Furmonertinib Activity in NSCLC Harboring EGFR L858R and ERBB2 S310F Co-Mutations: A Case Report With Literature Review

Furmonertinib Activity in NSCLC Harboring EGFR L858R and ERBB2 S310F Co-Mutations: A Case Report With Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Furmonertinib Activity in NSCLC Harboring EGFR L858R and ERBB2 S310F Co-Mutations: A Case Report With Literature Review Shiyue Liu, Runze Cao, Hong Li, Dongdong Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6769788/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract While targeted therapies have remarkably transformed the landscape of lung adenocarcinoma (LUAD) management, the clinical implications of concurrent mutations in EGFR and ERBB2 remain inadequately understood due to their exceptional rarity in patients. This lack of understanding leads to significant uncertainty regarding therapeutic strategies for individuals with such co-mutations, as neither single-agent EGFR tyrosine kinase inhibitors (TKIs) nor HER2-targeted therapies have demonstrated established efficacy in this specific molecular context. Here, we present a compelling case involving a 61-year-old female patient diagnosed with advanced LUAD, with both EGFR L858R (exon 21) and ERBB2 S310F mutations identified through comprehensive next-generation sequencing. The patient received a treatment regimen consisting of the third-generation EGFR TKI furmonertinib, combined with localized radiotherapy, which resulted in a marked and significant clinical response. Our findings indicate that furmonertinib may effectively address the therapeutic uncertainties associated with EGFR/ERBB2 co-mutations, presenting a promising clinically actionable strategy while we continue to await the advent of more personalized and tailored treatment solutions. Lung adenocarcinoma EGFR L858R mutation ERBB2 S310F mutation concurrent mutations furmonertinib Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Lung adenocarcinoma (LUAD), representing 40–50% of all non-small cell lung cancer (NSCLC) cases, has witnessed a paradigm shift in management through the identification of actionable driver mutations in EGFR , ALK , and ROS1 [1]. This molecular stratification has established genotype-directed therapy as the cornerstone of precision oncology, significantly improving patient outcomes. However, the clinical implications of concurrent driver mutations, particularly those involving EGFR and ERBB2 , remain poorly characterized due to their exceptional rarity and complex biological interplay. In NSCLC, EGFR mutations exhibit marked ethnic disparities, occurring in nearly 50% of Asian and 15% of Western patients [2]. Among these, the EGFR exon 21 L858R point mutation accounts for 40–45% of activating variants and is effectively targeted by third-generation EGFR tyrosine kinase inhibitors (TKIs) [3]. However, the coexistence of genetic events driven by tumor heterogeneity, such as ERBB2 amplification or PIK3CA mutations, can activate alternative signaling pathways, modifying tumor biology and therapeutic response, thereby presenting a substantial challenge in clinical practice [4]. Previous studies have shown that single-target treatments are often ineffective in the presence of co-mutations [5]. LUAD with EGFR mutations frequently coexists with other genetic alterations, including TP53, PIK3CA, MYC, MET , and KRAS mutations [6]. ERBB2 aberrations in NSCLC are of particular translational significance, occurring primarily through two molecular mechanisms: gene amplification (in ≤ 2% of cases) or somatic mutations (in 2–4% of cases) [7–9]. ERBB2 signaling activation induces resistance to EGFR-directed therapies by triggering the extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated pathways [10]. Emerging evidence has revealed a previously underappreciated role of ERBB2 in driving EGFR L861Q-induced tumorigenesis [11]. As a result, determining effective treatment regimens to prevent or delay resistance in cases with co-occurring EGFR and ERBB2 mutations remains a critical challenge in clinical practice. The ERBB2 mutational spectrum shows distinct molecular stratification, with approximately 80% consisting of kinase domain insertions (exon 20) and 15% consisting of extracellular domain point mutations (exon 8). The ERBB2 S310F (c.929C > T) mutation has been identified in some solid tumors and is a rare but predominant hotspot mutation [12]. The coexistence of EGFR L858R and ERBB2 S310F mutations represents an exceptionally rare molecular subset, presenting unique clinical challenges. Case reports have documented responses to the second-generation EGFR-TKI afatinib (a pan-HER inhibitor) in tumors with co-occurring EGFR and ERBB2 mutations, but clinical evidence for third-generation EGFR-TKIs remains lacking [13]. Here, we present the first reported case showing a significant clinical response in a patient with LUAD carrying both EGFR L858R and ERBB2 S310F mutations, who was successfully treated with the third-generation EGFR-TKI furmonertinib combined with radiotherapy. Case presention A 61-year-old female patient visited our hospital on January 4, 2024, due to persistent cough and sputum production for one month. Enhanced chest CT revealed a mass in the right lower lobe measuring 2.6 cm × 4.4 cm, accompanied by enlarged lymph nodes in the right supraclavicular area, mediastinum, and right pulmonary hilum (Fig. 1 a). Further investigations with abdominal MRI and enhanced brain MRI scans demonstrated metastatic lesions in the right pons and bilateral cerebellar hemispheres. Bone scans indicated metastases to the frontal bone, right humeral head, sternum, right 10th rib, lower cervical vertebrae, and T11, T12, L3, and L5 vertebrae, as well as the left hip bone (Fig. 1 b-c). Subsequently, the patient underwent a CT-guided percutaneous lung biopsy, and the pathology results were consistent with adenocarcinoma. Hematoxylin-eosin (HE) staining revealed atypical cells with abundant glandular structures (Fig. 2 a). Immunohistochemistry (IHC) showed positive expression for CK7, TTF-1, and Napsin A (Fig. 2 b-d). Accordingly, the final diagnosis was stage IV right lower lung adenocarcinoma (cT3N2M1, AJCC 8th edition staging system), accompanied by multiple distant metastases (bone and brain). With the patient's informed consent, Next-generation sequencing (NGS) was performed on the biopsy specimen. According to the National Comprehensive Cancer Network (NCCN) Guidelines in Oncology for NSCLC ( 2023 edition, version 3 )[14], it was recommended to initiate chemotherapy with pemetrexed (500 mg/m²) and carboplatin (AUC 5.0 mg/mL/min) every 21 days while awaiting the genetic test results. On January 12, 2024, the patient received one cycle of