Efficacy of TKIs in non-small cell lung cancer with atypical EGFR p.L747P and p.L747S mutations

Objectives: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are established first-line treatments for advanced non-small cell lung cancer (NSCLC) harboring common sensitizing EGFR mutations, such as exon 19 deletions (19del) and the exon 21 p.L858R point mutation. However, evidence regarding the efficacy of first-, second-, and third-generation EGFR-TKIs against uncommon EGFR exon 19 mutations, specifically p.L747P and p.L747S, remains limited, and the underlying mechanisms are not fully elucidated. This study aimed to evaluate the clinical efficacy of different-generation EGFR-TKIs in NSCLC patients harboring EGFR p.L747P or p.L747S mutations by integrating our institutional cases with published evidence.

Materials and methods: We identified patients with NSCLC harboring EGFR p.L747P or p.L747S mutations detected by next-generation sequencing (NGS) between 2020 and 2025 and retrospectively collected their clinical data. A literature review was conducted to identify and integrate relevant published case data.

Results: Among seven treated stage IV NSCLC patients with the p.L747P mutation, two who received second-generation EGFR-TKIs as first-line therapy had an objective response rate (ORR) of 0% and experienced rapid disease progression. In contrast, six patients received third-generation EGFR-TKIs as first- or second-line therapy, with two achieving stable disease (SD) and one achieving partial response (PR), with a substantially longer progression-free survival (PFS) of 12 to 40 months. Separately, six patients were found to harbor the p.L747S mutation concomitantly with a common TKI-sensitive mutation, none of whom had received prior EGFR-TKI therapy. Of these, two patients were treated with a third-generation TKI: 1 achieved SD and the other achieved partial response (PR).

Conclusions: This integrated retrospective analysis suggests that third-generation EGFR-TKIs may provide disease control (PR/SD) and prolonged PFS in a subset of NSCLC patients harboring uncommon EGFR p.L747P or p.L747S mutations, particularly those with co-existing sensitizing mutations or central nervous system metastases (CNS).

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 75-85% of all lung cancer cases (1). Epidermal growth factor receptor (EGFR) is the major driver oncogene in lung cancer, especially in Asian populations (2). Approximately 47-54% of patients diagnosed with advanced NSCLC in China harbor EGFR mutations (1). Short in-frame deletions in the amino acid ELREA of exon 19 (19del) and the exon 21 p.L858R point mutation are the most common alterations (3). Mutations in these regions change the spatial structure of the enzyme’s functional domain and lead to constitutive activation of EGFR and its downstream signaling activation (4).

EGFR mutations are oncogenic and alter the tyrosine kinase pocket of EGFR to a degree that enhances sensitivity to adenosine triphosphate (ATP)-competitive EGFR inhibitors. These factors increase the sensitivity of EGFR-mutated NSCLCs to EGFR tyrosine kinase inhibitors (TKIs) (5). The use of EGFR-TKIs has proven to be an effective therapy for advanced NSCLC with mutant EGFR (6–9). Patients with EGFR mutations, particularly those with exon 19 deletions (19del) or p.L858R mutations, are sensitive to TKIs (10). However, the characterization of rare EGFR mutations identified through gene sequencing remains insufficient (1, 4). Many uncommon EGFR mutations, such as p.G719X, p.S768I, and p.L861Q, affect approximately 10% of the NSCLC population (11–13), but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors (2). Uncommon EGFR alterations appear to carry heterogeneous molecular features with clinically variable responses to TKIs and shorter progression-free survival (PFS) than common EGFR mutations do (14).

The p.L747P results from codon 747 of exon 19 with a two-base-pair (bp) mutation (c.2239_2240 TT>CC), leading to the replacement of leucine by proline (15). Similar to other activating common EGFR mutations, p.L747P drives the oncogenesis. However, a limited number of case reports have demonstrated that NSCLC patients with this mutation showed various responses to EGFR-TKI treatment. According to the structure-based classification by Robichaux et al., p.L747P and p.L747S mutations fall into the P-loop and αC-helix compressing (PACC) subgroup. This classification predicts that these mutations confer reduced efficacy to first- and third-generation TKIs, while making them particularly vulnerable to second-generation TKIs like afatinib (16). An analysis of the three-dimensional structure of the EGFR kinase revealed that Leu747 is located at the end of strand β3 connecting to the C-helix and some hydrophobic residues to stabilize the inactive function of the kinase (17). Theoretically, the substitutions of L747 with Pro or Ser with minimal structural changes, could cause constitutional activity of the EGFR kinase, which is sensitive to EGFR-TKI treatment (17, 18). However, in the literature, these published cases have reported heterogeneous responses to TKIs (10, 15, 18–26).

