. The growth accelerated thereafter, reaching 59 publications in 2015 and peaking at 212 publications in 2022. The years 2021–2023 marked the most productive period, with over 150 publications annually. A slight decrease to 96 publications was observed in 2024, likely due to the partial year data.

The most cited article in this field, “EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib”, was published in Proceedings of the National Academy of Sciences in 2004, accumulating 3,603 citations (29). This seminal work established the prevalence of EGFR mutations in a specific lung cancer population and their correlation with treatment response. The second most cited article, “Erlotinib in lung cancer - molecular and clinical predictors of outcome”, appeared in The New England Journal of Medicine in 2005, with 1,556 citations (30). This study provided crucial insights into the molecular determinants of response to EGFR TKIs (Table S1).

Geographic distribution and collaboration networks

The analysis of country-wise contributions to research on immunotherapy for EGFR-mutant NSCLC reveals a global distribution with significant variations in output and impact (Figure 3A, Table 1). China emerged as the leading contributor with 602 articles [39.2% of total publications (TP)], followed by the USA (268 articles, 17.4%) and Japan (176 articles, 11.5%). These three countries collectively accounted for 68.1% of the TP in this field. In terms of TP, China ranked first with 2,566 publications, followed by the USA (n=1,503) and Japan (n=1,045). However, the USA led in total citations (TC) with 27,869, followed by China (n=13,689) and Japan (n=4,939). The proportion of multiple country publications (MCP ratio) varied significantly among countries. Switzerland had the highest MCP ratio (0.545), followed by the UK (0.435) and Spain (0.429), indicating strong international collaboration. In contrast, Japan (0.063) and India (0.067) showed lower levels of international collaboration. The average article citations also varied widely. Canada had the highest average with 85.9 citations per article, followed by Italy (57.7) and Australia (52.2). The visualization of international collaboration networks (Figure 3B) revealed complex interconnections among countries. The USA demonstrated the highest total link strength (n=519), indicating its central role in international collaborations. Germany (n=289) and China (n=271) also showed strong collaborative ties with other countries.

Figure 3 Geographic distribution and international collaboration analysis. (A) Distribution of corresponding author’s publications by country. (B) Countries’ publication volume and cooperation network diagram where node size represents publication count, line thickness indicates collaboration strength, and different colors represent distinct collaborative clusters. The visualization highlights both dominant contributors and the pattern of international knowledge exchange. MCP, multiple country publications; SCP, single country publications.

Journal distribution

The bibliometric analysis of high-impact journals in the field of immunotherapy for EGFR-mutant NSCLC reveals a diverse landscape of publications (Table 2). The journals with the highest H-index were Clinical Cancer Research [37], Journal of Thoracic Oncology [32], and Lung Cancer [29]. In terms of IF for 2023, Annals of Oncology led with 56.7, followed by Journal of Clinical Oncology (42.1) and Journal of Thoracic Oncology (21.0). All these top journals were ranked in the first quartile (Q1) according to the JCR for 2023, underscoring their high standing in the field. Journal of Clinical Oncology led in TC with 4,191, followed by Journal of Thoracic Oncology (n=3,382) and Clinical Cancer Research (n=3,102). In terms of TP, Lung Cancer had the highest output with 101 articles, followed by Journal of Thoracic Oncology (n=59) and Clinical Cancer Research (n=45).

The journal co-occurrence network analysis revealed strong interconnections among key publications (Figure 4A). Journal of Thoracic Oncology (link strength: 564), Lung Cancer (n=334), and Journal of Clinical Oncology (n=327) emerged as central nodes in the co-citation network. The journal coupling network analysis provided insights into the shared intellectual foundations of the publications (Figure 4B). Lung Cancer (link strength: 54,588), Journal of Thoracic Oncology (n=42,145), and Frontiers in Oncology (n=36,534) demonstrated the strongest coupling relationships.

Figure 4 Journal analysis network visualization. (A) Journal co-occurrence networks. Node size corresponds to citation frequency, connections represent co-citation relationships, and colors indicate distinct journal clusters by research focus. (B) Journal coupling networks. The strength of bibliographic coupling is represented by line thickness, revealing intellectual foundations shared across publication venues in this field.

