Osimertinib as a neoadjuvant therapy in resectable EGFR-mutant non-small cell lung cancer: a real-world, multicenter retrospective study
Highlight box
Key findings
• Osimertinib displays encouraging possibilities as a neoadjuvant therapy for individuals with operable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer, exhibiting adequate efficacy and an acceptable safety record.
What is known and what is new?
• Neoadjuvant therapy facilitates surgical resection and long-term survival of patients with locally advanced lung cancer. And targeted therapy has emerged as the predominant treatment modality for EGFR-mutated metastatic lung cancer.
• Thirty-eight patients underwent surgery, and 36 (94.7%) underwent successful R0 resection. The objective responses rate was 60.5% (23/38). Out of 38 patients, sixteen (42.1%) experienced adverse events due to treatment in the neoadjuvant phase, with none of them reaching grade 3. The 1-year overall survival (OS) rate is 94.2%, while the 2-year OS rate is 89.2%. The 1-year disease-free survival (DFS) rate is 87.9%, and the 2-year DFS rate remains at 87.9%.
What is the implication, and what should change now?
• The phase III clinical trial is expected to provide further efficacy and safety results. Neoadjuvant therapy of osimertinib may be a better option for patients with locally advanced lung cancer with EGFR mutations.
Introduction
Lung cancer is one of the leading causes of cancer-related deaths worldwide, including China (1,2). The primary approach for treating operable non-small cell lung cancer (NSCLC) is surgical removal. Nevertheless, a lot of patients with operable NSCLC still relapse after full removal, with survival rates at 5 years varying from 36% to 60% for individuals with stage II–IIIA cancer (3). Adjuvant and neoadjuvant therapies present promising avenues for enhancing clinical outcomes in cases of resectable NSCLC (4).
Using neoadjuvant therapy, tumor size can be reduced and occult micrometastases are eradicated, improving the likelihood of radical resection and improving survival. Compared to undergoing surgery without chemotherapy, neoadjuvant chemotherapy has been shown to improve the likelihood of achieving R0 resection and improve long-term outcomes, leading to a 5% increase in survival rates at 5 years for resectable NSCLC patients (5). However, there was no significant variation in the overall or disease-free survival (DFS) rates when comparing preoperative and postoperative chemotherapy treatments (6).
Neoadjuvant therapy with a first- or second-generation tyrosine kinase inhibitor (TKI) is under consideration for individuals diagnosed with epidermal growth factor receptor (EGFR)-mutated NSCLC (7). In the phase 2 ASCENT study, 58% of stage III EGFR mutant NSCLC patients (11 out of 19) showed a positive response to neoadjuvant afatinib, and the median overall survival (OS) was 69.1 months (8). The administration of neoadjuvant afatinib for a duration of eight weeks did not impede the patients’ ability to undergo subsequent standard chemo-radiotherapy with or without surgical intervention. However, the persistent issue of a high frequency of central nervous system recurrence poses a significant challenge. Further research is needed to determine if EGFR-TKIs can serve as a neoadjuvant treatment for individuals with EGFR-mutated NSCLC.
During the FLAURA phase 3 study, osimertinib, a third-generation EGFR-TKI, demonstrated superior objective response rate (ORR) and reduced central nervous system (CNS) recurrence rates when compared to gefitinib or erlotinib, resulting in its approval for first-line therapy in EGFR-mutated advanced NSCLC (9). Hence, Osimertinib has been approved for use as a supplementary therapy in individuals with operable NSCLC who possess EGFR-sensitizing mutations. It is expected that osimertinib will be effective as neoadjuvant treatment. Although researches have investigated the safety and effectiveness of neoadjuvant osimertinib treatment for lung cancer, there is currently a lack of data on survival results (7).
The objective of this research is to assess the safety, feasibility, and possible survival advantages of administering neoadjuvant osimertinib therapy in individuals with operable NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-541/rc).
Methods
The study’s design and the individuals involved
This retrospective study was conducted at ten centers in mainland China, focusing on the patients with resectable lung adenocarcinoma with EGFR mutation who underwent neoadjuvant therapy with osimertinib followed by surgical resection between July 2018 and April 2023. Clinical records were reviewed in this real-world, multicenter study. The preoperative staging procedure included obtaining a sample of the tumor before treatment, a computed tomography (CT) scan of the chest with contrast enhancement, and/or positron emission tomography (PET)/CT scan. The eighth edition of the TNM classification system was utilized to establish the stage of the lung cancer tumors (10). The study has been documented in the Chinese Clinical Trial Registry with the registration number ChiCTR2100049954. The participants received 80 mg of osimertinib once daily before undergoing surgical resection.