Although there is extensive clinical experience with EGFR inhibitors in common activating exon 19del and exon 21 p.L858R mutations, and more recently with exon 20 insertions, the efficacy against rare EGFR mutations is less clear. In such cases, clinicians must rely on preclinical studies, case reports, or small subsets from clinical trials for treatment guidance (26). The effectiveness of EGFR-TKIs in patients with these two rare point mutations in exon 19 of EGFR is seldom discussed. Therefore, a retrospective study was conducted on patients with either of these two uncommon mutations treated at West China Hospital of Sichuan University (WCH), supplemented by a review of published cases from PubMed. This study aimed to investigate the clinical characteristics and outcomes of these patients to evaluate the efficacy of EGFR-TKIs.

Materials and methods

Patient selection and data collection

We conducted a retrospective cohort study supplemented by a systematic literature review. Patients with NSCLC harboring EGFR p.L747P or p.L747S mutations, who were treated at WCH between October 2020 and October 2025, were identified through the institutional database. Clinical data, including demographics, treatment history, and imaging outcomes, were extracted from electronic medical records. For patients initially diagnosed elsewhere, formalin-fixed paraffin-embedded (FFPE) specimens were sent to the Department of Pathology at WCH for centralized analysis. All tumor samples underwent comprehensive genomic profiling via next-generation sequencing (NGS) using a panel covering 1021 cancer-related genes (Precision Medicine Center, WCH) to confirm EGFR mutation status. Intracranial response in patients with central nervous system (CNS) metastases was assessed via brain magnetic resonance imaging (MRI), per standard clinical protocols. The last follow-up date was November 30, 2025. Ethical approval was exempted for this retrospective study due to the use of de-identified patient data, in accordance with the guidelines of the Institutional Review Board of West China Hospital.

Systematic literature review

A parallel systematic search of the PubMed database was conducted to identify published case reports or series describing NSCLC patients with EGFR p.L747P or p.L747S mutations. The search strategy employed the following key terms: “uncommon EGFR mutations,” “EGFR exon 19 mutations,” “EGFR p.L747P,” and “EGFR p.L747S.” Neither date nor language restrictions were imposed. Retrieved articles were screened based on titles and abstracts, and full texts of potentially eligible reports were reviewed. Studies were included if they reported on patients with histologically confirmed NSCLC harboring either the p.L747P or p.L747S EGFR mutation (exclusively or in combination with other EGFR mutations) and provided extractable data on clinical characteristics and/or treatment outcomes. Data from eligible publications were systematically extracted and integrated with our institutional cohort for comparative analysis (2, 5, 10, 19–33).

Results

Demographics of enrolled patients

From October 2020 to October 2025 at WCH, a total of 4079 patients were diagnosed with NSCLC, and 2159 (52.9%) patients tested positive for EGFR mutations by NGS. Among these EGFR-mutant patients, only 16 NSCLC patients (0.74%) carrying uncommon EGFR p.L747P (n=10) or p.L747S (n=6) mutations were identified and retrieved. The median patient age was 63 (range, 37-84) years. Thirteen patients (81.3%) were female, and 13 patients (81.3%) were never-smokers. Most patients (62.5%) were diagnosed at advanced stages, whereas 6 patients (37.5%) were diagnosed at early stages. The clinical, demographic, and molecular characteristics of patients harboring the EGFR p.L747P or p.L747S mutation from this cohort and published data are summarized in Table 1.

Table 1

Table 1. Clinical characteristics of patients harboring EGFR p.L747P or p.L747S mutations in the WCH cohort and published cases.

Clinical outcomes

All 7 patients in this cohort from WCH, who had stage IV NSCLC harboring the p.L747P mutation, received EGFR-TKIs (Table 2). Two patients received second-generation EGFR-TKIs (afatinib) as first-line treatment. Neither of these 2 patients achieved an objective response, and both experienced progressive disease (PD). Among the 6 patients who received third-generation EGFR-TKIs as first- or second-line therapy, 2 achieved stable disease (SD) and 1 achieved partial response (PR), demonstrating a relatively long PFS ranging from 12 to over 40 months; notably, the patient with the longest PFS (>40 months) presented with brain metastases. However, 1 patient developed a rash within 30 days of receiving osimertinib, and after switching to almonertinib, the disease still progressed rapidly.