Author influence and cooperative network relationship

The analysis of author impact and collaboration networks in immunotherapy research for EGFR-mutant NSCLC reveals a diverse landscape of scientific contributions and collaborations. As shown in Table 3, Nakagawa Kazuhiko emerged as a leading researcher with the highest H-index [18] and G-index [22]. Wu Yi-Long followed with an H-index of 16 and the highest G-index [25]. Zhang Li demonstrated the highest M-index (1.3). In terms of TP, Wu Yi-Long led with 25, closely followed by Nakagawa Kazuhiko and Zhang Li (22 each). However, TC presented a different hierarchy, with Gregory J. Riely receiving the most citations (n=3,349), followed by James Chih-Hsin Yang (n=2,733) and Nakagawa Kazuhiko (n=2,524). The collaboration network analysis revealed Caicun Zhou as the most collaborative author with a total link strength of 101, followed by Kazuhiko Nakagawa (n=88) and Chunxia Su (n=85).

The central area of the visualization map displayed a red cluster containing authors such as Fred R. Hirsch and Federico Cappuzzo, alongsided a purple cluster featuring Julien Mazieres and Benjamin Besse. The left side of the map was dominated by a blue cluster featuring authors like Kazuhiko Nakagawa, Kazuko Sakai, and Kazuto Nishio, while the bottom section contained a light blue cluster including Keunchil Park, Myung-ju Ahn, and Jong-mu Sun. A prominent yellow-green cluster appeared on the right side, centered around Caicun Zhou with multiple connections to authors like Xuefei Li and Likun Hou. Additional significant groupings included a green cluster with authors like Yi-Long Wu and Li Zhang, and an orange cluster at the top showing connections between authors including Haiquan Chen and Yuan Li (Figure 5).

Figure 5 Visualization map depicting the collaboration among different authors.

Number of institutional publications and cooperative network relations

As shown in Figure 6A, Harvard University led in publication output with 173 articles, followed by the University of Texas System (158 articles) and UT MD Anderson Cancer Center (130 articles). The top 10 institutions included five from the USA, three from China, one from France, and one from Canada, indicating a concentration of research in North America and East Asia. Citation impact presented a different hierarchy. Dana Farber Cancer Institute garnered the most citations (n=4,044), despite producing fewer publications (n=33) than the top publishers. Massachusetts General Hospital (4,789 citations, 20 publications) and University of Colorado (4,814 citations, 33 publications) also demonstrated high impact relative to their publication volume. The collaboration network analysis, based on total link strength, identifies Dana Farber Cancer Institute as the most collaborative institution (link strength: 117), followed by National Cancer Center (n=105) and AstraZeneca (n=101). The visualization map (Figure 6B) illustrated distinct collaborative clusters. One cluster centered on Asian institutions including Shanghai Jiao Tong University, Guangdong Academy of Medical Sciences, and National Taiwan University Hospital. Another cluster focused on North American institutions such as Dana Farber Cancer Institute, Massachusetts General Hospital, and University of Colorado. Institutional diversity was evident, with academic centers, specialized cancer institutes, and pharmaceutical companies (e.g., AstraZeneca) all represented among top collaborators.

Figure 6 Institutional distribution and collaboration patterns. (A) Distribution of corresponding author’s publications by institutions. (B) Visualization map depicting the collaboration among different institutions where node size reflects institutional publication volume, connecting lines represent collaborative relationships, and clusters (color-coded) indicate groups of institutions that frequently collaborate. Major collaborative hubs and regional networks are highlighted.

The data indicates significant international collaboration, with 183 institutions involved in cross-border research partnerships publishing at least six articles. This underscored the global nature of research efforts in this area. These findings quantitatively demonstrated the collaborative and international character of research in immunotherapy for EGFR-mutant NSCLC, with research concentration in specialized cancer centers and leading academic institutions across multiple countries.

Keywords analysis

The keyword analysis of research on immunotherapy for EGFR-mutant NSCLC revealed evolving trends and focal points in the field from 1995 to 2024. The co-occurrence network visualization (Figure 7) illustrated the interconnectedness of key research themes. “Chemotherapy” emerged as the most frequent keyword (314 occurrences) with the highest total link strength (n=1,880), indicating its central role in the research landscape. “Gefitinib” (296 occurrences, link strength 1,755) and “mutations” (295 occurrences, link strength 1,600) followed closely, highlighting the significance of targeted therapies and genetic alterations in this field. The temporal distribution of keywords, represented by color gradients, shows a shift from earlier topics (blue) such as “expression” and “tyrosine kinase” to more recent focus areas (yellow) including “nivolumab” and “ICIs”.

