Osimertinib with chemotherapy in advanced non-small cell lung cancer with vaginal metastasis harboring EGFR exon 21 L858R and NTRK1 exon 16 V679M mutations: a case report with prolonged progression-free survival

Introduction

Background

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, accounting for approximately 40% of non-small cell lung cancer (NSCLC) cases (1). Advances in understanding molecular carcinogenesis and the identification of oncogenic drivers have greatly promoted the development of targeted therapies for NSCLC, thereby extending survival in patients with actionable driver mutations (2). Prevalent metastatic sites in NSCLC encompassed brain (29%), bone (25%), adrenal gland (15%), liver (13%), and skin (3%) (3). Epidermal growth factor receptor (EGFR) mutations are one of the most common driver mutations in NSCLC patients, with an overall pooled prevalence of 32.3%, ranging from 38.4% in China to 14.1% in Europe (4,5). Among Chinese patients with LUAD, the EGFR mutation rate reaches as high as 50.3% (6). The mutation primarily includes classical variants such as exon 19 deletions and exon 21 L858R point mutations, which together account for approximately 90% of all EGFR alterations. EGFR mutations are more common in LUAD patients who are of Asian ethnicity, younger, female, or non-smokers/light smokers (7). Alterations in neurotrophic tyrosine kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) are rare in NSCLC, the incidence of NTRK gene fusion reported in transcontinental studies ranges from 0.1% to 3.3%. NTRK fusions rarely co-occur with other classical driver mutations, the most frequently observed co-mutations in tumors harboring NTRK fusions involve TP53, PTEN, and PIK3CA (8).

Rationale and knowledge gap

With the development of next-generation sequencing (NGS) technology, an increasing number of co-mutations have been found in patients with advanced EGFR-mutated NSCLC. These co-mutations may be one of the mechanisms of primary drug resistance, among which TP53 mutations are the most common co-mutations (4). Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), was initially approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with acquired drug resistance after EGFR-TKI therapy, and later approved as a first-line treatment (9). Combining chemotherapy with anti-EGFR targeted therapy has been proven to effectively delay the development of drug resistance, thereby improving survival outcomes in patients with advanced EGFR-mutated NSCLC (2). The first-generation tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, are recommended as first-line therapy for patients with NTRK fusion-positive locally advanced or metastatic NSCLC. However, resistance to these agents may eventually emerge through on-target or off-target mechanisms (8). A systematic literature search (PubMed and Embase, up to June 2025) revealed no reported cases of NSCLC with vaginal metastasis harboring concurrent EGFR exon 21 L858R and NTRK1 exon 16 V679M mutations. Two previous cases of NSCLC vaginal metastasis have been reported (10,11), but neither involved EGFR/NTRK1 co-mutations nor documented long-term progression-free survival (PFS) with osimertinib-chemotherapy combination. This case therefore addresses a critical knowledge gap regarding the efficacy of osimertinib combined with chemotherapy in such rare scenarios.

Objective

Despite the existence of numerous approved targeted therapies, genetic testing remains underutilized in clinical practice. Herein, we present a rare case of vaginal metastasis from lung cancer that benefited from genetic testing and subsequent targeted therapy (osimertinib) combined with chemotherapy. This case provides critical evidence for managing rare EGFR/NTRK1 co-mutations in NSCLC with unusual metastases. We present this article in accordance with the CARE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-15/rc).

Case presentation

A 54-year-old non-smoking woman was referred to the local hospital in January 2024 due to intermittent minor vaginal bleeding for four months following intercourse. Her surgical history includes a total hysterectomy for uterine fibroids in 2008 and a left upper lobectomy for LUAD in 2020 (pathological stage: pT2N0M0), with no evidence of recurrence in the 4 years postoperatively. She did not undergo radiotherapy or chemotherapy following lung cancer operation. Subsequently, she experienced depression and has been taking mirtazapine orally once daily; her depressive symptoms are currently stable.