Data collection and evaluation
The study gathered various clinical data, such as demographic characteristics, radiological and pathological evaluations of response, surgical specifics, complications, toxicity profiles, and prognostic outcomes. Radiologic reactions were categorized into complete response (CR, indicating absence of remaining illness), partial response (PR, demonstrating a reduction in size of at least 30%), progressive disease (PD, characterized by a size increase of at least 20% or new lesions), and stable disease (SD, suggesting a size change of less than 20% increase or less than 30% reduction). Pathologic complete response (pCR) and major pathologic response (MPR) were defined as the absence of viable tumor cells in the remaining tumor for pCR and the presence of 10% or fewer viable tumor cells for MPR. The surgical data encompassed details such as the degree of resection, surgical technique employed, duration of the operation, estimated blood loss, and length of postoperative hospitalization. The toxicity profiles were assessed by examining treatment-induced adverse events (AEs) and abnormal laboratory results according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (11).
Follow-up
Follow-up was conducted via outpatient appointments or phone conversations. One patient was lost to follow-up. The final follow-up visit was scheduled for December 2023.
Statistical analysis
Continuous variables were presented as either means and standard deviations or medians and interquartile ranges (IQRs), while categorical variables were displayed as counts and percentages. Statistical analyses were performed using STATA software.
Ethical statement
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee for Medical Research and New Medical Technology of Sichuan Cancer Hospital (No. SCCHEC-02-2022-103) and all participating institutions were informed and agreed with the study. Individual consent for this retrospective analysis was waived.
Results
Patient characteristics
Between July 31, 2018, and April 28, 2023, 38 people were enrolled and underwent neoadjuvant osimertinib therapy. Table 1 displays the demographic traits of the 38 individuals. Among the 38 participants, the median age was 57.5 years (IQR, 51–66.5 years), 12 (31.6%) participants were male, 7 (18.4%) participants had a history of smoking and 18 (47.4%) participants had a performance status of 1. The pathological type of all patients was adenocarcinoma. The preoperative clinical staging included 7 patients with stage I, 6 (15.8%) with stage II, 23 (60.5%) with stage III, and 2 (5.3%) with stage IV. Before surgery, next-generation sequencing analysis of the tissue samples revealed that 19 (50.0%) patients had the exon 19 deletion mutation, 14 (36.9%) had the exon 21 L858R mutation, 2 (5.3%) had the T790M mutation, 1 (2.6%) had the L861Q mutation, 1 (2.6%) had the 20 A763_Y764insFQEA mutation, and 1 (2.6%) had the p.L747-T751delinsP mutation.
Table 1
| Characteristics | Value (n=38) |
|---|---|
| Age (years) | 57.5 (51–66.5) |
| Sex | |
| Male | 12 (31.6) |
| Female | 26 (68.4) |
| Smoking | |
| Current | 7 (18.4) |
| Never | 31 (81.6) |
| Tumor histology | |
| Adenocarcinoma | 38 (100.0) |
| EGFR mutation | |
| Exon 19 deletion | 19 (50.0) |
| Exon 21 L858R mutation | 14 (36.8) |
| T790M | 2 (5.3) |
| L861Q | 1 (2.6) |
| 20 A763_Y764insFQEA | 1 (2.6) |
| p.L747-T751delinsP | 1 (2.6) |
| Sample source | |
| Tissue | 37 (97.4) |
| Plasma | 1 (2.6) |
| ECOG performance status | |
| 0 | 20 (52.6) |
| 1 | 18 (47.4) |
| BMI (kg/m2) | 22.23 (21.54–24.87) |
| Staging | |
| I | 7 (18.4) |
| II | 6 (15.8) |
| III | 23 (60.5) |
| IV | 2 (5.3) |
Data are presented as n (%) or median (interquartile range). EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative Oncology Group; BMI, body mass index.
Treatment regimens and response assessment
As a result of a multidisciplinary team meeting, the treatment plans for each patient were jointly determined by the attending surgeon and oncologist. Osimertinib was administered daily at an 80 mg dose. The middle dosage duration was 62.5 days with an IQR of 51 to 89.5 days, as shown in Table 2. Fifteen patients had SD, 22 had PR, and 1 had CR on preoperative CT evaluation, resulting in an ORR of 60.5%. PD was not observed in any patients. Figure 1 displays the waterfall diagram illustrating the preoperative maximum improvement in the target lesion for each patient treated with neoadjuvant osimertinib. After surgery, 30 out of 38 patients (78.9%) had a decrease in the severity of their condition, and 13 out of 23 patients (56.5%) with pN1–3 had a decrease in the severity of lymph node involvement. And there are 11 (28.9%) patients obtained MPR and only 1 (2.6%) of them obtained pCR.