Figure 7 Visual analysis of keyword co-occurrence network distribution. Node size represents keyword frequency, connections indicate co-occurrence, colors reflect temporal evolution (blue to yellow indicating earlier to more recent terms), and spatial proximity suggests conceptual relatedness.

The keyword burst analysis provided insights into emerging research trends. “Growth factor receptor” exhibited the strongest citation burst (strength 27.35) from 2005 to 2016, coinciding with the rise of targeted therapies (Figure 8). “Gefitinib” and “sensitivity” showed similarly strong bursts (27.28 and 17.07, respectively) during the same period, underscoring the initial focus on EGFR TKIs. More recent bursts were observed for “nsclc” (strength 10.67, 2021–2024), “ICIs” (10.62, 2021–2024), and “osimertinib” (10.36, 2021–2024), indicating a shift towards broader lung cancer contexts, immunotherapy, and next-generation EGFR inhibitors. “Immunotherapy” itself showed a burst from 2022 to 2024 (strength 9.95), reflecting its growing prominence in recent research. The temporal pattern of keyword bursts reveals distinct phases in research focus: (I) early emphasis on molecular mechanisms (1995–2004): “expression”, “tyrosine kinase”; (II) rise of targeted therapies (2005–2015): “gefitinib”, “EGFR mutations”; (III) transition to immunotherapy (2016–2020): “nivolumab”, “pathway”; (IV) integration of approaches (2021–2024): “ICIs”, “osimertinib”, “immunotherapy”.

Figure 8 Top 20 keywords with the strongest citation bursts. Bar length represents the duration of the burst period, color intensity indicates burst strength, and positioning on the vertical axis reflects relative importance.

Discussion

General information

This bibliometric analysis distinguishes itself from previous studies in several key aspects. While prior analyses have examined either EGFR mutations or immunotherapy in lung cancer separately, our study specifically addresses their intersection, providing unique insights into this rapidly evolving therapeutic landscape. Compared to recent bibliometric analyses by Wang et al. and Huang et al., our study employs a more comprehensive timeframe (1995–2024 vs. 2014–2023), enabling the capture of the complete evolution from early molecular discoveries to current integrated treatment approaches. Additionally, our analysis includes publications from researchers in Asian countries where EGFR mutations are more prevalent, offering a more globally representative perspective of English-language literature.

The analysis of high-impact journals in this field reveals a concentration of influential publications in specialized oncology journals. Clinical Cancer Research, Journal of Thoracic Oncology, and Lung Cancer emerged as the most impactful journals based on their H-index and citation counts. This distribution reflects the multidisciplinary nature of the research, spanning basic science, translational medicine, and clinical oncology. The prominence of Journal of Thoracic Oncology and Lung Cancer in both publication volume and citation impact underscores the field’s strong connection to thoracic oncology. These journals have consistently provided platforms for pivotal studies in EGFR-mutant NSCLC, including landmark trials of EGFR TKIs and emerging immunotherapy approaches (31). The journal co-occurrence network analysis highlighted the central role of Journal of Thoracic Oncology, Lung Cancer, and Journal of Clinical Oncology in shaping the discourse in this field. These journals have been instrumental in publishing research that bridges the gap between molecular understanding of EGFR mutations and clinical applications of targeted therapies and immunotherapies (32). The strong coupling relationships observed among these journals suggest a cohesive research community with shared intellectual foundations, facilitating rapid dissemination and integration of new findings.