pemetrexed in combination with carboplatin but subsequently declined further treatment due to severe gastrointestinal adverse effects. NGS examination revealed an EGFR exon 21 mutation (c.2573T > G, p.L858R) (Fig. 2 e), with an abundance of 18.10%; meanwhile, an ERBB mutation (c.929C > T, p.S310F) was also identified, with a mutation abundance of 24.30% (Fig. 2 f). In light of the identified EGFR exon 21 L858R mutation, treatment with furmonertinib was initiated at a dosage of 80 mg once daily. Due to significant pain symptoms from thoracolumbar metastases, the patient received radiotherapy for bone metastases on January 18, 2024. A total dose of 30 Gy in 10 fractions was administered to the thoracic vertebrae 11 and 12, and lumbar vertebra 3. Lumbar vertebra 5 received 36 Gy in 12 fractions (Fig. 1 d ) . Additionally, zoledronic acid therapy was administered. In March 2024, the patient received stereotactic radiotherapy for the right pontine metastasis, with a prescribed dose of 30 Gy delivered in 5 fractions ( Fig. 1 e ) . After three months of treatment, the tumor showed significant size reduction, and the patient's symptoms and functional status improved. The patient then continued maintenance therapy with Furmonertinib. During this period, the pulmonary lesions and adjacent lymph nodes received 30 sessions of radiotherapy, totaling 60 Gy (Fig. 1 f). Post-radiotherapy, changes consistent with radiation-induced lung interstitial fibrosis were observed, and the residual lung lesions were largely obscured. Details of the changes in pulmonary lesions during treatment are presented in Fig. 3 . Currently, the patient's condition remains stable, with a comprehensive overview of the diagnostic and treatment process outlined in Fig. 4 . Discussion The L858R mutation in EGFR exon 21 is a major driver alteration in LUAD, showing exceptional sensitivity to third-generation EGFR TKIs. In contrast, ERBB2 mutations are rare but biologically significant, promoting receptor dimerization and constant downstream pathway activation, thus driving oncogenesis [15]. Major ERBB2 mutation hotspots (e.g., G776, L755S, and A775_G776insYVMA) are found in only 2%-5% of LUAD cases [12]. The ERBB2 S310F mutation, a newly identified variant, is extremely rare in lung cancer. Importantly, our case represents only the second globally reported instance of co-occurring EGFR L858R and ERBB2 S310F mutations [16]. Treating EGFR-co-mutated LUAD is complicated by substantial molecular heterogeneity, including diverse EGFR mutation subtypes and various co-occurring genomic alterations, along with a lack of consensus therapeutic guidelines. Most studies suggest that tumors in co-mutated patients exhibit higher malignancy, a greater propensity for metastasis, and poor efficacy from single-agent EGFR TKIs, with shorter progression-free survival (PFS) [17]. TP53 is the most frequently co-mutated gene and may contribute to primary resistance to EGFR-TKI treatment in patients with sensitive EGFR mutations and poor clinical outcomes [18]. The therapeutic efficacy of EGFR-TKIs is significantly reduced in EGFR-mutant lung cancer patients with concurrent Wnt/β-catenin activation and cell cycle gene aberrations (particularly CDK4/CDK6), leading to notably poorer PFS outcomes[6]. Existing studies show that treatment response to EGFR-TKIs in tumors harboring concurrent EGFR and ERBB2 mutations is strongly influenced by the specific EGFR mutation locus [11]. In L861Q-expressing cells, significantly higher ERBB2 phosphorylation levels and enhanced EGFR-ERBB2 heterodimerization were observed compared to L858R-expressing cells. Consistent with these findings, in vitro studies showed that pan-ERBB inhibitors had stronger growth-suppressive effects in cells with compound L861Q/G719X mutations compared to EGFR-specific tyrosine kinase inhibitors [11]. Given the presence of an EGFR L858R mutation in this patient, we selected EGFR-TKI as the primary treatment. Furmonertinib, a novel third-generation EGFR-TKI, has been approved in China for first-line treatment of locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations, with superior median PFS compared to osimertinib (20.8 vs. 18.9 months), as well as for T790M-positive NSCLC following progression on first-line EGFR-TKIs [19]. Its innovative trifluoroethoxyl group enhances drug-target interaction through electron-withdrawing effects, enabling optimal binding to the EGFR kinase domain [20]. Beyond its approved indications, clinical trials demonstrate efficacy against P-loop and αC-helix compressing (PACC) mutations and EGFR exon 20 insertions [21, 22]. Furmonertinib exhibits a favorable safety profile, maintaining tolerability even at higher doses for CNS metastases, achieving enhanced efficacy without added toxicity [20, 23]. Given these advantages and the patient's concurrent brain metastases, furmonertinib was chosen as the optimal therapeutic intervention. he patient achieved sustained disease control following furmonertinib combined with local radiotherapy, demonstrating the remarkable efficacy of this third-generation EGFR-TKI in treating this rare co-mutation profile. The optimal treatment strategy after disease progression on first-line third-generation EGFR-TKI therapy remains undefined. For patients with CNS metastases, osimertinib combined with pemetrexed-platinum shows significantly superior PFS compared to osimertinib monotherapy (24.9 vs. 13.8 months; HR = 0.47, 95% CI 0.33–0.66), establishing targeted-chemotherapy combination as a viable option, though with increased risk of grade ≥ 3 adverse events [24, 25]. Alternatively, tumors with ERBB2 mutations/amplifications may benefit from HER2-targeted agents [26]. Mechanistically, dual ERBB2/EGFR inhibition has been shown to overcome acquired resistance and resensitize tumors to anti-EGFR therapies [27], positioning EGFR-TKI/HER2-targeted drug combinations as another actionable approach. This study is limited by its nature as a single case report of a rare EGFR/ERBB2 co-mutation, which limits broader clinical extrapolation due to the rarity of such profiles in routine NGS testing and the patient's inability to tolerate chemotherapy, thus restricting the evaluation of combination chemo-targeted therapy, an approach with demonstrated PFS benefits in CNS metastases. Furthermore, the conservative 80mg furmonertinib dosing without escalation to the potentially more CNS-effective 160mg dose used in clinical trials, combined with the short follow-up period that precluded comprehensive assessment of long-term outcomes and toxicities, may have impacted therapeutic observations. Nevertheless, these findings provide preliminary evidence supporting third-generation EGFR-TKI efficacy against this mutation