Table 2

Table 2. Clinical characteristics and outcomes of 10 NSCLC patients with EGFR p.L747P mutations from WCH.

Initial testing via amplification refractory mutation system PCR (ARMS-PCR) in Patient 10 detected an EGFR 19del but missed the p.L747P mutation, which was later revealed by NGS (20.6% abundance) after gefitinib failure. Given the presence of brain metastases, low systemic disease burden, and toxicity profile of alternative regimens, osimertinib was selected over the genomically recommended second-generation EGFR-TKI. The patient achieved sustained thoracic and intracranial responses on osimertinib at the 12-month follow-up.

The clinical characteristics of the 6 patients harboring the EGFR p.L747S mutation are summarized in Table 3. In our study, the p.L747S mutation, previously documented to confer resistance to EGFR-TKIs, was identified in only 6 individuals. All of these patients carried concurrent TKI-sensitive mutations (e.g., 19del, p.L858R, or p.G719C), and none had received EGFR-TKI treatment prior to NGS testing. Of these, only the 2 patients with stage IVB disease received third-generation EGFR-TKIs: Patient 5 (with brain metastases) achieved a PR on osimertinib with a PFS of >9 months. Patient 4 achieved SD on furmonertinib (PFS 5 months), was switched to almonertinib due to hematologic toxicity, and maintained SD for a further 8 months with ongoing response at the last follow-up. The remaining 4 early-stage patients did not receive TKI therapy.

Table 3

Table 3. Clinical characteristics and outcomes of 6 NSCLC patients with EGFR p.L747S mutations from WCH.

Reviewing the published literature, we identified 21 patients harboring p.L747P (n=12) or p.L747S (n=9) mutations. The following analysis focuses on the 12 patients with p.L747P, whose data were integrated into our study (Table 1). The median age of the cohort was 63.1 years (range, 41-84). Nine patients (75.0%) were female and 6 (50.0%) were never-smokers. Regarding disease stage, 9 (75.0%) had stage IV lung adenocarcinoma, 1 (8.3%) had stage IIIA disease, and staging information was unavailable for 2 (16.7%). All 12 patients received EGFR-TKIs, including gefitinib (n=7), afatinib (n=6), osimertinib (n=4), erlotinib (n=3), and dacomitinib (n=1). As some patients received multiple lines of therapy, the total number of treatment instances exceeds the patient number. Treatment responses are summarized in Table 4.

Table 4

Table 4. Clinical characteristics of 12 published lung adenocarcinoma patients harboring the EGFR p.L747P mutation.

Notably, initial testing via PCR-based methods misclassified the mutations in patients 2, 9, and 12 as common EGFR 19del, whereas subsequent NGS correctly identified these variants as p.L747P. Patient 12, who received gefitinib, exhibited PD, showing a treatment response similar to that of Patient 10 in our cohort. Analysis of TKI efficacy across different generations revealed heterogeneous outcomes. Among those treated with first-generation TKIs, 4 who received gefitinib showed resistance with PD while 3 achieved SD, with PFS ranging from 4 to 18 months. Of the 6 patients treated with second-generation TKIs, 1 who received afatinib achieved a PR (PFS of 4 months), 3 achieved SD on afatinib with PFS ranging from 4 to 24 months, and 1 had PD. Notably, 1 patient achieved SD for 7 months with afatinib and subsequently achieved a PR with a PFS of 17 months after switching to dacomitinib. Regarding third-generation TKIs, 3 patients with the p.L747P mutation who received osimertinib achieved a PFS ranging from 4 to 36 months, whereas 1 patient failed to respond, with a PFS of only 1 month.

The EGFR p.L747S mutation was identified in 9 patients, with detailed information extracted from published studies summarized in Table 5. Their ages ranged from 62 to 82 years, with 5 males and 4 reporting a smoking history. Age and gender data were unavailable for 2 patients. Among them, 6 received specified EGFR-TKIs: 3 with first-generation (erlotinib or gefitinib), 1 with second-generation (afatinib), and 2 with third-generation (osimertinib). The overall treatment outcomes were as follows: 1 patient achieved a PR, and the rest maintained SD. The 3 patients on first-generation TKIs had a PFS of 6–48 months. The patient receiving afatinib achieved SD with a PFS of 6 months, while the 2 on osimertinib achieved a PFS of 12 and 16 months, respectively.

Table 5

Table 5. Clinical characteristics of 9 NSCLC patients harboring the EGFR p.L747S mutation in the published literature.