A colposcopy detected a lesion approximately 2 cm in diameter on the left side of the vaginal stump, which was subsequently diagnosed as adenocarcinoma following a biopsy. The patient declined the local hospital’s recommendation for surgery and was subsequently transferred to our institution for further evaluation.

The gynecological examination revealed that the vaginal stump was fixed and measured about 4 cm in diameter, and invaded the pelvic wall. Pathological consultation identified poorly differentiated adenocarcinoma, consistent with clear cell carcinoma, as indicated by immunohistochemical analysis. A computed tomography (CT) scan demonstrated an absence of the uterus, thickening of the left portion of the vaginal stump, and a soft tissue density mass measuring approximately 3.3 cm × 2.2 cm with indistinct boundaries adjacent to the left posterior wall of the bladder, as well as thickened pelvic peritoneum on the left side—findings suggestive of neoplastic lesions. Additionally, multiple soft tissue nodules were scattered throughout the pelvic cavity, potentially indicative of implant metastases. The attending professor concluded that achieving satisfactory tumor shrinkage via direct surgery would be challenging; therefore, the patient received two cycles of neoadjuvant chemotherapy (January to February 2024) consisting of carboplatin (577 mg, intravenous, day 1) and paclitaxel (259 mg, intravenous, day 1), administered every 3 weeks, which achieved a partial response (PR). No complications other than grade 1 fatigue were observed during neoadjuvant chemotherapy. Follow-up CT scans revealed a reduction in both the volume of pelvic soft tissue nodules and thickening of the left vaginal stump and left pelvic peritoneum (Figure 1). Both CT scans also showed postoperative changes in the upper lobe of her left lung while revealing inflammatory nodules consistent with chronic inflammation elsewhere. No obvious signs of lung cancer recurrence were observed.

Figure 1 CT scans showing pelvic changes before and after neoadjuvant chemotherapy. (A,C) Pre-chemotherapy: arrows indicate the left vaginal stump mass and scattered pelvic nodules; (B,D) post-chemotherapy: arrows indicate reduced size of the vaginal stump mass and decreased volume of pelvic nodules. CT, computed tomography.

In March 2024, the patient underwent an exploratory laparotomy, including partial colpectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, para-aortic lymphadenectomy, omentectomy, and cytoreductive surgery for malignant tumor cells. Pathological examination revealed that all resected tissues (except lymph nodes) exhibited metastatic involvement of LUAD, consistent with stage IV disease (Figure 2). Immunohistochemistry demonstrated that tumor cells were positive for CK7, CK8, CK20, TTF-1, and Napsin-A, and negative for PR, P16, Pax-8, WT-1, SATB2, CDX-2, CD10, and GATA3. Review of the patient’s 2008 surgical records confirmed that the uterine fibroids were pathologically diagnosed as benign leiomyoma. Immunohistochemical analysis of the 2024 vaginal mass (positive for TTF-1 and Napsin-A, negative for desmin and smooth muscle actin) further ruled out homology with the previous uterine fibroids. The patient provided pathological sections from both the current operation and the 2020 lung cancer surgery to a specialized pathology department for consultation, confirming that both cancers originated from the same source. NGS of the tumor tissue revealed EGFR exon 21 (L858R) missense mutation and NTRK1 exon 16 (V679M) missense mutation. The patient received two cycles of postoperative carboplatin-paclitaxel chemotherapy, but subsequent treatment was discontinued due to hypoleukocytosis. A pelvic magnetic resonance imaging (MRI) scan conducted three months post-surgery showed no significant abnormalities. Vaginal bleeding resolved completely one month after surgery and has not recurred during follow-up. In June 2024, the patient began taking osimertinib 80 mg daily. The patient reported an exacerbation of depressive symptoms following surgery, which alleviated after adjusting mirtazapine dosage. No adverse or unanticipated events (e.g., surgical complications, severe toxicities) were observed postoperatively or during osimertinib treatment. She expressed her satisfaction with the medical treatment delivered by our healthcare team and extended her gratitude for the attentive care provided.