profile, while highlighting the need for multicenter collaborative studies to establish optimal dosing strategies and evaluate combination approaches with HER2-targeted agents in such are molecular subsets. Conclusion We present the first report showing the clinical efficacy of furmonertinib combined with radiotherapy in a LUAD patient with concurrent EGFR L858R and ERBB2 S310F mutations. Our findings suggest that furmonertinib may be a viable therapeutic option for patients with these rare co-mutations. While the molecular mechanisms underlying treatment response in this dual-mutation context remain unclear, this case provides relevant evidence supporting furmonertinib’s potential to address the therapeutic dilemma posed by EGFR/ERBB2 co-alterations, which may inform treatment decisions until more comprehensive molecularly-guided strategies are available for this rare patient subset. Abbreviations MRI, Magnetic resonance imaging; LUAD, lung adenocarcinoma; HE, Hematoxylin and eosin; IHC, Immunohistochemistry; NGS, next-generation sequencing; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; EGFR-TKI, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; PACC, P-loop and αC-helix compressing; PFS, progression-free survival. Declarations Acknowledgements Not Applicable. Authors’ contributions S.L and R.C were responsible for conceptualizing the case, collecting data, conducting the literature review, and drafting the initial manuscript; H.L and D.Z oversaw the overall project, provided significant editorial input, conducted the final review of the manuscript, and ensured the integrity of the research. All authors have read and agreed to the published version of the manuscript. Funding This study was supported by National Natural Science Foundation of China (Grants number: 82200214), Foundation of Hubei Xiangyang No. 1 People’s Hospital of Youth programs (XYY2025QN07) and the Natural Science Foundation of Hubei Province (2022CFB890). Availability of data and materials All data generated or analyzed during this study are included in this published article. The clinical data supporting the conclusions of this manuscript will be made available by the authors. Clinical trial number Not Applicable. Ethics approval and consent to participate This study has been approved by the Ethics Committee of the First People's Hospital of Xiangyang, affiliated with Hubei University of Medicine. The Institutional Ethics Committee approved the acquisition of all samples and the methods used, with approval number: XYYY20240074. Our study complies with the requirements of the Declaration of Helsinki. Informed consent statements for case reporting and publication were obtained from the participants and their families. The patient and their families consented to the publication of anonymized data in an open-access journal. All treatment methods adhered to relevant guidelines and regulations. All data have been anonymized. Consent for publication Consent was signed by the patient for all the images, other personal and clinical details. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article. Conflict of interests The authors declare that they have no competing interests. References H. Kim et al. , "Proteogenomic characterization identifies clinical subgroups in EGFR and ALK wild-type never-smoker lung adenocarcinoma," Exp Mol Med, vol. 56, no. 9, pp. 2082-2095, Sep 2024, doi: 10.1038/s12276-024-01320-0. A. C. Tan and D. S. W. Tan, "Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations," J Clin Oncol, vol. 40, no. 6, pp. 611-625, Feb 20 2022, doi: 10.1200/JCO.21.01626. Q. Wu, W. Qian, X. Sun, and S. Jiang, "Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021," J Hematol Oncol, vol. 15, no. 1, p. 143, Oct 8 2022, doi: 10.1186/s13045-022-01362-9. D. A. Belchis et al. , "Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma," Oncotarget, vol. 7, no. 29, pp. 45237-45248, Jul 19 2016, doi: 10.18632/oncotarget.9931. H. Wang et al. , "Lung adenocarcinoma with EGFR 19Del and an ALK rearrangement benefits from alectinib instead of an EGFR-TKI: A case report," Medicine (Baltimore), vol. 101, no. 35, p. e30316, Sep 2 2022, doi: 10.1097/MD.0000000000030316. C. M. Blakely et al. , "Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers," (in eng), Nature genetics, vol. 49, no. 12, pp. 1693-1704, Dec 2017, doi: 10.1038/ng.3990. S. Y. Ha et al. , "Lung cancer in never-smoker Asian females is driven by oncogenic mutations, most often involving EGFR," Oncotarget, vol. 6, no. 7, pp. 5465-74, Mar 10 2015, doi: 10.18632/oncotarget.2925. N. Cancer Genome Atlas Research, "Comprehensive molecular profiling of lung adenocarcinoma," Nature, vol. 511, no. 7511, pp. 543-50, Jul 31 2014, doi: 10.1038/nature13385. J. Mazieres et al. , "Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives," J Clin Oncol, vol. 31, no. 16, pp. 1997-2003, Jun 1 2013, doi: 10.1200/JCO.2012.45.6095. K. Yonesaka et al. , "Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab," Science Translational Medicine, vol. 3, no. 99, pp. 99ra86-99ra86, 2011, doi: doi:10.1126/scitranslmed.3002442. H. Sato et al. , "Allele-Specific Role of ERBB2 in the Oncogenic Function of EGFR L861Q in EGFR-Mutant Lung Cancers," (in eng), Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, vol. 16, no. 1, pp. 113-126, Jan 2021, doi: 10.1016/j.jtho.2020.09.019. M. E. Arcila et al. , "Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas," Clin Cancer Res, vol. 18, no. 18, pp. 4910-8, Sep 15 2012, doi: 10.1158/1078-0432.CCR-12-0912. E. Plomer, M. Früh, A. Lauber, I. Demmer, W. Jochum, and K. L. Koster, "Prolonged Response to Afatinib and Crizotinib in a Rare Case of EGFR-, HER2-, MET- and ROS1-Alterated Lung Adenocarcinoma," (in eng), International journal of molecular sciences, vol. 25, no. 11, May 23 2024, doi: 10.3390/ijms25115698. L. Zhu et al. , "[Updated Interpretation of the NCCN Clinical Practice Guidelines (Version 3. 