Table 2
| Characteristics | Value (n=38) |
|---|---|
| Duration of neoadjuvant therapy (days) | 62.5 [51–89.5] |
| Time from neoadjuvant completion to resection (days) | 2 [1–8.5] |
| Hospitalization post-surgery (days) | 7 [5–9] |
| Surgery type | |
| VATS wedge resection | 2 (5.3) |
| VATS lobectomy | 25 (65.8) |
| Open lobectomy | 11 (28.9) |
| Surgical outcomes | |
| R0 resection | 36 (94.7) |
| R1 resection | 0 |
| R2 resection | 2 (5.3) |
| Intraoperative blood loss (mL) | 100 [50–187.5] |
| Operative duration (min) | 142.5 [101.5–180] |
Data are presented as n (%) or median (interquartile range). VATS, video-assisted thoracoscopic surgery.
Surgery-related information
All patients underwent surgery. The median time from neoadjuvant completion to resection was 2 days (IQR, 1–8.5 days; Table 2). Out of the 38 patients, 27 had video-assisted or robot-assisted thoracoscopic surgery, while 11 had open thoracotomy (Table 2). Thirty-six out of 38 patients underwent an R0 resection, resulting in a success rate of 94.7%, while 2 patients achieved an R2 resection, accounting for 5.3%. The median operative time was 142.5 min (IQR, 101.5–180 min). The median bleeding volume was 100 mL (IQR, 50–187.5 mL). There were no fatalities in the perioperative phase. The median postoperative hospital stay was 7 days (IQR, 5–9 days).
Toxicity profile
Out of 38 patients, 16 (42.1%) experienced AEs due to treatment in the neoadjuvant phase, with none of them reaching grade 3. The common adverse effects associated with treatment included skin irritation [14 (36.8%)], stomach upset [5 (13.2%)], mouth sores [1 (2.6%)] and increased liver enzyme levels [1 (2.6%)]. Of all 38 participants, 2 (5.3%) had diarrhea of grade 2 and 1 had elevated aminotransferase of grade 2. None of the participants encountered drug withdrawal or surgical delays as a result of the AEs.
Follow-up
A single patient was not able to be tracked for further monitoring. The remaining 37 patients underwent routine postoperative check-ups. The average duration of observation was 24.9 months, with a range of 2.5 to 63.7 months. The 1-year OS rate stands at 94.2%, while the 2-year OS rate is 89.2%. The 1-year DFS rate is 87.9%, and the 2-year DFS rate is 87.9% (Figure 2).
Discussion
Targeted therapy has emerged as the predominant treatment modality for EGFR-mutated metastatic lung cancer (12). ADAURA trial has shown that adjuvant osimertinib is a very successful treatment for individuals with surgically removed EGFR-mutated stage NSCLC, leading to a reduced chance of both local and distant cancer relapses, improved DFS of central nervous system and a reliable AEs record (13). The full understanding of osimertinib’s effectiveness as a neoadjuvant therapy for operable NSCLC remains unclear.
Four studies examining the efficacy of neoadjuvant osimertinib in treating surgically resectable EGFR-mutant NSCLC, consisting of two phase 2 trials (14,15) and 2 retrospective real-world analyses (16,17), demonstrated the feasibility and safety of this approach, with the ORR from 80% to 69.2%. Our study was the largest in terms of number of patients and the only one with survival data. Our study enrolled 38 patients with EGFR-mutated lung adenocarcinoma who underwent neoadjuvant osimertinib therapy, revealing a radiologic response assessment with an ORR of 60.5%. Regarding the evaluation of pathological response, neoadjuvant treatment with osimertinib demonstrated positive results, with 78.9% of individuals experiencing a decrease in pathological stage and 56.5% of patients with pN1–3 showing a reduction in lymph node involvement. 36 out of 38 patients underwent an R0 resection, resulting in a success rate of 94.7%, while 2 patients achieved an R2 resection, accounting for 5.3%. And there are 11 (28.9%) patients obtained MPR and only 1 (2.6%) of them obtained pCR. The 1-year OS rate stands at 94.2%, while the 2-year OS rate is 89.2%. The 1-year DFS rate is 87.9%, and the 2-year DFS rate is 87.9%.