Figure 2 Pathological confirmation of LUAD with vaginal metastasis. Hematoxylin-eosin staining, (A) ×40, (B) ×200. LUAD, lung adenocarcinoma.

As of June 2025 (latest follow-up), the patient remains asymptomatic with no radiological evidence of recurrence or metastasis. She has attained a 14-month PFS following the surgical intervention. Tumor assessments (chest and abdomen CT scans) conducted every three months at a local hospital confirmed stable disease. We will continue to follow up on this patient. A graphical timeline of the case evolution is presented in Figure 3.

Figure 3 Timeline of clinical events, interventions, and outcomes. CT, computed tomography; EGFR, epidermal growth factor receptor; LUAD, lung adenocarcinoma; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; NTRK1, neurotrophic tyrosine kinase; PFS, progression-free survival.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Key findings

A 54-year-old female patient with a history of stage pT2N0M0 LUAD (2020) presented with a vaginal mass in January 2024. Pathological and immunohistochemical analysis confirmed the vaginal mass was a metastasis from LUAD, and NGS identified rare co-mutations of EGFR exon 21 L858R and NTRK1 exon 16 V679M. Following neoadjuvant chemotherapy, radical surgery, and postoperative osimertinib treatment, the patient achieved 14 months of PFS as of June 2025, with complete resolution of vaginal bleeding and no recurrence.

Strengths and limitations

This case, due to its rarity (first report of EGFR/NTRK1 co-mutated NSCLC with vaginal metastasis), offers valuable insights and serves as an important reference for clinicians in gynecology, respiratory medicine, and pathology. When patients with a history of lung cancer present with a vaginal mass, the possibility of vaginal metastasis from lung cancer should be carefully considered, and further genetic testing, such as NGS, should be conducted. This case report, however, has certain limitations. Firstly, the relatively short follow-up duration (14 months) limits conclusions regarding long-term efficacy and safety of the treatment regimen. Secondly, the patient’s chemotherapy was interrupted due to hypoleukocytosis, which may have influenced the treatment outcomes—whether completing the full chemotherapy course would further improve survival remains unclear. Lastly, the patient harbored two gene mutations; however, only one targeted drug (osimertinib) was administered due to concerns about potential adverse reactions from combination targeted therapy and the high cost of treatment. This discrepancy may potentially impact the overall efficacy of the treatment.

Comparison with similar research

Primary vaginal cancer is rare, accounting for only 1–2% of all female genital tract malignancies worldwide and representing approximately 10% of all malignant tumors of the vagina. The majority of suspicious vaginal lesions are, in fact, metastatic deposits from cervical or vulvar cancers, or secondary involvement from other primary malignancies such as those originating in the breast, endometrium, trophoblast, ovary, or lymphoma (12). To date, only two cases of vaginal metastasis originating from lung cancer have been documented in the literature (10,11). The first case involved a 67-year-old postmenopausal woman with a previous LUAD diagnosis, treated with partial lung resection. Two-years following surgery, the patient complained of increasing urinary problems, and a suspected tumor was identified with a gynecologic examination together with the imaging (ultrasound scan). Histological and immunohistochemical examinations of a vaginal excision biopsy revealed a metastatic adenocarcinoma, with the staining reactivity indicating primary lung neoplasia. The patient was disease-free after 5 months (10); the second case involved a 46-year-old patient with primitive adenosquamous lung carcinoma and vaginal metastasis, who was currently closely monitored, after starting the medical therapy with entrectinib (11). Neither of the two cases reported driver mutations. The first patient exhibited a PFS of 5 months, whereas the survival outcome for the second case was not documented. In contrast, our case features unique EGFR/NTRK1 co-mutations and achieved a prolonged PFS of 14 months with the combination of osimertinib and chemotherapy. A recent Phase III, international, open-label clinical trial has demonstrated that the combination of osimertinib and chemotherapy results in significantly prolonged PFS compared to osimertinib monotherapy in patients with EGFR-mutated NSCLC (13), which supports the efficacy of our treatment regimen. A prospective cohort study demonstrated that osimertinib combined with chemotherapy tended to improve objective response rate and prolong PFS in advanced EGFR-mutated NSCLC patients with concurrent TP53 mutations, with a significant benefit observed specifically in those harboring the L858R mutation (14). Additionally, an international multicenter retrospective cohort study demonstrated that among EGFR-mutated NSCLC patients who experienced disease progression during osimertinib treatment, continuation of osimertinib in combination with subsequent platinum-based pemetrexed chemotherapy was associated with a significant prolongation of PFS, although no overall survival (OS) benefit was observed. Furthermore, the sustained use of osimertinib combined with this chemotherapy regimen appeared to reduce the risk of central nervous system (CNS) disease progression (15).