Published studies indicate that the p.L747S mutation can emerge as a resistance mechanism to prior gefitinib therapy, co-occurring with the original p.L858R mutation (5, 32). Specifically, 2 patients developed the secondary p.L747S mutation alongside the activating p.L858R mutation after treatment with gefitinib. These 2 patients (cases 5 and 9) carrying the p.L858R-L747S mutations achieved a partial radiographic response to erlotinib (150 mg/day) that lasted for 6 months.

Discussion

Due to the rarity of the p.L747P and p.L747S mutations in NSCLC, their precise incidence remains challenging to determine. A cohort study from Taiwan, China, identified only 12 cases among 2,031 EGFR-mutant LUAD patients, corresponding to an incidence of approximately 0.59% (18). In our study, 16 patients (0.74%) harbored these uncommon mutations, confirming their low prevalence in the EGFR-mutant population. Current evidence suggests that the EGFR p.L747P mutation is generally associated with intrinsic resistance to first- (e.g., erlotinib, gefitinib) and third-generation (e.g., osimertinib) EGFR inhibitors, while exhibiting greater sensitivity to second-generation (e.g., afatinib, dacomitinib) EGFR-TKIs (23, 26). Using a patient-derived xenograft model with the p.L747P mutation, Yang et al. predicted that second-generation TKIs have the strongest binding affinity to the p.L747P mutant protein. Cellular kinase inhibition assays and xenograft experiments further confirmed that afatinib potently inhibits p.L747P-mutant cells, significantly suppresses tumor growth (P<0.001), and reduces phosphorylation of EGFR and its downstream signaling pathways (15). Recent reports also indicate that afatinib demonstrates superior activity compared to other EGFR-TKIs in patients with p.L747P or p.L747S mutations (18, 35). In a study by Moran et al., 1 patient with the p.L747P mutation achieved a PR as the best response, received afatinib for 10 months, and was still on treatment at data cutoff. Another patient with the p.L747S mutation also achieved a PR, was treated with afatinib for 4.1 months, and continued to receive the drug at data cutoff (36). Similarly, Li et al. reported a patient carrying p.L747P who was treated with later-line dacomitinib and achieved partial remission, with a PFS of 17 months (23).

In contrast to these reports emphasizing second-generation TKI efficacy, and contrary to the structure-based prediction by Robichaux et al. which classifies p.L747P/p.L747S into a subgroup (PACC) with predicted sensitivity to second-generation TKIs (16), our clinical observations present a divergent narrative. In our cohort, none of the patients who received first- or second-generation TKIs achieved a tumor response. However, half of those treated with third-generation TKIs attained either a PR (lasting over 14 months) or SD (ranging from 12 to 40 months). This apparent discrepancy between preclinical prediction, prior case reports, and our findings necessitates careful interpretation within the specific context of our study. First, our cohort’s sample size is limited, and the observed benefit with third-generation TKIs was primarily in the form of disease stabilization. Second, and critically, our patient population exhibited considerable heterogeneity. It included individuals across different disease stages (early to advanced), with varying EGFR mutation profiles (isolated p.L747P/p.L747S vs. compound mutations coexisting with classic sensitizing alterations such as exon 19del or p.L858R), and diverse treatment histories (ranging from TKI-naïve to multiple prior lines). This heterogeneity, particularly the presence of co-existing sensitizing mutations in all p.L747S cases, likely constitutes a major confounding factor, potentially altering overall kinase dynamics and drug response, thereby limiting direct comparability of outcomes across different TKI classes. We hypothesize that these compound genotypes, rather than the isolated p.L747P/p.L747S mutation alone, may be a key determinant of the clinical outcomes observed with third-generation TKIs in our series. It is essential to distinguish this clinical observation from the underlying molecular mechanism, which remains speculative without functional validation.

Resistance to EGFR-TKIs is categorized as either primary or acquired. Primary resistance denotes the immediate ineffectiveness of therapy, while acquired resistance refers to disease progression following a period of clinical benefit. Although acquired resistance in advanced NSCLC patients with sensitive EGFR mutations is well-characterized, understanding of primary resistance remains limited (10, 37, 38). The p.L747S mutation is a rare alteration previously reported to confer TKI resistance, a finding supported by preclinical evidence (30). For instance, Costa et al. demonstrated that Ba/F3 cell lines expressing the p.L858R-p.L747S double mutation exhibit intermediate resistance to gefitinib, suggesting that p.L747S may attenuate drug-induced apoptosis (39). This preclinical finding of resistance for the p.L858R-p.L747S double mutant intriguingly contrasts with the clinical benefit we observed in our p.L747S patients (who also had co-existing sensitizing mutations) treated with third-generation TKIs, again highlighting the complex translation from model systems to patient outcomes. However, clinical outcomes can be complex. Among our 6 patients with p.L747S, 2 received third-generation TKI: 1 achieved SD and the other had a PR. This aligns with the findings of Chiba M et al., who reported that cell lines with uncommon secondary mutations like p.L858R-p.L747S retain sensitivity to irreversible EGFR-TKIs (40). Furthermore, Swami U et al. suggest that patients with coexisting TKI-sensitive and -resistant mutations may benefit from TKI therapy, potentially achieving extended survival, possibly through strategies such as dose escalation (30).

