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Case Report

Combined Use of Gefitinib and Bevacizumab in Advanced Non-Small-Cell Lung Cancer with EGFR G719S/S768I Mutations and Acquired C797S Without T790M After Osimertinib: A Case Report and Literature Review

by
Wenting Lu
1,
Jiayi Sun
2,3,
Yawan Jing
2,3,
Jing Xu
1,
Chengming Huang
1,
Yi Deng
1,
Panwen Tian
2,3 and
Yalun Li
2,3,*
1
Department of Respiratory and Critical Care Medicine, Integrated Care Management Center, Institute of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China
2
Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Respiratory Health and Multimorbidity, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Center/Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu 610041, China
3
Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu 610041, China
*
Author to whom correspondence should be addressed.
Curr. Oncol. 2025, 32(4), 201; https://doi.org/10.3390/curroncol32040201
Submission received: 11 February 2025 / Revised: 19 March 2025 / Accepted: 27 March 2025 / Published: 28 March 2025
(This article belongs to the Section Thoracic Oncology)
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Abstract

:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in non-small-cell lung cancer (NSCLC) with sensitizing mutations. However, patients with uncommon EGFR mutations show variable responses, and resistance often develops. The C797S mutation is a common resistance mechanism after third-generation EGFR-TKI osimertinib therapy, with no standard treatment established. A 37-year-old Chinese woman with advanced NSCLC harboring EGFR G719S/S768I mutations developed an acquired C797S mutation without T790M after second- and third-generation EGFR-TKI therapy. She was treated with a combination of gefitinib and bevacizumab, achieving a partial response, particularly in liver metastases. Her overall survival exceeded 60 months. Gefitinib combined with bevacizumab demonstrates efficacy in managing NSCLC with uncommon EGFR mutations and overcoming acquired C797S resistance. This combination therapy offers a promising treatment strategy for patients with limited options after resistance to second- and third-generation EGFR-TKIs.

1. Introduction

Epidermal growth factor receptor (EGFR) mutations, a common oncogenic driver in non-small-cell lung cancer (NSCLC), can be targeted by EGFR tyrosine kinase inhibitors (TKIs) to improve patient prognosis. The EGFR exon 19 deletion and exon 21 L858R mutations are the most common activating and sensitizing EGFR mutations, accounting for 85–90% of EGFR mutation-positive cases [1]. Additionally, 10–15% of EGFR mutations are uncommon mutations [2], including EGFR 20ins, G719X, S768I, and L861Q. While limited information is available on the efficacy of EGFR-TKIs for these mutations, current clinical data suggest that they are more sensitive to second- and third-generation EGFR-TKIs than to first-generation EGFR-TKIs, excluding EGFR 20ins [3].
However, targeted therapy inevitably leads to acquired resistance. The most significant mechanism of resistance to first- and second-generation EGFR-TKIs is the acquired EGFR exon 20 p.T790M (T790M) [4]. Osimertinib, a third-generation EGFR-TKI, effectively targets the T790M mutation. However, following second-line treatment with osimertinib, 38% of patients developed resistance due to EGFR abnormalities, with the most common being the EGFR C797S mutation [5]. The T790M and C797S mutations in the EGFR gene are classified as either cis or trans based on their allelic relationship. The T790M-trans-C797S mutation responds to combined first- and third-generation EGFR-TKIs, whereas the T790M-cis-C797S mutation is resistant to all generations of EGFR-TKIs [6]. Based on previous research, patients with the C797S mutation may retain some sensitivity to first- or second-generation EGFR-TKI, such as gefitinib and afatinib [7]. The strategy to effectively overcome C797S-based osimertinib resistance involves fourth-generation EGFR-TKIs, most of which are currently in Phase I/II clinical trials. Therefore, there is no standard treatment for NSCLC patients with C797S mutation, particularly for those who develop this mutation without the T790M mutation after first-line therapy.
To date, there have been no reported cases of NSCLC with EGFR G719S/S768I/C797S triple mutations or their treatments. Here, we describe a patient diagnosed with stage IVB lung adenocarcinoma exhibiting uncommon EGFR mutations, G719S/S768I. After the progression of afatinib treatment, osimertinib was administered. Despite the absence of the T790M mutation, the C797S resistance mutation was identified. Ultimately, the combination of gefitinib and bevacizumab resulted in a partial response (PR) in the patient.