The analysis reveals a global research effort with significant contributions from East Asia, North America, and Europe. China emerged as the leading contributor in terms of publication volume, followed by the USA and Japan. This distribution may be associated with the higher prevalence of EGFR mutations in Asian populations, which could potentially influence research priorities in these regions (33). However, the USA led in TC, suggesting a potentially strong impact of its research output. The high average citation rates of publications from Canada, Italy, and Australia suggest that impactful research is not limited to the highest-volume producers. Institutional analysis highlighted the dominance of specialized cancer centers and leading academic institutions. Harvard University, the University of Texas System, and UT MD Anderson Cancer Center led in publication output, while Dana Farber Cancer Institute, Massachusetts General Hospital, and the University of Colorado demonstrated high citation impact. The strong performance of these institutions can be attributed to their robust research infrastructure, multidisciplinary teams, and access to large patient populations for clinical studies (34). The collaboration network analysis revealed strong international ties, particularly centered on institutions in the USA and East Asia. This pattern of collaboration likely reflects the global nature of clinical trials in this field and the need for large, diverse patient cohorts to study the complex interactions between EGFR mutations, immunotherapy response, and ethnic variations (35). The bibliometric trends identified in this analysis correlate with developments in the clinical trial landscape and regulatory advancements in NSCLC treatment. Publications on “ICIs” (2018–2024) parallel the increase in clinical trials combining EGFR-TKIs with immunotherapy during this period (36). Keyword burst patterns often precede regulatory milestones by 2–3 years, as shown by the burst in “T790M” literature (2012–2015) preceding Food and Drug Administration (FDA) approval of osimertinib in 2015 (37). This temporal relationship between bibliometric indicators and clinical development underscores the value of such analyses in anticipating therapeutic trends. The author impact analysis identified key researchers driving the field forward. Kazuhiko Nakagawa, Yi-Long Wu, and Li Zhang emerged as highly influential authors based on their H-index, G-index, and publication output. These researchers have made significant contributions to understanding the molecular basis of EGFR mutations and developing targeted therapies (8). The high citation impact of authors like Gregory J. Riely and James Chih-Hsin Yang reflects their pivotal role in conducting and reporting landmark clinical trials that have shaped treatment paradigms in EGFR-mutant NSCLC (38). The collaboration network analysis revealed distinct clusters of researchers, likely representing thematic or geographical groupings. The strong collaborative ties observed, particularly among authors like Caicun Zhou and Kazuhiko Nakagawa, underscore the importance of multi-institutional and international collaborations in advancing the field. These collaborations have been crucial in conducting large-scale genomic studies and multinational clinical trials that have elucidated the complex interplay between EGFR signaling and immune responses.

Research hotspots

The keyword analysis of immunotherapy research for EGFR-mutant NSCLC provides a panoramic view of the field’s evolution and current focus. This landscape reflects the rapid advancements in understanding tumor biology and the development of novel therapeutic strategies over the past two decades.

The prominence of “chemotherapy” alongside targeted therapies like “gefitinib” and “erlotinib” illustrates the complex treatment paradigm in EGFR-mutant NSCLC. Historically, platinum-based chemotherapy was the standard of care for advanced NSCLC, offering modest survival benefits at the cost of significant toxicity (39). The discovery of EGFR mutations as oncogenic drivers in a subset of NSCLC patients heralded the era of targeted therapy, with TKIs such as gefitinib and erlotinib demonstrating unprecedented efficacy in this molecular subgroup (40). However, the persistent high ranking of “chemotherapy” underscores its enduring role, particularly in managing resistance to targeted therapies or as part of combination approaches (41).

The high frequency of “mutations” and “EGFR” reflects the paradigm shift towards precision oncology. The identification of EGFR mutations as predictive biomarkers for TKI response has revolutionized treatment selection, leading to remarkable improvements in progression-free survival and quality of life for patients with EGFR-mutant NSCLC (41). This focus on molecular profiling has spurred the development of increasingly sensitive diagnostic techniques, from traditional polymerase chain reaction (PCR)-based methods to next-generation sequencing and liquid biopsies, enabling more precise and dynamic treatment tailoring (42).

The emergence of “open-label” as a prominent keyword signals a trend towards more transparent and adaptive clinical trial designs. This shift is partly driven by the need for faster drug development pipelines in oncology, where the rapid evolution of targeted therapies and immunotherapies has outpaced traditional clinical trial paradigms. Open-label studies, while potentially subject to bias, offer the advantage of real-time data access and the flexibility to modify trial protocols based on emerging safety and efficacy signals. This approach has been particularly valuable in studying rare molecular subgroups and in evaluating combination therapies (43).