2023) for Non-small Cell Lung Cancer]," Zhongguo Fei Ai Za Zhi, vol. 26, no. 6, pp. 407-415, Jun 20 2023, doi: 10.3779/j.issn.1009-3419.2023.102.18. G. S. Herter-Sprie, H. Greulich, and K. K. Wong, "Activating Mutations in ERBB2 and Their Impact on Diagnostics and Treatment," Front Oncol, vol. 3, p. 86, 2013, doi: 10.3389/fonc.2013.00086. Y. Jia, S. M. Ali, S. Saad, C. A. Chan, V. A. Miller, and B. Halmos, "Successful treatment of a patient with Li-Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib," (in eng), Cancer biology & therapy, vol. 15, no. 8, pp. 970-4, Aug 2014, doi: 10.4161/cbt.29173. H. Yu et al. , "Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma," (in eng), Molecular therapy oncolytics, vol. 21, pp. 158-170, Jun 25 2021, doi: 10.1016/j.omto.2021.03.015. K. Qin, H. Hou, Y. Liang, and X. Zhang, "Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis," BMC Cancer, vol. 20, no. 1, p. 328, Apr 16 2020, doi: 10.1186/s12885-020-06805-5. Y. Shi et al. , "Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study," (in eng), The Lancet. Respiratory medicine, vol. 10, no. 11, pp. 1019-1028, Nov 2022, doi: 10.1016/s2213-2600(22)00168-0. Y. Shi et al. , "Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation," (in eng), Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, vol. 15, no. 6, pp. 1015-1026, Jun 2020, doi: 10.1016/j.jtho.2020.01.010. X. Le et al. , "PL04.07 FURTHER: A Global, Randomized Study of Firmonertinib at Two Dose Levels in TKI-Naive, Advanced NSCLC with EGFR PACC Mutations," Journal of Thoracic Oncology, vol. 19, no. 10, Supplement, pp. S5-S6, 2024/10/01/ 2024, doi: https://doi.org/10.1016/j.jtho.2024.09.019. H. Sa, Y. Shi, C. Ding, and K. Ma, "A real-world study of the efficacy and safety of furmonertinib for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations," (in eng), Journal of cancer research and clinical oncology, vol. 149, no. 10, pp. 7729-7742, Aug 2023, doi: 10.1007/s00432-023-04726-x. X. Zheng et al. , "P2.09-36 Efficacy and Safety of Furmonertinib 160 mg as First-line Therapy for EGFR-mutated Advanced NSCLC Patients with CNS Metastases," Journal of Thoracic Oncology, vol. 18, no. 11, p. S348, 2023, doi: 10.1016/j.jtho.2023.09.609. P. Janne et al. , "PL03.13 Osimertinib With/Without Platinum-Based Chemotherapy as First-line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA2)," Journal of Thoracic Oncology, vol. 18, no. 11, Supplement, pp. S36-S37, 2023/11/01/ 2023, doi: https://doi.org/10.1016/j.jtho.2023.09.009. D. Planchard et al. , "Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC," (in eng), The New England journal of medicine, vol. 389, no. 21, pp. 1935-1948, Nov 23 2023, doi: 10.1056/NEJMoa2306434. J. Zeng, W. Ma, R. B. Young, and T. Li, "Targeting HER2 genomic alterations in non-small cell lung cancer," J Natl Cancer Cent, vol. 1, no. 2, pp. 58-73, Jun 2021, doi: 10.1016/j.jncc.2021.04.001. C. Wang, T. Li, W. Fu, and S. Hu, "Chapter 10 - Targeting ERBB2 overcomes resistance to the anti-EGFR therapeutic antibody cetuximab," in Novel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies , S. Hu Ed.: Academic Press, 2023, pp. 75-81. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6769788","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":483338108,"identity":"93a4f77c-7c3a-428c-8bcb-902c0dead663","order_by":0,"name":"Shiyue Liu","email":"","orcid":"","institution":"Hubei Univeristy of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shiyue","middleName":"","lastName":"Liu","suffix":""},{"id":483338109,"identity":"2e9a91ce-d111-4cd6-be8c-01d7bbdab3bd","order_by":1,"name":"Runze Cao","email":"","orcid":"","institution":"Wuxi Huishan District People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Runze","middleName":"","lastName":"Cao","suffix":""},{"id":483338110,"identity":"9caf4490-7463-41b4-b8cd-ee6f5ab2aa86","order_by":2,"name":"Hong Li","email":"","orcid":"","institution":"Rheinische Friedrich-Wilhelms University of Bonn","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Li","suffix":""},{"id":483338111,"identity":"913d15f7-ebb7-482a-8164-711df33bda56","order_by":3,"name":"Dongdong Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACCRDBBiISgLgCTEIEidRyhmQtjG1EaJGf3fzs4Zcymzx59+RjD7/OO5xncID54G0eBrs8XFoY5xwzN5Y5l1ZseOZZurHstsPFBgfYkq15GJKLcWlhlkgwk5ZsO5y4cUYOkLHtduKGAzxm0jwMBxIbcGhhk0j/hqRlDkgL/ze8WngkcswkPwK1zAczGsC2sOHVIiGRUybNcC4tcQPPszRphmP/E2ceZjO2nGOQjFOL/Iz0bZI/ymwS57cnH5P8UZOW2He8+eGNNxV2OLWAg4AHSBgcgDIYmEGEAR71QMD4A2RdA5QxCkbBKBgFowAdAABLRFrBW00P6gAAAABJRU5ErkJggg==","orcid":"","institution":"Hubei Univeristy of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Dongdong","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-05-28 16:08:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6769788/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6769788/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87028490,"identity":"67c94535-8978-4373-af9d-a5be09b4d664","added_by":"auto","created_at":"2025-07-18 12:32:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1189545,"visible":true,"origin":"","legend":"\u003cp\u003eCT and MRI Imaging Results of the Patient and Corresponding Radiation Therapy Targets. \u003cstrong\u003eA\u003c/strong\u003e: Occupation in the right upper lung. \u003cstrong\u003eB\u003c/strong\u003e: Metastasis in the right brachial region. \u003cstrong\u003eC\u003c/strong\u003e:\u003cstrong\u003e \u003c/strong\u003eMetastasis in the T11 and T12 vertebrae, as well as L3 and L5 vertebrae. \u003cstrong\u003eD\u003c/strong\u003e: Radiation therapy target for the metastases in the T11, T12, L3, and L5 vertebrae. \u003cstrong\u003eE\u003c/strong\u003e: Radiation therapy target for the metastasis in the right pons. \u003cstrong\u003eF\u003c/strong\u003e: Radiation therapy target for the lung tumor and the draining lymph nodes.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6769788/v1/cd85f697403df9fb5565010c.png"},{"id":87028491,"identity":"63e874a2-9714-4fc5-b67b-6c09e8d10cf5","added_by":"auto","created_at":"2025-07-18 12:32:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":838560,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological findings of the lung mass and NGS results. \u003cstrong\u003eA\u003c/strong\u003e: HE staining revealed pulmonary adenocarcinoma cells. \u003cstrong\u003eB, C, D\u003c/strong\u003e: Immunohistochemical examination indicated malignant cells immunoreactive for CK7 (B), TTF-1 (C), and Napsin A (D). E: EGFR exon 21 mutation (c.2573T\u0026gt;G, p.L858R); F: ERBB mutation (c.929C\u0026gt;T, p.S310F). Magnification 100×.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6769788/v1/400b2c0a5b9b63aee1e7b418.png"},{"id":87030004,"identity":"ca16dbfc-150c-43ea-bf20-ce7a53bd3c92","added_by":"auto","created_at":"2025-07-18 12:40:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1815063,"visible":true,"origin":"","legend":"\u003cp\u003eCT scan of the patient throughout the whole course of diagnosis andtreatment. Figures \u003cstrong\u003eA-D\u003c/strong\u003e, imaging changes of chest CT (mediastinal window and pulmonary window) at different times.