Explanations of findings

The main histological subtype of primary vaginal cancer is squamous cell carcinoma, accounting for 90%. Adenocarcinoma accounts for approximately 8% to 10% (12). Upon pathologically identifying a vaginal tumor as adenocarcinoma, it is crucial to consider the possibility that the lesion may represent a metastasis (16). A comprehensive immunohistochemical panel is indispensable for ensuring an accurate diagnosis. Transcription termination factor 1 (TTF1) and napsin A serve as specific markers for LUAD (2), and TTF-1 positivity increases the likelihood of detecting EGFR or ALK mutations (17). In our case, TTF-1 and Napsin-A positivity in the vaginal mass confirmed its pulmonary origin, while negative desmin and smooth muscle actin ruled out homology with the 2008 benign uterine leiomyoma.

For all patients with advanced or metastatic lung tumors, molecular profiling is recommended following histological diagnosis. NGS plays a pivotal role in identifying rare co-mutations (e.g., EGFR and NTRK1 in this case), enabling personalized treatment selection. By detecting actionable mutations, NGS guides targeted therapy decisions, which is particularly critical for rare metastases like vaginal involvement in NSCLC, where standard treatments may be ineffective. If an EGFR mutation is confirmed, first-line treatment with EGFR-TKI is advised. Specifically, osimertinib is the preferred option when exon 19 deletion or exon 21 L858R EGFR mutations are confirmed, particularly in cases involving brain metastases (7). NTRK gene fusions have been identified as a potential resistance mechanism to EGFR-TKIs in patients with EGFR-mutated NSCLC, which indicates that the combined treatment of EGFR-TKI and TRK inhibitors may be an alternative treatment option for patients with EGFR-TKI resistance mediated by NTRK fusion. Further research is currently being conducted to address drug resistance and improve survival outcomes (8).

Implications and actions needed

In summary, the coexistence of EGFR and NTRK mutations is an exceptionally rare event for which there is no established standard therapy. In our study, radical surgery facilitated an accurate diagnosis, and the combination of osimertinib and chemotherapy demonstrated a superior PFS (14 months) in comparison to a similar case (5 months) (10). Further in-depth research is imperative to identify appropriate treatments for patients harboring concurrent driver gene mutations. Most current clinical trials and available drugs remain in the research and development phase, with recent data indicating limited efficacy (18). To achieve a breakthrough in molecular targeted therapy for advanced NSCLC and improve patient outcomes, it is essential for researchers to develop new drugs to overcome drug resistance and design clinical trials for combination therapies targeting multiple driver mutations

Conclusions

We present the first case of vaginal metastasis from LUAD harboring EGFR exon 21 L858R and NTRK1 exon 16 V679M mutations. A treatment regimen combining osimertinib with chemotherapy achieved a prolonged PFS of 14 months, highlighting the efficacy of this approach for such rare cases. Genomic testing, particularly NGS, is strongly recommended for all patients diagnosed with NSCLC to ensure the optimal selection of targeted therapeutic agents. Furthermore, there is an urgent necessity to develop personalized treatment strategies for patients who possess coexisting driver gene mutations. Ongoing research into novel pharmacological agents and combination therapies is essential to broaden the clinical benefits available to a wider patient population and enhance outcomes in NSCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-15/rc