It is worth noting that our study included seven patients with stage IB lung cancer, six patients with stage II lung cancer and two patients with stage IV lung cancer. The patients with stage IB/II lung cancer initially refused surgery and later requested it after receiving osimertinib treatment. And one patient with stage IV had a single adrenal metastasis and another patient with stage IV had a contralateral intrapulmonary metastasis, and both became eligible for surgery following osimertinib conversion treatment in line with current NCCN treatment guidelines. Due to the lack of research evidence on the duration of neoadjuvant osimertinib treatment, the duration of medication in this retrospective study was determined jointly by the patients and their doctors. Moreover, the varying treatment durations in the real world better reflect the safety and efficacy of third-generation TKIs.
The effectiveness of neoadjuvant therapy for resectable or potentially resectable NSCLC is well-established in the academic literature (18). There is a continuous discussion in the medical field regarding the most effective neoadjuvant treatment approach for NSCLC patients with EGFR-sensitive mutations, specifically focusing on whether targeted therapy or chemotherapy should be prioritized (19). No large phase III clinical trial has shown that EGFR-TKI therapy in neoadjuvant therapy definitively improves patient survival (20). Prior phase III randomized controlled studies have demonstrated that EGFR-TKI targeted treatment leads to a significant improvement in progression-free survival when compared to platinum-based chemotherapy for patients with EGFR-positive NSCLC (21). In addition, EGFR-TKIs appear to have better tolerability in comparison to chemotherapy (22). Despite the promising results from the trials, further research is necessary to fully assess the potential advantages of neoadjuvant EGFR-TKI therapy. Robust randomized trials assessing the impact of neoadjuvant EGFR-TKI treatment on OS can offer more conclusive data for informing clinical choices.
In the EMERGING-CTONG 1103 Phase II trial, neoadjuvant treatment with first-generation EGFR-TKI was compared to neoadjuvant chemotherapy using a comparative analysis. The trial results showed a positive response in reducing tumor volume when using neoadjuvant EGFR-TKI treatment (21). In comparison to the platinum-based doublet chemotherapy group, the neoadjuvant EGFR-TKI treatment group exhibited a notable rise in median PFS, with a hazard ratio of 0.39 (95% CI, 0.23 to 0.67; P<0.001) and a median PFS of 21.5 months.
Ongoing research is investigating the efficacy of third-generation EGFR-TKIs as neoadjuvant therapy compared to first- and second-generation EGFR-TKIs. Recent studies indicated that neoadjuvant osimertinib demonstrated a higher overall response rate when compared to first- or second-generation EGFR-TKIs for the treatment of patients with EGFR-mutated NSCLC (7). Osimertinib showed superior ORR when compared to erlotinib in multiple trials, such as the NCT01217619 trial (42.1%) (23), EMERGING-CTONG 1103 trial (54.1%) (22), the afatinib trial (70.2%) (24), and an icotinib trial (42%) (25). In addition, our research demonstrated a notably higher rate of R0 resection at 94.7% when compared to the rates of R0 resection reported in previous studies involving TKIs (ranging from 50% to 94%) as well as chemotherapy or chemoradiotherapy (ranging from 71% to 80%) (7,26,27). It is worth noting that the MPR rate of a previous study was 11% (7), while our study had an MPR rate of 28.9%. This phenomenon could potentially be explained by constraints in sample size, the specific EGFR-TKI utilized, or variances in subsequent therapies administered to the patients. The preoperative administration of osimertinib appears to be associated with a higher likelihood of achieving radiologic remission when compared to first-generation TKIs. The potential correlation between improved survival outcomes and increased ORR after neoadjuvant osimertinib therapy should be approached with caution.
Several limitations must be acknowledged in the current study. It is crucial to acknowledge that this research is looking back at past events, which may lead to selection bias. Additionally, the size of the sample was limited and the duration of the follow-up was brief. Thirdly, this multicenter study has varying durations of neoadjuvant osimertinib therapy and variability of postoperative adjuvant therapy, potentially causing bias in survival data.
Conclusions
The safety and possibility of using neoadjuvant osimertinib treatment for surgically resectable EGFR-mutated NSCLC have been shown. Additional extensive future research is needed to establish whether osimertinib as a neoadjuvant treatment is more effective than traditional TKIs or chemotherapy for these patients.
Acknowledgments
A part of the manuscript has been presented in 2021 WCLC (abstract number: P03.02) and 2024 ESTS (abstract number: P334).