The high ranking of “expression” and “resistance” highlights the ongoing challenges in managing EGFR-mutant NSCLC. Despite initial dramatic responses to EGFR TKIs, acquired resistance invariably develops, typically within 9–14 months of treatment initiation (10). The mechanisms of resistance are diverse, including secondary EGFR mutations (e.g., T790M), activation of bypass signaling pathways, and phenotypic transformations. Understanding these resistance mechanisms has driven the development of next-generation TKIs and informed strategies for sequential or combination therapies (44).

The emergence of immunotherapy-related terms, such as “nivolumab”, among the most frequently cited keywords signals a growing research interest and shifting investigative focus in NSCLC treatment. Despite initial skepticism—driven by the characteristically low TMB and perceived reduced immunogenicity of EGFR-mutant tumors (45)—recent investigations have begun exploring combination strategies with EGFR-targeted agents or application after TKI failure (46). This growing research interest, however, starkly contrasts with current clinical guidelines that advise against ICIs use in treatment-naïve EGFR-mutant patients. This discrepancy highlights a critical unmet need and the persistent challenge of integrating immunotherapy into the treatment paradigm for this molecular subset. While these exploratory strategies may represent a promising frontier, their definitive clinical utility awaits validation through larger, prospective trials.

The prominence of “1st-line treatment” and “multicenter” keywords underscores the field’s focus on optimizing initial therapy and conducting robust, large-scale clinical trials. This emphasis reflects the recognition that the choice of first-line treatment can profoundly impact the overall treatment trajectory and long-term outcomes in EGFR-mutant NSCLC (8). Multicenter trials have been crucial in establishing new standards of care, such as the superiority of osimertinib as first-line therapy over earlier-generation TKIs (47).

The diverse array of keywords related to specific drugs (gefitinib, erlotinib, docetaxel) alongside broader concepts (therapy, survival) illustrates the multifaceted nature of EGFR-mutant NSCLC management. This diversity reflects the ongoing challenges in sequencing multiple lines of therapy, managing toxicities, and balancing quality of life with treatment efficacy (48). It also highlights the need for personalized treatment approaches that consider not only the molecular profile of the tumor but also patient preferences and goals of care.

While mainstream research keywords focus on EGFR mutations and treatment response-related topics, our analysis also reveals several areas worthy of attention that remain understudied. “Tumor microenvironment” appears in 75 articles, but its frequency is significantly lower than “mutations” (n=295) and “expression” (n=214), indicating that understanding of the immune ecology of EGFR-mutant tumors remains to be deepened. Similarly, “combination therapy” appears as a keyword in 96 articles, but in-depth exploration of specific combination regimens (such as EGFR-TKIs with ICIs, anti-angiogenic agents, or chemotherapy) remains limited. “Biomarkers” appears in 122 articles, but research on specific biomarkers predicting immunotherapy response in EGFR-mutant patients remains insufficient. Immunosuppressive mechanisms such as “T cell exhaustion” and “regulatory T cells” in the context of EGFR mutations are even more rarely studied, appearing in only 18 and 24 articles, respectively. These research gaps represent important directions for future exploration, especially considering the potential synergistic effects between targeted therapy and immunotherapy.

In conclusion, the keyword analysis reveals a field characterized by rapid innovation, complex treatment algorithms, and persistent challenges. The research hotspots identified suggest a concerted effort to overcome treatment resistance, optimize therapy sequencing, and integrate diverse treatment modalities including targeted therapies, immunotherapies, and traditional chemotherapy. As the field continues to evolve, key priorities include developing strategies to delay or prevent resistance to targeted therapies, identifying biomarkers predictive of immunotherapy response in EGFR-mutant tumors, and optimizing combination approaches to maximize efficacy while minimizing toxicity.

Research trends

The landscape of NSCLC treatment has undergone a remarkable transformation over the past two decades, driven largely by advances in our understanding of the EGFR and its role in lung cancer pathogenesis. This evolution, traced through the analysis of burst keywords, reflects not only scientific breakthroughs but also the changing paradigms in cancer treatment and clinical trial design.

Late 1990s to 2010: dawn of the era of molecular targeting

The initial burst of “EGFR expression” coincided with Rusch et al.’s 1997 study (49), which highlighted the prevalence of EGFR overexpression in NSCLC. This study found that EGFR is frequently overexpressed in resectable NSCLC, setting the stage for subsequent targeted therapy studies.