Notably, a substantial proportion of uncommon EGFR mutations cannot be detected by the PCR-based methods commonly used in clinical practice. Furthermore, variables such as tumor sample adequacy, quality, and heterogeneity further complicate these detection techniques. The combination of these factors results in inaccuracies and biases in the reported incidence of less common EGFR mutations (41). With these methods, the p.L747P mutation may be incorrectly identified as 19del or false-negative as wild type, resulting in incorrect information for the guidance of clinical management (23, 42, 43). Given the urgent need for more comprehensive genetic profiling in advanced NSCLC, the clinical introduction of NGS with broad gene panels has significantly improved the detection of uncommon EGFR alterations and enables accurate characterization of EGFR mutation status (44, 45). Therefore, for patients treated with a first-generation EGFR-TKI for a reported 19del, who develop primary resistance, NGS can be used to re-evaluate these cases, providing critical information for more personalized therapy (18). With the increasing clinical use of NGS, the identification of patients who carry the p.L747P mutation but were initially diagnosed with EGFR exon 19 deletion is expected to become more common (2).

Several key limitations of this study must be acknowledged. First, its retrospective nature, small sample size, and inherent biases associated with the literature review restrict the generalizability of the findings. Moreover, the pronounced clinical and molecular heterogeneity within our cohort-spanning diverse disease stages, EGFR mutation profiles (isolated versus compound), and prior treatment lines-hinders direct outcome comparison and complicates the attribution of efficacy to any specific TKI generation. Second, while potential mechanisms are proposed to explain the observed sensitivity to third-generation TKIs, such explanations remain speculative without functional validation. Therefore, future research should integrate two essential approaches: well-designed prospective studies that include larger, molecularly characterized cohorts with stratified analyses, and functional experiments using appropriate models to clarify the underlying biology and drug sensitivity of these rare EGFR variants.

Conclusions

NGS is recommended for accurate detection of rare EGFR p.L747P/p.L747S mutations, as PCR may misclassify them as 19del or wild-type. Third-generation EGFR-TKIs may provide modest disease control (SD/PR) and prolonged PFS in select patients with these mutations, particularly those with compound EGFR alterations or CNS metastases. However, these findings are preliminary due to small sample size and heterogeneity, and conclusions regarding “superior efficacy” should be viewed cautiously. Future prospective studies with larger cohorts and functional validation are needed to clarify the optimal TKI for this patient population.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

Ethical approval was not required for the studies involving humans because This study was a retrospective analysis of existing clinical and genomic data. All patient data were anonymized and de-identified prior to analysis. According to the national regulations (e.g., China’s “Ethical Review Measures for Biomedical Research Involving Humans”) and the institutional policy of West China Hospital, Sichuan University, ethical approval is waived for this type of non-interventional, retrospective study that uses anonymized data and poses minimal risk to participants. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were obtained from patients who provided written informed consent during their diagnosis and treatment at West China Hospital, Sichuan University. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

Author contributions

QH: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. JW: Conceptualization, Data curation, Formal analysis, Writing – original draft. JJ: Investigation, Project administration, Resources, Writing – review & editing. ZD: Conceptualization, Methodology, Validation, Writing – review & editing. KX: Project administration, Resources, Writing – review & editing. WZ: Formal analysis, Validation, Writing – review & editing. WL: Formal analysis, Validation, Writing – review & editing. BC: Formal analysis, Validation, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Sichuan Provincial Natural Science Foundation for Outstanding Young Scholars (Grant No.2024NSFJQ0051).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was used in the creation of this manuscript. During the preparation of this work, the authors used deepseek exclusively for the purpose of improving language, grammar, and readability. All scientific content, data analysis, interpretation of results, and clinical insights were solely generated by the human authors. The authors have thoroughly reviewed and edited the AI-generated content and take full responsibility for the entirety of the published work.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. (2014) 9:154–62. doi: 10.1097/jto.0000000000000033