Funding: This work was supported by grants from
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-541/rc
Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-541/dss
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-541/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-541/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee (EC) for Medical Research and New Medical Technology of Sichuan Cancer Hospital (No. SCCHEC-02-2022-103) and all participating institutions were informed and agreed with the study. Individual consent for this retrospective analysis was waived.
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
- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
- Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent 2024;4:47-53. [Crossref] [PubMed]
- Asamura H, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015;10:1675-84.
- Muthusamy B, Patil PD, Pennell NA. Perioperative Systemic Therapy for Resectable Non-Small Cell Lung Cancer. J Natl Compr Canc Netw 2022;20:953-61. [Crossref] [PubMed]
- Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71. [Crossref] [PubMed]
- MacLean M, Luo X, Wang S, et al. Outcomes of neoadjuvant and adjuvant chemotherapy in stage 2 and 3 non-small cell lung cancer: an analysis of the National Cancer Database. Oncotarget 2018;9:24470-9. [Crossref] [PubMed]
- Yu Z, Xu F, Zou J. Feasibility and safety of EGFR-TKI neoadjuvant therapy for EGFR-mutated NSCLC: A meta-analysis. Eur J Clin Pharmacol 2024;80:505-17. [Crossref] [PubMed]
- Piper-Vallillo A, Mak R, Lanuti M, et al. FP01.05 the ASCENT trial: a phase II study of neoadjuvant/adjuvant Afatinib, Chemoradiation +/- Surgery for Stage III EGFR-Mutant NSCLC. J Thorac Oncol 2021;16:S188.
- Cheng Y, He Y, Li W, et al. Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Target Oncol 2021;16:165-76. [Crossref] [PubMed]
- Detterbeck FC, Boffa DJ, Kim AW, et al. The Eighth Edition Lung Cancer Stage Classification. Chest 2017;151:193-203.
- Freites-Martinez A, Santana N, Arias-Santiago S, et al. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr (Engl Ed) 2021;112:90-2. [Crossref] [PubMed]
- Baik CS, Chamberlain MC, Chow LQ. Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer. J Thorac Oncol 2015;10:1268-78. [Crossref] [PubMed]
- Herbst RS, Wu YL, John T, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol 2023;41:1830-40. [Crossref] [PubMed]
- Lv C, Fang W, Wu N, et al. Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial. Lung Cancer 2023;178:151-6. [Crossref] [PubMed]
- Peled N, Roisman LC, Levison E, et al. Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study. Int J Radiat Oncol Biol Phys 2023;117:105-14. [Crossref] [PubMed]
- Hu Y, Ren S, Yang L, et al. Osimertinib as Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: A Case Series. Front Pharmacol 2022;13:912153. [Crossref] [PubMed]
- Liu B, Liu X, Xing H, et al. A new, potential and safe neoadjuvant therapy strategy in epidermal growth factor receptor mutation-positive resectable non-small-cell lung cancer-targeted therapy: a retrospective study. Front Oncol 2024;14:1349172. [Crossref] [PubMed]
- Chaft JE, Shyr Y, Sepesi B, et al. Preoperative and Postoperative Systemic Therapy for Operable Non-Small-Cell Lung Cancer. J Clin Oncol 2022;40:546-55. [Crossref] [PubMed]
- Wang C, Yuan X, Xue J. Targeted therapy for rare lung cancers: Status, challenges, and prospects. Mol Ther 2023;31:1960-78. [Crossref] [PubMed]
- Tsuboi M, Weder W, Escriu C, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol 2021;17:4045-55. [Crossref] [PubMed]
- Zhong WZ, Yan HH, Chen KN, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial. Signal Transduct Target Ther 2023;8:76. [Crossref] [PubMed]
- Zhong WZ, Chen KN, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol 2019;37:2235-45. [Crossref] [PubMed]
- Xiong L, Li R, Sun J, et al. Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study. Oncologist 2019;24:157-e64. [Crossref] [PubMed]
- Bian D, Sun L, Hu J, et al. Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study. Nat Commun 2023;14:4655. [Crossref] [PubMed]
- Wang T, Liu Y, Zhou B, et al. Effects of icotinib on early-stage non-small-cell lung cancer as neoadjuvant treatment with different epidermal growth factor receptor phenotypes. Onco Targets Ther 2016;9:1735-41. [Crossref] [PubMed]
- Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-56. [Crossref] [PubMed]
- Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer 2010;69:86-93. [Crossref] [PubMed]