The subsequent burst of “tyrosine kinase inhibitors” reflects the rapid development and clinical investigation of gefitinib and erlotinib. The year 2004 was a turning point in this field, when Lynch et al. (50) and Paez et al. (51) almost simultaneously reported the association between EGFR mutations and the efficacy of TKIs in the New England Journal of Medicine and Science. The study by Lynch et al. described for the first time the relationship between EGFR exon 19 deletion and L858R point mutation and clinical response to gefitinib. This finding explains why only a fraction of NSCLC patients show a significant response to EGFR-TKIs. The study by Paez et al. further confirmed this finding and provided additional molecular biological evidence.

These breakthrough studies have rapidly changed the treatment paradigm of NSCLC, triggering a series of clinical trials targeting patients with EGFR mutations. Gefitinib and erlotinib, as the first generation of EGFR-TKIs, have become a research hotspot. In 2005, Shepherd et al. (52) published a study in the New England Journal of Medicine showing that erlotinib could significantly prolong survival in NSCLC patients who had previously failed chemotherapy. Although selection for EGFR mutation status was not available at the time, this study paved the way for subsequent targeted therapy studies.

2005–2010: the rise of evidence-based medicine and clinical trial methodology

As targeted therapies gained traction, the research focus shifted towards rigorous evidence-based evaluation, reflected in the burst of keywords like “randomized controlled trial” and “progression-free survival”. The IPASS study (IRESSA Pan-Asia Study) by Mok et al. in 2009 was a watershed moment, providing the first evidence of EGFR-TKI superiority over standard chemotherapy in the first-line setting for patients with EGFR mutations (53). This period also saw significant advancements in molecular testing techniques. The evolution from direct sequencing to more sensitive methods like the Amplification Refractory Mutation System (ARMS) enhanced the accuracy and accessibility of EGFR mutation detection, as detailed by Ellison et al. (54).

2010–2015: unraveling resistance mechanisms

The widespread adoption of EGFR-TKIs inevitably led to the emergence of acquired resistance as a major clinical challenge. The burst of keywords such as “T790M mutation” and “acquired resistance” reflects this shift in research priorities. In 2011, Sequist et al. (55) published a study in the journal Science Translational Medicine that thoroughly explored the mechanism of EGFR-TKI resistance. This study revealed multiple resistance mechanisms through serial biopsies of resistant patients, with the T790M mutation being the most common, accounting for about 50% to 60% of acquired resistance cases. The study by Sequist et al. not only confirmed the importance of the T790M mutation, but also identified other resistance mechanisms, such as MET amplification (56), PIK3CA mutation (57), and even SCLC transformation (58). These findings provide key insights into understanding the complexity of EGFR-TKI resistance and point the way for subsequent therapeutic strategy development. This discovery spurred the development of third-generation EGFR-TKIs, exemplified by osimertinib. Jänne et al.’s 2015 study demonstrated the efficacy of osimertinib in patients with T790M-positive NSCLC who had progressed on prior EGFR-TKI therapy, offering a new line of defense against resistance (59).

2015–2020: the immunotherapy revolution and personalized strategies

The emergence of “circulating tumor DNA” reflects the growing interest in liquid biopsy techniques, as highlighted by Oxnard et al.’s work. In 2016, the study by Oxnard et al. (60) explored the possibility of using plasma genotyping to predict the outcome of osimertinib treatment. This study shows that circulating tumor DNA (ctDNA) detection can effectively identify the T790M mutation, providing a new method for non-invasive drug resistance monitoring. “PD-L1 expression” burst indicates the exploration of immunotherapy in EGFR-mutant NSCLC. The success of ICIs in other NSCLC subtypes prompted exploration of these agents in EGFR-mutant NSCLC. However, Gainor et al.’s 2016 study revealed the limited efficacy of PD-1 inhibitors in this population, underscoring the complex relationship between EGFR mutations and the tumor immune microenvironment (61). This period also saw an increased focus on biomarker research and personalized treatment strategies. The IASLC statement paper by Rolfo et al. in 2018 on liquid biopsy in NSCLC reflects the growing importance of non-invasive monitoring and comprehensive genomic analysis in guiding treatment decisions (62).