PubMed Abstract | Crossref Full Text | Google Scholar

2. Yoshizawa T, Uchibori K, Araki M, Matsumoto S, Ma B, Kanada R, et al. Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity. NPJ Precis Oncol. (2021) 5:32. doi: 10.1038/s41698-021-00170-7

PubMed Abstract | Crossref Full Text | Google Scholar

3. Mitsudomi T and Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. (2007) 98:1817–24. doi: 10.1111/j.1349-7006.2007.00607.x

PubMed Abstract | Crossref Full Text | Google Scholar

4. Pao W and Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. (2010) 10:760–74. doi: 10.1038/nrc2947

PubMed Abstract | Crossref Full Text | Google Scholar

5. Costa DB, Nguyen KS, Cho BC, Sequist LV, Jackman DM, Riely GJ, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res. (2008) 14:7060–7. doi: 10.1158/1078-0432.Ccr-08-1455

PubMed Abstract | Crossref Full Text | Google Scholar

6. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. (2009) 361:947–57. doi: 10.1056/NEJMoa0810699

PubMed Abstract | Crossref Full Text | Google Scholar

7. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. (2012) 13:239–46. doi: 10.1016/s1470-2045(11)70393-x

PubMed Abstract | Crossref Full Text | Google Scholar

8. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. (2015) 16:141–51. doi: 10.1016/s1470-2045(14)71173-8

PubMed Abstract | Crossref Full Text | Google Scholar

9. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. (2018) 378:113–25. doi: 10.1056/NEJMoa1713137

PubMed Abstract | Crossref Full Text | Google Scholar

10. Huang J, Wang Y, Zhai Y, and Wang J. Non-small cell lung cancer harboring a rare EGFR L747P mutation showing intrinsic resistance to both gefitinib and osimertinib (AZD9291): A case report. Thorac Cancer. (2018) 9:745–9. doi: 10.1111/1759-7714.12637

PubMed Abstract | Crossref Full Text | Google Scholar

11. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. (2005) 97:339–46. doi: 10.1093/jnci/dji055

PubMed Abstract | Crossref Full Text | Google Scholar

12. Pallis AG, Voutsina A, Kalikaki A, Souglakos J, Briasoulis E, Murray S, et al. ‘Classical’ but not ‘other’ mutations of EGFR kinase domain are associated with clinical outcome in gefitinib-treated patients with non-small cell lung cancer. Br J Cancer. (2007) 97:1560–6. doi: 10.1038/sj.bjc.6604068

PubMed Abstract | Crossref Full Text | Google Scholar

13. Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. (2015) 16:830–8. doi: 10.1016/s1470-2045(15)00026-1

PubMed Abstract | Crossref Full Text | Google Scholar

14. Evans M, O’Sullivan B, Smith M, Hughes F, Mullis T, Trim N, et al. Large-scale EGFR mutation testing in clinical practice: analysis of a series of 18,920 non-small cell lung cancer cases. Pathol Oncol Res. (2019) 25:1401–9. doi: 10.1007/s12253-018-0460-2

PubMed Abstract | Crossref Full Text | Google Scholar

15. Yang G, Liu C, Hu J, Sun Y, Hu P, Liu L, et al. The lifted veil of uncommon EGFR mutation p.L747P in non-small cell lung cancer: molecular feature and targeting sensitivity to tyrosine kinase inhibitors. Front Oncol. (2022) 12:843299. doi: 10.3389/fonc.2022.843299

PubMed Abstract | Crossref Full Text | Google Scholar

16. Robichaux JP, Le X, Vijayan RSK, Hicks JK, Heeke S, Elamin YY, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature. (2021) 597:732–7. doi: 10.1038/s41586-021-03898-1

PubMed Abstract | Crossref Full Text | Google Scholar

17. He M, Capelletti M, Nafa K, Yun CH, Arcila ME, Miller VA, et al. EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin Cancer Res. (2012) 18:1790–7. doi: 10.1158/1078-0432.Ccr-11-2361

PubMed Abstract | Crossref Full Text | Google Scholar

18. Liang SK, Ko JC, Yang JC, and Shih JY. Afatinib is effective in the treatment of lung adenocarcinoma with uncommon EGFR p.L747P and p.L747S mutations. Lung Cancer. (2019) 133:103–9. doi: 10.1016/j.lungcan.2019.05.019

PubMed Abstract | Crossref Full Text | Google Scholar

19. Zhou T, Zhou X, Li P, Qi C, and Ling Y. EGFR L747P mutation in one lung adenocarcinoma patient responded to afatinib treatment: a case report. J Thorac Dis. (2018) 10:E802–e805. doi: 10.21037/jtd.2018.12.26

PubMed Abstract | Crossref Full Text | Google Scholar

20. Yu G, Xie X, Sun D, Geng J, Fu F, Zhang L, et al. EGFR mutation L747P led to gefitinib resistance and accelerated liver metastases in a Chinese patient with lung adenocarcinoma. Int J Clin Exp Pathol. (2015) 8:8603–6.