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6769788/v1/e934a2c5633b7866e4ebad73.png"},{"id":87028494,"identity":"363556c4-ac15-4341-9a78-b0cb11b96b71","added_by":"auto","created_at":"2025-07-18 12:32:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":70537,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of the patient's events from diagnosis to treatment. CT, \u0026nbsp;computed tomography; AC, pemetrexed plus carboplatin; IMRT, intensity-modulated radiation therapy; SBRT, stereotactic body radiation therapy\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6769788/v1/179272311c088da7e2a0f0bf.png"},{"id":91619804,"identity":"fae94c97-6be2-40b6-9947-3b1c3b15722b","added_by":"auto","created_at":"2025-09-18 11:17:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5063418,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6769788/v1/b974585b-4f4c-406e-b221-61fede2bc6b1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Furmonertinib Activity in NSCLC Harboring EGFR L858R and ERBB2 S310F Co-Mutations: A Case Report With Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung adenocarcinoma (LUAD), representing 40\u0026ndash;50% of all non-small cell lung cancer (NSCLC) cases, has witnessed a paradigm shift in management through the identification of actionable driver mutations in \u003cem\u003eEGFR\u003c/em\u003e, \u003cem\u003eALK\u003c/em\u003e, and \u003cem\u003eROS1\u003c/em\u003e[1]. This molecular stratification has established genotype-directed therapy as the cornerstone of precision oncology, significantly improving patient outcomes. However, the clinical implications of concurrent driver mutations, particularly those involving \u003cem\u003eEGFR\u003c/em\u003e and \u003cem\u003eERBB2\u003c/em\u003e, remain poorly characterized due to their exceptional rarity and complex biological interplay.\u003c/p\u003e\u003cp\u003eIn NSCLC, \u003cem\u003eEGFR\u003c/em\u003e mutations exhibit marked ethnic disparities, occurring in nearly 50% of Asian and 15% of Western patients [2]. Among these, the EGFR exon 21 L858R point mutation accounts for 40\u0026ndash;45% of activating variants and is effectively targeted by third-generation EGFR tyrosine kinase inhibitors (TKIs) [3]. However, the coexistence of genetic events driven by tumor heterogeneity, such as ERBB2 amplification or PIK3CA mutations, can activate alternative signaling pathways, modifying tumor biology and therapeutic response, thereby presenting a substantial challenge in clinical practice [4].\u003c/p\u003e\u003cp\u003ePrevious studies have shown that single-target treatments are often ineffective in the presence of co-mutations [5]. LUAD with EGFR mutations frequently coexists with other genetic alterations, including \u003cem\u003eTP53, PIK3CA, MYC, MET\u003c/em\u003e, and \u003cem\u003eKRAS\u003c/em\u003e mutations [6]. ERBB2 aberrations in NSCLC are of particular translational significance, occurring primarily through two molecular mechanisms: gene amplification (in \u0026le;\u0026thinsp;2% of cases) or somatic mutations (in 2\u0026ndash;4% of cases) [7\u0026ndash;9]. ERBB2 signaling activation induces resistance to EGFR-directed therapies by triggering the extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated pathways [10]. Emerging evidence has revealed a previously underappreciated role of ERBB2 in driving EGFR L861Q-induced tumorigenesis [11]. As a result, determining effective treatment regimens to prevent or delay resistance in cases with co-occurring EGFR and ERBB2 mutations remains a critical challenge in clinical practice.\u003c/p\u003e\u003cp\u003eThe ERBB2 mutational spectrum shows distinct molecular stratification, with approximately 80% consisting of kinase domain insertions (exon 20) and 15% consisting of extracellular domain point mutations (exon 8). The ERBB2 S310F (c.929C\u0026thinsp;\u0026gt;\u0026thinsp;T) mutation has been identified in some solid tumors and is a rare but predominant hotspot mutation [12]. The coexistence of EGFR L858R and ERBB2 S310F mutations represents an exceptionally rare molecular subset, presenting unique clinical challenges. Case reports have documented responses to the second-generation EGFR-TKI afatinib (a pan-HER inhibitor) in tumors with co-occurring EGFR and ERBB2 mutations, but clinical evidence for third-generation EGFR-TKIs remains lacking [13]. Here, we present the first reported case showing a significant clinical response in a patient with LUAD carrying both EGFR L858R and ERBB2 S310F mutations, who was successfully treated with the third-generation EGFR-TKI furmonertinib combined with radiotherapy.\u003c/p\u003e"},{"header":"Case presention","content":"\u003cp\u003eA 61-year-old female patient visited our hospital on January 4, 2024, due to persistent cough and sputum production for one month. Enhanced chest CT revealed a mass in the right lower lobe measuring 2.6 cm \u0026times; 4.4 cm, accompanied by enlarged lymph nodes in the right supraclavicular area, mediastinum, and right pulmonary hilum (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Further investigations with abdominal MRI and enhanced brain MRI scans demonstrated metastatic lesions in the right pons and bilateral cerebellar hemispheres. Bone scans indicated metastases to the frontal bone, right humeral head, sternum, right 10th rib, lower cervical vertebrae, and T11, T12, L3, and L5 vertebrae, as well as the left hip bone (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb-c). Subsequently, the patient underwent a CT-guided percutaneous lung biopsy, and the pathology results were consistent with adenocarcinoma. Hematoxylin-eosin (HE) staining revealed atypical cells with abundant glandular structures (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Immunohistochemistry (IHC) showed positive expression for CK7, TTF-1, and Napsin A (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb-d). Accordingly, the final diagnosis was stage IV right lower lung adenocarcinoma (cT3N2M1, AJCC 8th edition staging system), accompanied by multiple distant metastases (bone and brain).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWith the patient's informed consent, Next-generation sequencing (NGS) was performed on the biopsy specimen. According to the National Comprehensive Cancer Network (NCCN) Guidelines in Oncology for NSCLC (\u003cb\u003e2023 edition, version 3\u003c/b\u003e)[14], it was recommended to initiate chemotherapy with pemetrexed (500 mg/m\u0026sup2;) and carboplatin (AUC 5.0 mg/mL/min) every 21 days while awaiting the genetic test results. On January 12, 2024, the patient received one cycle of pemetrexed in combination with carboplatin but subsequently declined further treatment due to severe gastrointestinal adverse effects.