2. Case Presentation

In November 2019, a 37-year-old woman with no history of smoking was diagnosed with left lung adenocarcinoma with hilar mediastinal lymph node, left supraspinal lymph node, and extensive bone metastases (cT4N3M1c, stage IVB). Targetable mutation detection in tumor tissue using next-generation sequencing (NGS) by the GeneseeqPrime™ panel (Nanjing Geneseeq Technology Inc., Nanjing, China) [8] revealed EGFR exon 18 p.G719S mutation and EGFR exon 20 p.S768I mutation. The patient was administered with first-line afatinib (40 mg daily [qd] by mouth [po]) and subsequently developed new brain lesions (October 2020, Figure 1) after a 10-month period of stability. And the patient was then treated with second-line osimertinib (80 mg daily [qd] by mouth [po]). However, the patient’s brain lesions continued to deteriorate (February 2021, Figure 1). Due to the effectiveness of the third-generation EGFR-TKI treatment, third-line afatinib was reverted. Both brain and lung lesions remained stable for a duration of eight months. After developing resistance to afatinib, the patient exhibited disease progression in the brain lesions (November 2021, Figure 1), leading to the fourth-line almonertinib (220 mg daily [qd] by mouth [po]). After three months, the patient’s brain lesions showed increased progression (February 2022, Figure 1), prompting the initiation of fifth-line afatinib combined with pemetrexed. The patient expressed concerns regarding potential resistance to afatinib and requested a transition to osimertinib. After thorough evaluation and discussion, the clinical team concurred with proceeding with osimertinib as the subsequent line of therapy. The combination therapy resulted in stable disease (SD) and progression-free survival (PFS) of up to 21 months.
In November 2023, the patient developed multiple metastases in the chest wall, lungs, liver, and brain (Figure 1). Subsequently, a biopsy of a mass in the left chest wall confirmed the involvement of lung adenocarcinoma based on the pathological findings. NGS was performed with the patient’s tissue and revealed the retention of EGFR exon 18 p.G719S, EGFR exon 20 p.S768I, and the emergence of EGFR exon 20 p.C797S. Considering that patients may have developed resistance to osimertinib, the treatment was changed to gefitinib (250 mg daily [qd] by mouth [po]) combined with bevacizumab. After two months of treatment, the patient exhibited a significant reduction in the size of lung, brain, and liver metastases compared with their previous dimensions (January 2024, Figure 1). The lesions continued to show PR in June 2024. During combination therapy, the patient exhibited only grade 1 transaminase elevations, which improved with hepatoprotective treatment. No other adverse reactions, such as rash, proteinuria, or bleeding, were observed during this period. The patient continues to receive the combination therapy of gefitinib and bevacizumab. To date, the patient has achieved an overall survival (OS) of more than 60 months, with sustained clinical benefit and stable disease. The whole clinical course of treatment is shown in Figure 1. Antitumor responses were evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) [9].