PubMed Abstract | Google Scholar

21. Wang YT, Ning WW, Li J, and Huang JA. Exon 19 L747P mutation presented as a primary resistance to EGFR-TKI: a case report. J Thorac Dis. (2016) 8:E542–546. doi: 10.21037/jtd.2016.05.95

PubMed Abstract | Crossref Full Text | Google Scholar

22. Messeha SS, Nezami MA, Hager S, and Soliman KFA. A rare presentation of a non-asian female with metastatic non-small-cell lung cancer harboring EGFR L747P mutation with clinical response to multi-targeted epigenetic and EGFR inhibition. Anticancer Res. (2022) 42:441–7. doi: 10.21873/anticanres.15502

PubMed Abstract | Crossref Full Text | Google Scholar

23. Li Y, Guo W, Jiang B, Han C, Ye F, and Wu J. Case Report: Dacomitinib is effective in lung adenocarcinoma with rare EGFR mutation L747P and brain metastases. Front Oncol. (2022) 12:863771. doi: 10.3389/fonc.2022.863771

PubMed Abstract | Crossref Full Text | Google Scholar

24. Li J, Zhu L, Stebbing J, and Peng L. Afatinib treatment in a lung adenocarcinoma patient harboring a rare EGFR L747P mutation. J Cancer Res Ther. (2022) 18:1436–9. doi: 10.4103/jcrt.jcrt_433_22

PubMed Abstract | Crossref Full Text | Google Scholar

25. Huang X, Yang Y, Wang P, Wang J, Chen S, Mao X, et al. A rare EGFR mutation L747P conferred therapeutic efficacy to both gefitinib and osimertinib: A case report. Lung Cancer. (2020) 150:9–11. doi: 10.1016/j.lungcan.2020.09.017

PubMed Abstract | Crossref Full Text | Google Scholar

26. Gerber DE, Mayer M, Gagan J, and von Itzstein MS. Systemic and intracranial efficacy of osimertinib in EGFR L747P-mutant NSCLC: case report. JTO Clin Res Rep. (2022) 3:100291. doi: 10.1016/j.jtocrr.2022.100291

PubMed Abstract | Crossref Full Text | Google Scholar

27. van der Wekken AJ, Stigt JA, and A’T Hart N. A novel EGFR mutation in exon 19 showed stable disease after TKI treatment. J Thorac Oncol. (2012) 7:e8. doi: 10.1097/JTO.0b013e31825ccae8

PubMed Abstract | Crossref Full Text | Google Scholar

28. Luo Y, Lin L, Shufeng C, Liu C, Li Z, and Liu K. Osimertinib treatment response in a patient with lung adenocarcinoma harboring two rare EGFR mutations: A case report. Oncol Lett. (2024) 28:501. doi: 10.3892/ol.2024.14634

PubMed Abstract | Crossref Full Text | Google Scholar

29. Grolleau E, Haddad V, Boissière L, Falchero L, and Arpin D. Clinical efficacy of osimertinib in a patient presenting a double EGFR L747S and G719C mutation. J Thorac Oncol. (2019) 14:e151–3. doi: 10.1016/j.jtho.2019.02.034

PubMed Abstract | Crossref Full Text | Google Scholar

30. Swami U, Ma D, and Zhang J. Response to erlotinib in a patient with compound EGFR L747S and exon 19 deletion. J Thorac Oncol. (2018) 13:e129–30. doi: 10.1016/j.jtho.2018.03.034

PubMed Abstract | Crossref Full Text | Google Scholar

31. He Q, Shi X, Zhu H, Yan J, and Yu XM. A case treated with Crizotinib after secondary MET amplification of A double Rare L747S and G719S EGFR mutation Pulmonary Sarcomatoid Carcinoma. Ann Oncol. (2020) 31:544–6. doi: 10.1016/j.annonc.2020.01.010