\u003c/p\u003e\u003cp\u003eNGS examination revealed an EGFR exon 21 mutation (c.2573T\u0026thinsp;\u0026gt;\u0026thinsp;G, p.L858R) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee), with an abundance of 18.10%; meanwhile, an ERBB mutation (c.929C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.S310F) was also identified, with a mutation abundance of 24.30% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef). In light of the identified EGFR exon 21 L858R mutation, treatment with furmonertinib was initiated at a dosage of 80 mg once daily. Due to significant pain symptoms from thoracolumbar metastases, the patient received radiotherapy for bone metastases on January 18, 2024. A total dose of 30 Gy in 10 fractions was administered to the thoracic vertebrae 11 and 12, and lumbar vertebra 3. Lumbar vertebra 5 received 36 Gy in 12 fractions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed\u003cb\u003e)\u003c/b\u003e. Additionally, zoledronic acid therapy was administered.\u003c/p\u003e\u003cp\u003eIn March 2024, the patient received stereotactic radiotherapy for the right pontine metastasis, with a prescribed dose of 30 Gy delivered in 5 fractions \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee\u003cb\u003e)\u003c/b\u003e. After three months of treatment, the tumor showed significant size reduction, and the patient's symptoms and functional status improved. The patient then continued maintenance therapy with Furmonertinib. During this period, the pulmonary lesions and adjacent lymph nodes received 30 sessions of radiotherapy, totaling 60 Gy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef). Post-radiotherapy, changes consistent with radiation-induced lung interstitial fibrosis were observed, and the residual lung lesions were largely obscured. Details of the changes in pulmonary lesions during treatment are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Currently, the patient's condition remains stable, with a comprehensive overview of the diagnostic and treatment process outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe L858R mutation in EGFR exon 21 is a major driver alteration in LUAD, showing exceptional sensitivity to third-generation EGFR TKIs. In contrast, ERBB2 mutations are rare but biologically significant, promoting receptor dimerization and constant downstream pathway activation, thus driving oncogenesis [15]. Major ERBB2 mutation hotspots (e.g., G776, L755S, and A775_G776insYVMA) are found in only 2%-5% of LUAD cases [12]. The ERBB2 S310F mutation, a newly identified variant, is extremely rare in lung cancer. Importantly, our case represents only the second globally reported instance of co-occurring EGFR L858R and ERBB2 S310F mutations [16].\u003c/p\u003e\u003cp\u003eTreating EGFR-co-mutated LUAD is complicated by substantial molecular heterogeneity, including diverse EGFR mutation subtypes and various co-occurring genomic alterations, along with a lack of consensus therapeutic guidelines. Most studies suggest that tumors in co-mutated patients exhibit higher malignancy, a greater propensity for metastasis, and poor efficacy from single-agent EGFR TKIs, with shorter progression-free survival (PFS) [17]. TP53 is the most frequently co-mutated gene and may contribute to primary resistance to EGFR-TKI treatment in patients with sensitive EGFR mutations and poor clinical outcomes [18]. The therapeutic efficacy of EGFR-TKIs is significantly reduced in EGFR-mutant lung cancer patients with concurrent Wnt/β-catenin activation and cell cycle gene aberrations (particularly CDK4/CDK6), leading to notably poorer PFS outcomes[6].\u003c/p\u003e\u003cp\u003eExisting studies show that treatment response to EGFR-TKIs in tumors harboring concurrent EGFR and ERBB2 mutations is strongly influenced by the specific EGFR mutation locus [11]. In L861Q-expressing cells, significantly higher ERBB2 phosphorylation levels and enhanced EGFR-ERBB2 heterodimerization were observed compared to L858R-expressing cells. Consistent with these findings, in vitro studies showed that pan-ERBB inhibitors had stronger growth-suppressive effects in cells with compound L861Q/G719X mutations compared to EGFR-specific tyrosine kinase inhibitors [11]. Given the presence of an EGFR L858R mutation in this patient, we selected EGFR-TKI as the primary treatment.\u003c/p\u003e\u003cp\u003eFurmonertinib, a novel third-generation EGFR-TKI, has been approved in China for first-line treatment of locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations, with superior median PFS compared to osimertinib (20.8 vs. 18.9 months), as well as for T790M-positive NSCLC following progression on first-line EGFR-TKIs [19]. Its innovative trifluoroethoxyl group enhances drug-target interaction through electron-withdrawing effects, enabling optimal binding to the EGFR kinase domain [20]. Beyond its approved indications, clinical trials demonstrate efficacy against P-loop and αC-helix compressing (PACC) mutations and EGFR exon 20 insertions [21, 22]. Furmonertinib exhibits a favorable safety profile, maintaining tolerability even at higher doses for CNS metastases, achieving enhanced efficacy without added toxicity [20, 23]. Given these advantages and the patient's concurrent brain metastases, furmonertinib was chosen as the optimal therapeutic intervention. he patient achieved sustained disease control following furmonertinib combined with local radiotherapy, demonstrating the remarkable efficacy of this third-generation EGFR-TKI in treating this rare co-mutation profile.\u003c/p\u003e\u003cp\u003eThe optimal treatment strategy after disease progression on first-line third-generation EGFR-TKI therapy remains undefined. For patients with CNS metastases, osimertinib combined with pemetrexed-platinum shows significantly superior PFS compared to osimertinib monotherapy (24.9 vs. 13.8 months; HR\u0026thinsp;=\u0026thinsp;0.47, 95% CI 0.33\u0026ndash;0.66), establishing targeted-chemotherapy combination as a viable option, though with increased risk of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events [24, 25]. Alternatively, tumors with ERBB2 mutations/amplifications may benefit from HER2-targeted agents [26]. Mechanistically, dual ERBB2/EGFR inhibition has been shown to overcome acquired resistance and resensitize tumors to anti-EGFR therapies [27], positioning EGFR-TKI/HER2-targeted drug combinations as another actionable approach.\u003c/p\u003e\u003cp\u003eThis study is limited by its nature as a single case report of a rare EGFR/ERBB2 co-mutation, which limits broader clinical extrapolation due to the rarity of such profiles in routine NGS testing and the patient's inability to tolerate chemotherapy, thus restricting the evaluation of combination chemo-targeted therapy, an approach with demonstrated PFS benefits in CNS metastases. Furthermore, the conservative 80mg furmonertinib dosing without escalation to the potentially more CNS-effective 160mg dose used in clinical trials, combined with the short follow-up period that precluded comprehensive assessment of long-term outcomes and toxicities, may have impacted therapeutic observations. Nevertheless, these findings provide preliminary evidence supporting third-generation EGFR-TKI efficacy against this mutation profile, while highlighting the need for multicenter collaborative studies to establish optimal dosing strategies and evaluate combination approaches with HER2-targeted agents in such are molecular subsets.