3. Discussion

The EGFR T790M mutation alters the affinity of EGFR for ATP, significantly reducing the effectiveness of first- and second-generation EGFR-TKIs in competing for binding [10]. Osimertinib effectively targets both primary activating mutations and T790M resistance mutations [11]. However, resistance inevitably develops during treatment [12]. Common mechanisms of osimertinib resistance include the EGFR C797S mutation, MET amplification, T790M deletion, BRAF mutations, and KRAS mutations [13,14,15]. The EGFR C797S mutation is the primary cause of acquired resistance to osimertinib, often arising after the T790M mutation. Recently, C797S mutations have been documented in a few cases of T790M-negative patients following osimertinib treatment. It is well known that first-generation EGFR-TKIs are ineffective in patients with the T790M mutation. However, their efficacy in patients with C797S-positive and T790M-negative mutations remains uncertain. We summarized previous studies on the clinical outcomes of subsequent treatments in patients who developed C797S resistance mutations following osimertinib therapy [16,17,18,19,20]. In these cases, re-biopsies were performed on lung tissue, pleural effusion, plasma, and cerebrospinal fluid. The characteristics and clinical data of the patients are presented in Table 1. All patients received osimertinib and exhibited EGFR C797S-positive and T790M-negative resistance mutations. Notably, two patients with lung adenocarcinoma harboring the EGFR 19del and T790M mutations acquired the C797S mutation after failing osimertinib treatment and subsequently achieved partial remission with gefitinib.
Initially, we selected first-line targeted therapy with afatinib based on a pooled analysis of first-line studies showing favorable responses to afatinib in patients with G719X, S768I, and L861Q mutations, with a PFS comparable to that of common EGFR mutations [21,22]. Additionally, Passaro A et al. [23] demonstrated the promising efficacy of afatinib in a cohort of patients with brain metastases or rare EGFR mutations. In our study, the patient experienced therapeutic failure, as indicated by time to failure, after 10 and 8 months of afatinib treatment, consistent with findings from previous studies [21].
The patient in this case did not exhibit T790M mutation after progressing on afatinib treatment. However, the patient developed a C797S mutation during osimertinib treatment. The C797S mutation affects the cysteine residue at position 797 of the EGFR protein, and osimertinib demonstrated a strong antitumor effect by covalently binding to EGFR 797 cysteine [7,24]. Unfortunately, the C797S mutation blocks this binding, leading to further acquired resistance [25]. The case reported by Rangachari et al. [7,26] showed that in the presence of the C797S mutation alone, without T790M, resistant NSCLC patients may still retain sensitivity to gefitinib. The in vitro results presented by Niederst et al. [6] showed that EGFR Del19/C797S-positive and T790M-negative cell lines were resistant to third-generation EGFR-TKIs but remained sensitive to gefitinib. This may be due to the fact that the first-generation EGFR-TKI is primarily a reversible, non-selective inhibitor with a quinoline–amine structural motif that is not dependent on the cysteine at 797 to inhibit EGFR [24]. Consequently, first-generation EGFR-TKIs, such as gefitinib, still exert an inhibitory effect on the C797S mutation.
Studies have demonstrated that following the development of resistance to EGFR-TKIs, the level of tumor vascular endothelial growth factor (VEGF) increases [27], reducing tumor cell dependence on the EGFR signal and increasing dependence on the VEGF pathway. Preclinical studies have shown that an overactive VEGF/VEGFR pathway and tumor angiogenesis play a crucial role in the development of resistance to EGFR-TKIs. Bevacizumab, a monoclonal antibody that inhibits VEGF, has been utilized in various cancers due to its ability to suppress tumor angiogenesis. Studies indicate that bevacizumab can lead to significant improvements in PFS when used as a single agent, particularly in patients who cannot tolerate other chemotherapy options [28].
A previous Phase II clinical study showed that bevacizumab combined with first-generation EGFR-TKI significantly prolonged PFS in patients with NSCLC carrying EGFR mutations [29]. The combination of bevacizumab with an EGFR-TKI may enhance antitumor efficacy by targeting distinct pathogenic pathways, including angiogenesis and EGFR activation [30]. Additionally, in cases of tertiary C797S mutation, reintroducing a first-generation EGFR-TKI can still target the original sensitive EGFR mutation, even in the absence of T790M [16]. Thus, the dual targeting of the VEGF and EGFR pathways may effectively prevent drug resistance [31]. This is evidenced by our clinical case, which demonstrated the effectiveness of combining gefitinib, a first-generation EGFR-TKI, with bevacizumab in treating the EGFR C797S mutation following progression on the third-generation EGFR-TKI osimertinib.
Although gefitinib is typically well tolerated, it is associated with several adverse effects, including rash, diarrhea, and liver function abnormalities [32]. In addition, bevacizumab may lead to potential complications such as hypertension, bleeding, and gastrointestinal perforation [33]. The concomitant use of these two agents could increase the incidence of adverse events. Nevertheless, data from a Phase II clinical trial conducted in Japan indicated that serious adverse events associated with the combination of gefitinib and bevacizumab included grade 3 rash, hypertension, elevated aspartate aminotransferase and alanine aminotransferase, proteinuria, intracranial bleeding, and grade 4 gastrointestinal perforation [34]. Notably, no treatment-related deaths were reported. Fortunately, the patient in this case did not experience any of the serious adverse reactions, but close monitoring is still necessary during the combination therapy.
The EGFR C797S mutation is a key driver of resistance to third-generation EGFR-TKIs, making the development of next-generation inhibitors crucial for NSCLC treatment. Several fourth-generation EGFR-TKIs are currently in clinical trials. Although BLU-945 was one of the most advanced fourth-generation EGFR-TKIs [35,36], it was discontinued due to its dose-limiting toxicity and limited clinical benefit. EAI045, which targets the EGFR activator subunit, has proven ineffective as a monotherapy in blocking EGFR-driven cell proliferation, though it demonstrates significant antitumor activity in vitro and in animal models when combined with cetuximab [37,38]. Additionally, BDTX-1535, an orally bioavailable, potent, selective, and irreversible allosteric EGFR inhibitor, has shown promising preliminary efficacy and durability in Phase II trials in patients with relapsed or refractory EGFR-mutant NSCLC [39,40]. These agents offer novel therapeutic options with the potential to overcome resistance to third-generation EGFR-TKIs in NSCLC and other lung cancers.
For patients who develop a C797S mutation without a concurrent T790M mutation following treatment with EGFR-TKIs, the range of effective therapeutic options remains limited. In this case, while the patient exhibited PR to the combination of gefitinib and bevacizumab, the assessment of efficacy and the duration of treatment were relatively brief. It is therefore not possible to ascertain with certainty the precise efficacy of this combination therapy. Further studies with extended follow-up periods, along with overall survival and quality of life data, are required to evaluate the potential of this combination therapy in such cases.