The keyword analysis reveals the dynamic relationship between targeted therapies and immunotherapy in EGFR-mutant NSCLC research. While these two treatment modalities initially emerged as independent developmental trajectories, they have gradually converged in research focus since 2015. In the early period (2000–2010), EGFR-TKI-related keywords (“gefitinib”, “erlotinib”, “EGFR mutations”) dominated, reflecting targeted therapy as the research core. Between 2010 and 2015, as resistance-related terms such as “T790M” and “acquired resistance” emerged, research emphasis shifted toward addressing treatment resistance. Immunotherapy terms (e.g., “PD-L1”, “nivolumab”) began to increase significantly after 2015, but did not emerge as a major research direction until 2018–2020, suggesting an evolution where the two treatment modalities were initially separate before gradually converging. Notably, terms such as “combination therapy” and “sequential therapy” significantly increased after 2018, indicating that research focus has shifted from comparing the two treatment approaches to exploring their optimized integration strategies, particularly in overcoming EGFR-TKI resistance.

2021 to present: novel combinations and challenging disease states

The analysis of keyword bursts delineates a clear research trajectory: the field is intensively focused on combating resistance via combination approaches. The continued prominence of “resistance mechanisms” as a key term underscores its status as the central challenge. This has catalyzed research into persistent clinical problems, such as brain metastases (63), and the validation of new targets like HER2 mutations in resistant cases (64). Concurrently, the exploration of combination regimens, exemplified by atezolizumab plus chemotherapy (65), aims to improve outcomes. Importantly, our analysis highlights the ascent of two transformative therapeutic classes: bispecific antibodies and antibody-drug conjugates (ADCs). Agents like amivantamab (EGFR-MET) (66), and ADCs targeting patritumab deruxtecan (HER3-DXd) and datopotamab deruxtecan (TROP2-DXd) (67,68) are gaining momentum, signaling a pivot towards highly targeted therapies and constituting a major future research front. This shift in keyword priority from conventional therapies to immunotherapies and combinations has profound implications. While immunotherapy represents an active area of investigation, its role in EGFR-mutant NSCLC remains to be clearly defined. Future research must prioritize determining the optimal sequencing, patient selection biomarkers, and combination strategies to ensure safety and efficacy, rather than broadly applying immunotherapy in this population.

Strengths and limitations

This study provides a comprehensive overview of global research trends in immunotherapy for EGFR-mutant NSCLC, utilizing multiple bibliometric tools to analyze a large dataset spanning over two decades. The analysis of international collaboration networks and identification of key research institutions and authors offer valuable insights for future collaborative efforts. However, several limitations should be acknowledged. The reliance on citation counts as a measure of impact may not fully capture the clinical significance of research, as highly cited papers do not necessarily correspond with significant advancements in patient outcomes. Additionally, the exclusion of non-English publications may underrepresent contributions from non-English speaking regions, particularly significant given the high incidence of EGFR mutations in Asian populations. Furthermore, the use of a single database (WoSCC) may not include all relevant studies, especially those published in newer or less recognized journals, potentially limiting the scope of our analysis. To capture the complete evolution of the EGFR-mutant NSCLC treatment landscape, we intentionally employed a broad search strategy, which explains why some highly cited articles in our analysis appear less directly related to immunotherapy but were foundational to understanding EGFR-mutant tumor biology. The standard bibliometric analysis methodology does not typically incorporate sensitivity analyses, and these were not implemented in our study, which may affect the robustness assessment of our findings.

Conclusions

The evolution of EGFR-mutant NSCLC research reflects the rapid advancement of precision medicine. While our bibliometric analysis captures a growing body of literature on immunotherapy, it is critical to contextualize this trend: ICIs have demonstrated limited efficacy and are not a recommended standard of care for the majority of patients with EGFR-mutant NSCLC. In contrast, the true research frontier has pivoted towards novel therapeutic classes designed to overcome TKI resistance. As highlighted by recent landmark trials, ADCs such as patritumab deruxtecan (HER3-DXd) and bispecific antibodies like amivantamab are showing significant clinical activity and now represent the most dynamic area of investigation. Therefore, future research must prioritize the strategic development and integration of these emerging agents. The role of immunotherapy, while still explored, should be cautiously investigated in well-defined patient subgroups or novel combinations, rather than being pursued as a broad strategy. This shift underscores the necessity of aligning future research efforts with the most promising clinical evidence to meaningfully improve patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2242/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2242/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2242/coif). The 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.

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