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe present the first report showing the clinical efficacy of furmonertinib combined with radiotherapy in a LUAD patient with concurrent EGFR L858R and ERBB2 S310F mutations. Our findings suggest that furmonertinib may be a viable therapeutic option for patients with these rare co-mutations. While the molecular mechanisms underlying treatment response in this dual-mutation context remain unclear, this case provides relevant evidence supporting furmonertinib\u0026rsquo;s potential to address the therapeutic dilemma posed by EGFR/ERBB2 co-alterations, which may inform treatment decisions until more comprehensive molecularly-guided strategies are available for this rare patient subset.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMRI, Magnetic resonance imaging; LUAD, lung adenocarcinoma; HE, Hematoxylin and eosin; IHC, Immunohistochemistry; NGS, next-generation sequencing; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; EGFR-TKI, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; PACC, P-loop and \u0026alpha;C-helix compressing; PFS, progression-free survival.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.L and R.C were responsible for conceptualizing the case, collecting data, conducting the literature review, and drafting the initial manuscript; H.L and D.Z oversaw the overall project, provided significant editorial input, conducted the final review of the manuscript, and ensured the integrity of the research. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by National Natural Science Foundation of China (Grants number: 82200214), Foundation of Hubei Xiangyang No. 1 People\u0026rsquo;s Hospital of Youth programs (XYY2025QN07) and the Natural Science Foundation of Hubei Province (2022CFB890).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article. The clinical data supporting the conclusions of this manuscript will be made available by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by the Ethics Committee of the First People\u0026apos;s Hospital of Xiangyang, affiliated with Hubei University of Medicine. The Institutional Ethics Committee approved the acquisition of all samples and the methods used, with approval number: XYYY20240074. Our study complies with the requirements of the Declaration of Helsinki. Informed consent statements for case reporting and publication were obtained from the participants and their families. The patient and their families consented to the publication of anonymized data in an open-access journal. All treatment methods adhered to relevant guidelines and regulations. All data have been anonymized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent was signed by the patient for all the images, other personal and clinical details. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eH. Kim\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Proteogenomic characterization identifies clinical subgroups in EGFR and ALK wild-type never-smoker lung adenocarcinoma,\u0026quot; \u003cem\u003eExp Mol Med, \u003c/em\u003evol. 56, no. 9, pp. 2082-2095, Sep 2024, doi: 10.1038/s12276-024-01320-0.\u003c/li\u003e\n\u003cli\u003eA. C. Tan and D. S. W. Tan, \u0026quot;Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations,\u0026quot; \u003cem\u003eJ Clin Oncol, \u003c/em\u003evol. 40, no. 6, pp. 611-625, Feb 20 2022, doi: 10.1200/JCO.21.01626.\u003c/li\u003e\n\u003cli\u003eQ. Wu, W. Qian, X. Sun, and S. Jiang, \u0026quot;Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021,\u0026quot; \u003cem\u003eJ Hematol Oncol, \u003c/em\u003evol. 15, no. 1, p. 143, Oct 8 2022, doi: 10.1186/s13045-022-01362-9.\u003c/li\u003e\n\u003cli\u003eD. A. Belchis\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma,\u0026quot; \u003cem\u003eOncotarget, \u003c/em\u003evol. 7, no. 29, pp. 45237-45248, Jul 19 2016, doi: 10.18632/oncotarget.9931.\u003c/li\u003e\n\u003cli\u003eH. Wang\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Lung adenocarcinoma with EGFR 19Del and an ALK rearrangement benefits from alectinib instead of an EGFR-TKI: A case report,\u0026quot; \u003cem\u003eMedicine (Baltimore), \u003c/em\u003evol. 101, no. 35, p. e30316, Sep 2 2022, doi: 10.1097/MD.0000000000030316.\u003c/li\u003e\n\u003cli\u003eC. M. Blakely\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers,\u0026quot; (in eng), \u003cem\u003eNature genetics, \u003c/em\u003evol. 49, no. 12, pp. 1693-1704, Dec 2017, doi: 10.1038/ng.3990.\u003c/li\u003e\n\u003cli\u003eS. Y. Ha\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Lung cancer in never-smoker Asian females is driven by oncogenic mutations, most often involving EGFR,\u0026quot; \u003cem\u003eOncotarget, \u003c/em\u003evol. 6, no. 7, pp. 5465-74, Mar 10 2015, doi: 10.18632/oncotarget.2925.\u003c/li\u003e\n\u003cli\u003eN. Cancer Genome Atlas Research, \u0026quot;Comprehensive molecular profiling of lung adenocarcinoma,\u0026quot; \u003cem\u003eNature, \u003c/em\u003evol. 511, no. 7511, pp. 543-50, Jul 31 2014, doi: 10.1038/nature13385.\u003c/li\u003e\n\u003cli\u003eJ. Mazieres\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives,\u0026quot; \u003cem\u003eJ Clin Oncol, \u003c/em\u003evol. 31, no. 16, pp. 1997-2003, Jun 1 2013, doi: 10.1200/JCO.2012.45.6095.\u003c/li\u003e\n\u003cli\u003eK. Yonesaka\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab,\u0026quot; \u003cem\u003eScience Translational Medicine, \u003c/em\u003evol. 3, no. 99, pp. 99ra86-99ra86, 2011, doi: doi:10.1126/scitranslmed.3002442.\u003c/li\u003e\n\u003cli\u003eH. Sato\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Allele-Specific Role of ERBB2 in the Oncogenic Function of EGFR L861Q in EGFR-Mutant Lung Cancers,\u0026quot; (in eng), \u003cem\u003eJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, \u003c/em\u003evol. 16, no. 1, pp. 113-126, Jan 2021, doi: 10.1016/j.jtho.2020.09.019.\u003c/li\u003e\n\u003cli\u003eM. E. Arcila\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas,\u0026quot; \u003cem\u003eClin Cancer Res, \u003c/em\u003evol. 18, no. 18, pp. 4910-8, Sep 15 2012, doi: 10.1158/1078-0432.CCR-12-0912.\u003c/li\u003e\n\u003cli\u003eE. Plomer, M. Fr\u0026uuml;h, A. Lauber, I. Demmer, W. Jochum, and K. L. Koster, \u0026quot;Prolonged Response to Afatinib and Crizotinib in a Rare Case of EGFR-, HER2-, MET- and ROS1-Alterated Lung Adenocarcinoma,\u0026quot; (in eng), \u003cem\u003eInternational journal of molecular sciences, \u003c/em\u003evol. 25, no. 11, May 23 2024, doi: 10.3390/ijms25115698.