4. Conclusions

In summary, we reported the clinical benefit of gefitinib combined with bevacizumab in a case characterized by EGFR G719S and S768I mutations/T790M negativity/C797S mutation-mediated resistance to osimertinib. Currently, treatment options for osimertinib-induced C797S mutation resistance are limited. This combination treatment may offer a potential new strategy.

Author Contributions

Conceptualization, W.L. and Y.L.; methodology, W.L., P.T. and Y.L.; software, W.L.; validation, P.T. and Y.L.; formal analysis, W.L., P.T. and Y.L.; investigation, W, L., J.S., Y.J., J.X., C.H. and Y.D.; resources, P.T. and Y.L.; data curation, W.L., J.S., Y.J., J.X., C.H. and Y.D.; writing—original draft preparation, W.L. and Y.L.; writing—review and editing, W.L., J.S., Y.J., J.X., C.H., Y.D., P.T. and Y.L.; visualization, W.L. and Y.L.; supervision, P.T. and Y.L.; project administration, W.L., P.T. and Y.L.; funding acquisition, P.T. and Y.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82470099 to Y Li, No. 82473213 to P Tian, 92159302 to W Li), Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0522806/2024ZD0522800 to P Tian, 2024ZD0522801 to Y Li, 2024ZD0522806 to W Lu).

Institutional Review Board Statement

This study was conducted in accordance with the principles of the Declaration of Helsinki, and the patient provided written informed consent. IRB approval is not required at our institution for case-report studies.

Informed Consent Statement

Written informed consent was obtained from the patient for the anonymized information and the accompanying images to be published in this article.