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-15/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-15/coif). X.H. serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from June 2024 to December 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rina A, Maffeo D, Minnai F, et al. The Genetic Analysis and Clinical Therapy in Lung Cancer: Current Advances and Future Directions. Cancers (Basel) 2024;16:2882. [Crossref] [PubMed]
2. Chen P, Liu Y, Wen Y, et al. Non-small cell lung cancer in China. Cancer Commun (Lond) 2022;42:937-70. [Crossref] [PubMed]
3. Wang S, Tang W, Jin F, et al. Comprehensive Analysis of Lung Cancer Metastasis: Sites, Rates, Survival, and Risk Factors-A Systematic Review and Meta-Analysis. Clin Respir J 2025;19:e70107. [Crossref] [PubMed]
4. Liu S, Yu J, Zhang H, et al. TP53 Co-Mutations in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy. Front Oncol 2022;12:860563. [Crossref] [PubMed]
5. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016;7:78985-93. [Crossref] [PubMed]
6. Wang S, Wang Z. EGFR mutations in patients with non-small cell lung cancer from mainland China and their relationships with clinicopathological features: a meta-analysis. Int J Clin Exp Med 2014;7:1967-78.
7. Gálffy G, Morócz É, Korompay R, et al. Targeted therapeutic options in early and metastatic NSCLC-overview. Pathol Oncol Res 2024;30:1611715. [Crossref] [PubMed]
8. Liu F, Wei Y, Zhang H, et al. NTRK Fusion in Non-Small Cell Lung Cancer: Diagnosis, Therapy, and TRK Inhibitor Resistance. Front Oncol 2022;12:864666. [Crossref] [PubMed]
9. Gou Q, Gou Q, Gan X, et al. Novel therapeutic strategies for rare mutations in non-small cell lung cancer. Sci Rep 2024;14:10317. [Crossref] [PubMed]
10. Jahnke A, Domke R, Makovitzky J, et al. Vaginal metastasis of lung cancer: a case report. Anticancer Res 2005;25:1645-8.
11. Savasta F, Giana M, Libretti A, et al. Vaginal metastasis of lung cancer: A case report. Case Rep Womens Health 2023;39:e00536. [Crossref] [PubMed]
12. Adams TS, Maluleke JC, Cuello MA. Cancer of the vagina: 2025 update. Int J Gynaecol Obstet 2025;171:48-59. [Crossref] [PubMed]
13. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy. 258 in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023;389:1935-48. [Crossref] [PubMed]
14. Li J, Zhan X, Shao M, et al. Osimertinib plus chemotherapy versus osimertinib for patients with advanced NSCLC with concomitant EGFR and TP53 mutations: a prospective cohort study. Sci Rep 2025;15:20952. [Crossref] [PubMed]
15. Patil T, Gao D, Watson A, et al. The efficacy of continuing osimertinib with platinum pemetrexed chemotherapy upon progression in patients with metastatic non-small cell lung cancer harboring sensitizing EGFR mutations. Lung Cancer 2025;199:108040. [Crossref] [PubMed]
16. Sadatomo A, Koinuma K, Horie H, et al. An isolated vaginal metastasis from rectal cancer. Ann Med Surg (Lond) 2016;5:19-22. [Crossref] [PubMed]
17. Court A, Laville D, Dagher S, et al. Anti-CK7/CK20 Immunohistochemistry Did Not Associate with the Metastatic Site in TTF-1-Negative Lung Cancer. Diagnostics (Basel) 2022;12:1589. [Crossref] [PubMed]
18. Bouchard N, Daaboul N. Lung Cancer: Targeted Therapy in 2025. Curr Oncol 2025;32:146. [Crossref] [PubMed]