\u003c/li\u003e\n\u003cli\u003eL. Zhu\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;[Updated Interpretation of the NCCN Clinical Practice Guidelines (Version 3. 2023) \u2029for Non-small Cell Lung Cancer],\u0026quot; \u003cem\u003eZhongguo Fei Ai Za Zhi, \u003c/em\u003evol. 26, no. 6, pp. 407-415, Jun 20 2023, doi: 10.3779/j.issn.1009-3419.2023.102.18.\u003c/li\u003e\n\u003cli\u003eG. S. Herter-Sprie, H. Greulich, and K. K. Wong, \u0026quot;Activating Mutations in ERBB2 and Their Impact on Diagnostics and Treatment,\u0026quot; \u003cem\u003eFront Oncol, \u003c/em\u003evol. 3, p. 86, 2013, doi: 10.3389/fonc.2013.00086.\u003c/li\u003e\n\u003cli\u003eY. Jia, S. M. Ali, S. Saad, C. A. Chan, V. A. Miller, and B. Halmos, \u0026quot;Successful treatment of a patient with Li-Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib,\u0026quot; (in eng), \u003cem\u003eCancer biology \u0026amp; therapy, \u003c/em\u003evol. 15, no. 8, pp. 970-4, Aug 2014, doi: 10.4161/cbt.29173.\u003c/li\u003e\n\u003cli\u003eH. Yu\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma,\u0026quot; (in eng), \u003cem\u003eMolecular therapy oncolytics, \u003c/em\u003evol. 21, pp. 158-170, Jun 25 2021, doi: 10.1016/j.omto.2021.03.015.\u003c/li\u003e\n\u003cli\u003eK. Qin, H. Hou, Y. Liang, and X. Zhang, \u0026quot;Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis,\u0026quot; \u003cem\u003eBMC Cancer, \u003c/em\u003evol. 20, no. 1, p. 328, Apr 16 2020, doi: 10.1186/s12885-020-06805-5.\u003c/li\u003e\n\u003cli\u003eY. Shi\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study,\u0026quot; (in eng), \u003cem\u003eThe Lancet. Respiratory medicine, \u003c/em\u003evol. 10, no. 11, pp. 1019-1028, Nov 2022, doi: 10.1016/s2213-2600(22)00168-0.\u003c/li\u003e\n\u003cli\u003eY. Shi\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation,\u0026quot; (in eng), \u003cem\u003eJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, \u003c/em\u003evol. 15, no. 6, pp. 1015-1026, Jun 2020, doi: 10.1016/j.jtho.2020.01.010.\u003c/li\u003e\n\u003cli\u003eX. Le\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;PL04.07 FURTHER: A Global, Randomized Study of Firmonertinib at Two Dose Levels in TKI-Naive, Advanced NSCLC with EGFR PACC Mutations,\u0026quot; \u003cem\u003eJournal of Thoracic Oncology, \u003c/em\u003evol. 19, no. 10, Supplement, pp. S5-S6, 2024/10/01/ 2024, doi: https://doi.org/10.1016/j.jtho.2024.09.019.\u003c/li\u003e\n\u003cli\u003eH. Sa, Y. Shi, C. Ding, and K. Ma, \u0026quot;A real-world study of the efficacy and safety of furmonertinib for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations,\u0026quot; (in eng), \u003cem\u003eJournal of cancer research and clinical oncology, \u003c/em\u003evol. 149, no. 10, pp. 7729-7742, Aug 2023, doi: 10.1007/s00432-023-04726-x.\u003c/li\u003e\n\u003cli\u003eX. Zheng\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;P2.09-36 Efficacy and Safety of Furmonertinib 160 mg as First-line Therapy for EGFR-mutated Advanced NSCLC Patients with CNS Metastases,\u0026quot; \u003cem\u003eJournal of Thoracic Oncology, \u003c/em\u003evol. 18, no. 11, p. S348, 2023, doi: 10.1016/j.jtho.2023.09.609.\u003c/li\u003e\n\u003cli\u003eP. Janne\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;PL03.13 Osimertinib With/Without Platinum-Based Chemotherapy as First-line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA2),\u0026quot; \u003cem\u003eJournal of Thoracic Oncology, \u003c/em\u003evol. 18, no. 11, Supplement, pp. S36-S37, 2023/11/01/ 2023, doi: https://doi.org/10.1016/j.jtho.2023.09.009.\u003c/li\u003e\n\u003cli\u003eD. Planchard\u003cem\u003e et al.\u003c/em\u003e, \u0026quot;Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC,\u0026quot; (in eng), \u003cem\u003eThe New England journal of medicine, \u003c/em\u003evol. 389, no. 21, pp. 1935-1948, Nov 23 2023, doi: 10.1056/NEJMoa2306434.\u003c/li\u003e\n\u003cli\u003eJ. Zeng, W. Ma, R. B. Young, and T. Li, \u0026quot;Targeting HER2 genomic alterations in non-small cell lung cancer,\u0026quot; \u003cem\u003eJ Natl Cancer Cent, \u003c/em\u003evol. 1, no. 2, pp. 58-73, Jun 2021, doi: 10.1016/j.jncc.2021.04.001.\u003c/li\u003e\n\u003cli\u003eC. Wang, T. Li, W. Fu, and S. Hu, \u0026quot;Chapter 10 - Targeting ERBB2 overcomes resistance to the anti-EGFR therapeutic antibody cetuximab,\u0026quot; in \u003cem\u003eNovel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies\u003c/em\u003e, S. Hu Ed.: Academic Press, 2023, pp. 75-81.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lung adenocarcinoma, EGFR L858R mutation, ERBB2 S310F mutation, concurrent mutations, furmonertinib","lastPublishedDoi":"10.21203/rs.3.rs-6769788/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6769788/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile targeted therapies have remarkably transformed the landscape of lung adenocarcinoma (LUAD) management, the clinical implications of concurrent mutations in EGFR and ERBB2 remain inadequately understood due to their exceptional rarity in patients. This lack of understanding leads to significant uncertainty regarding therapeutic strategies for individuals with such co-mutations, as neither single-agent EGFR tyrosine kinase inhibitors (TKIs) nor HER2-targeted therapies have demonstrated established efficacy in this specific molecular context. Here, we present a compelling case involving a 61-year-old female patient diagnosed with advanced LUAD, with both EGFR L858R (exon 21) and ERBB2 S310F mutations identified through comprehensive next-generation sequencing. The patient received a treatment regimen consisting of the third-generation EGFR TKI furmonertinib, combined with localized radiotherapy, which resulted in a marked and significant clinical response. Our findings indicate that furmonertinib may effectively address the therapeutic uncertainties associated with EGFR/ERBB2 co-mutations, presenting a promising clinically actionable strategy while we continue to await the advent of more personalized and tailored treatment solutions.\u003c/p\u003e","manuscriptTitle":"Furmonertinib Activity in NSCLC Harboring EGFR L858R and ERBB2 S310F Co-Mutations: A Case Report With Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 12:32:18","doi":"10.21203/rs.3.rs-6769788/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4307ef85-62da-43c8-8d25-fd04bc9a9ce7","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-18T11:09:14+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 12:32:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6769788","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6769788","identity":"rs-6769788","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}