Data Availability Statement

All data underlying the findings of this study are available within this publication. Patient data from the West China Hospital in Sichuan University have been anonymized to ensure confidentiality. Due to ethical and legal restrictions related to data protection regulations, raw patient data cannot be shared publicly. Requests for further information may be directed to the corresponding author.

Acknowledgments

The authors kindly thank the physicians, nurses, and other staff at the hospital who assisted with the study.

Conflicts of Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abbreviations

The following abbreviations are used in this manuscript:
EGFREpidermal growth factor receptor
EGFR-TKIsEpidermal growth factor receptor tyrosine kinase inhibitors
NSCLCNon-small-cell lung cancer
PRPartial response
NGSNext-generation sequencing
SDStable disease
PFSProgression-free survival
OSOverall survival
VEGFVascular endothelial growth factor

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Curroncol 32 00201 g001
Figure 1. A summary of the patient’s clinical course. The upper panel shows the various treatments the patient received for EGFR-mutated non-small-cell lung cancer as well as the duration of each treatment. Asterisks indicate the time points for the response assessments. Green arrows indicate the primary lesion, while red arrows indicate the metastatic lesions. Genetic testing results for EGFR of the various tissue biopsies are shown below the corresponding CT images with their minor allele frequency. (A) Baseline chest CT scan and head MRI at diagnosis in November 2019. (B) SD on afitinib treatment in February 2020. (C) Lung lesion SD but head lesions PR on afitinib treatment in October 2020. (D) Lung lesion SD but head lesions PR on osimertinib treatment in February 2021. (E) SD on afitinib treatment in April 2021. (F) Lung lesion SD but head lesions PR on afitinib treatment in November 2021. (G) Lung lesion SD but head lesions PR on almonertinib in February 2022. (H) SD on afitinib treatment in May 2022. (I) Liver lesion and head lesion PD on osimertinib combined with pemetrexed treatment in November 2023. (J) PR on gefitinib and bevacizumab treatment in January 2024. Abbreviations: PFS, progression-free survival; PC, pemetrexed + cisplatin; SRT, stereotactic radiotherapy; Pem, pemetrexed; NTB, nab-paclitaxel + tirellizumab + bevacizumab; Bev, bevacizumab; SD, stable disease; PD, progressive disease; PR, partial response.
Figure 1. A summary of the patient’s clinical course. The upper panel shows the various treatments the patient received for EGFR-mutated non-small-cell lung cancer as well as the duration of each treatment. Asterisks indicate the time points for the response assessments. Green arrows indicate the primary lesion, while red arrows indicate the metastatic lesions. Genetic testing results for EGFR of the various tissue biopsies are shown below the corresponding CT images with their minor allele frequency. (A) Baseline chest CT scan and head MRI at diagnosis in November 2019. (B) SD on afitinib treatment in February 2020. (C) Lung lesion SD but head lesions PR on afitinib treatment in October 2020. (D) Lung lesion SD but head lesions PR on osimertinib treatment in February 2021. (E) SD on afitinib treatment in April 2021. (F) Lung lesion SD but head lesions PR on afitinib treatment in November 2021. (G) Lung lesion SD but head lesions PR on almonertinib in February 2022. (H) SD on afitinib treatment in May 2022. (I) Liver lesion and head lesion PD on osimertinib combined with pemetrexed treatment in November 2023. (J) PR on gefitinib and bevacizumab treatment in January 2024. Abbreviations: PFS, progression-free survival; PC, pemetrexed + cisplatin; SRT, stereotactic radiotherapy; Pem, pemetrexed; NTB, nab-paclitaxel + tirellizumab + bevacizumab; Bev, bevacizumab; SD, stable disease; PD, progressive disease; PR, partial response.
Curroncol 32 00201 g001
Table 1. Clinical characteristics and treatment outcomes of patients with NSCLC with acquired EGFR C797S after osimertinib resistance.
Table 1. Clinical characteristics and treatment outcomes of patients with NSCLC with acquired EGFR C797S after osimertinib resistance.
ArticleAge/GenderSmoking StatusHistologic TypeEGFR MutationEGFR-TKIResponse/PFS (m)Re-Biopsy SpecimenResistance MutationsSecond TreatmentResponse/PFS (m)Re-Biopsy SpecimenResistance MutationsThird TreatmentResponse/PFS (m)
Chic N 2017 [18]78/FNeverAC19DelAfatinibPR/30Lesion biopsyT790MOsimertinibPR/8Lesion biopsyT790M- C797S+GefitinibPR/NA
Enrico D 2023 [14]66/MFormerAC19Del, T790MOsimertinibPR/21Body fluidsNAOsimertinibSD/8BronchoscopyT790M- C797S+GefitinibPR/4
Goldberg ME 2018 [15]53/FNAAC19DelAfatinibPR/8Lesion biopsy T790MOsimertinibPR/5Lesion biopsy T790M- C797S+Osimertinib + GefitinibSD/5
Goldberg ME 2018 [15]41/MNAAC19DelAfatinibPR/23Liquid biopsyT790MOsimertinibPR/8Lesion biopsy T790M- C797S+A cMet inhibitor (clinical trial)NA
Russo A 2023 [16]46/FNeverACL858ROsimertinibPR/7Lesion biopsyC797SAfatinibPD/2Liquid biopsyC797SCar + Gem SD/3
Wang M 2021 [17]48/FNAAC19DelOsimertinibPR/18Cerebrospinal fluidC797SErlotinib + Pem + Cis +BevSD/4NAC797SErlotinibSD/10
Abbreviations: NSCLC: non-small-cell lung cancer; EGFR, Epidermal growth factor receptor; EGFR-TKI, Epidermal growth factor receptor tyrosine kinase inhibitors; PFS, progression-free survival; PR, partial response; SD, stable disease; AC: adenocarcinoma; Pem: pemetrexed; Cis: cisplatin; Bev: bevacizumab; Car: carboplatin; Gem: gemcitabine; NA: not applicable.
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MDPI and ACS Style