PubMed Abstract | Crossref Full Text | Google Scholar

32. Costa DB, Schumer ST, Tenen DG, and Kobayashi S. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J Clin Oncol. (2008) 26:1182–4. doi: 10.1200/jco.2007.14.9039

PubMed Abstract | Crossref Full Text | Google Scholar

33. Yamaguchi F, Fukuchi K, Yamazaki Y, Takayasu H, Tazawa S, Tateno H, et al. Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases. Oncol Lett. (2014) 7:357–60. doi: 10.3892/ol.2013.1705

PubMed Abstract | Crossref Full Text | Google Scholar

34. Coco S, Truini A, Vanni I, Genova C, Rosano C, Dal Bello MG, et al. Uncommon EGFR exon 19 mutations confer gefitinib resistance in advanced lung adenocarcinoma. J Thorac Oncol. (2015) 10:e50–52. doi: 10.1097/jto.0000000000000538

PubMed Abstract | Crossref Full Text | Google Scholar

35. Truini A, Starrett JH, Stewart T, Ashtekar K, Walther Z, Wurtz A, et al. The EGFR exon 19 mutant L747-A750>P exhibits distinct sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma. Clin Cancer Res. (2019) 25:6382–91. doi: 10.1158/1078-0432.Ccr-19-0780

PubMed Abstract | Crossref Full Text | Google Scholar

36. Moran T, Taus A, Arriola E, Aguado C, Dómine M, Rueda AG, et al. Clinical activity of afatinib in patients with non-small-cell lung cancer harboring uncommon EGFR mutations: A spanish retrospective multicenter study. Clin Lung Cancer. (2020) 21:428–436.e422. doi: 10.1016/j.cllc.2020.04.011

PubMed Abstract | Crossref Full Text | Google Scholar

37. Jin Y, Shao Y, Shi X, Lou G, Zhang Y, Wu X, et al. Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing. Oncotarget. (2016) 7:61755–63. doi: 10.18632/oncotarget.11237

PubMed Abstract | Crossref Full Text | Google Scholar

38. Stewart EL, Tan SZ, Liu G, and Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res. (2015) 4:67–81. doi: 10.3978/j.issn.2218-6751.2014.11.06

PubMed Abstract | Crossref Full Text | Google Scholar

39. Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. (2007) 4:1669–79. doi: 10.1371/journal.pmed.0040315

PubMed Abstract | Crossref Full Text | Google Scholar

40. Chiba M, Togashi Y, Bannno E, Kobayashi Y, Nakamura Y, Hayashi H, et al. Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A. BMC Cancer. (2017) 17:281. doi: 10.1186/s12885-017-3263-z

PubMed Abstract | Crossref Full Text | Google Scholar

41. O’Kane GM, Bradbury PA, Feld R, Leighl NB, Liu G, Pisters KM, et al. Uncommon EGFR mutations in advanced non-small cell lung cancer. Lung Cancer. (2017) 109:137–44. doi: 10.1016/j.lungcan.2017.04.016

PubMed Abstract | Crossref Full Text | Google Scholar

42. Vallée A, Le Loupp AG, and Denis MG. Efficiency of the Therascreen^® RGQ PCR kit for the detection of EGFR mutations in non-small cell lung carcinomas. Clin Chim Acta. (2014) 429:8–11. doi: 10.1016/j.cca.2013.11.014

PubMed Abstract | Crossref Full Text | Google Scholar

43. Seki Y, Fujiwara Y, Kohno T, Takai E, Sunami K, Goto Y, et al. Picoliter-droplet digital polymerase chain reaction-based analysis of cell-free plasma DNA to assess EGFR mutations in lung adenocarcinoma that confer resistance to tyrosine-kinase inhibitors. Oncologist. (2016) 21:156–64. doi: 10.1634/theoncologist.2015-0288

PubMed Abstract | Crossref Full Text | Google Scholar

44. Pepe F, De Luca C, Smeraglio R, Pisapia P, Sgariglia R, Nacchio M, et al. Performance analysis of SiRe next-generation sequencing panel in diagnostic setting: focus on NSCLC routine samples. J Clin Pathol. (2019) 72:38–45. doi: 10.1136/jclinpath-2018-205386

PubMed Abstract | Crossref Full Text | Google Scholar

45. Vigliar E, Malapelle U, de Luca C, Bellevicine C, and Troncone G. Challenges and opportunities of next-generation sequencing: a cytopathologist’s perspective. Cytopathology. (2015) 26:271–83. doi: 10.1111/cyt.12265

PubMed Abstract | Crossref Full Text | Google Scholar