Lu, W.; Sun, J.; Jing, Y.; Xu, J.; Huang, C.; Deng, Y.; Tian, P.; Li, Y. Combined Use of Gefitinib and Bevacizumab in Advanced Non-Small-Cell Lung Cancer with EGFR G719S/S768I Mutations and Acquired C797S Without T790M After Osimertinib: A Case Report and Literature Review. Curr. Oncol. 2025, 32, 201. https://doi.org/10.3390/curroncol32040201

AMA Style

Lu W, Sun J, Jing Y, Xu J, Huang C, Deng Y, Tian P, Li Y. Combined Use of Gefitinib and Bevacizumab in Advanced Non-Small-Cell Lung Cancer with EGFR G719S/S768I Mutations and Acquired C797S Without T790M After Osimertinib: A Case Report and Literature Review. Current Oncology. 2025; 32(4):201. https://doi.org/10.3390/curroncol32040201

Chicago/Turabian Style

Lu, Wenting, Jiayi Sun, Yawan Jing, Jing Xu, Chengming Huang, Yi Deng, Panwen Tian, and Yalun Li. 2025. "Combined Use of Gefitinib and Bevacizumab in Advanced Non-Small-Cell Lung Cancer with EGFR G719S/S768I Mutations and Acquired C797S Without T790M After Osimertinib: A Case Report and Literature Review" Current Oncology 32, no. 4: 201. https://doi.org/10.3390/curroncol32040201

APA Style

Lu, W., Sun, J., Jing, Y., Xu, J., Huang, C., Deng, Y., Tian, P., & Li, Y. (2025). Combined Use of Gefitinib and Bevacizumab in Advanced Non-Small-Cell Lung Cancer with EGFR G719S/S768I Mutations and Acquired C797S Without T790M After Osimertinib: A Case Report and Literature Review. Current Oncology, 32(4), 201. https://doi.org/10.3390/curroncol32040201

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