Neoadjuvant befotertinib plus vorolanib in resectable stage II–IIIB EGFR-mutant NSCLC: a study protocol for the prospective, single-arm phase I/II trial

Introduction

As the leading cause of cancer-related death worldwide, lung cancer is predominantly composed of non-small cell lung cancer (NSCLC), which accounts for approximately 80–85% of all cases (1). Although surgery is the cornerstone of curative-intent treatment for resectable NSCLC, recurrence remains frequent, and long-term outcomes for patients with stage II–III disease are still suboptimal despite multimodality therapy (2,3). Previous neoadjuvant studies of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including first- and third-generation agents, have demonstrated promising radiographic responses and acceptable perioperative safety; however, pathological regression has remained limited (4,5). A recent real-world surgical series also reported favorable long-term outcomes and surgical feasibility following neoadjuvant TKI-based multimodal therapy in patients with stage III NSCLC harboring driver gene mutations, despite limited pathological regression (6). Evidence from the phase III NeoADAURA trial demonstrated that neoadjuvant osimertinib, either alone or combined with chemotherapy, significantly improved major pathological response (MPR) compared with chemotherapy alone in resectable stage II–IIIB EGFR-mutant NSCLC. Nevertheless, the absolute rates of pathological response remained modest, with MPR rates of only 25–26% and pathological complete response (pCR) rates of 4–9% in the osimertinib-containing arms (7). EGFR activation promotes tumor-cell proliferation and survival through downstream mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling, and may also enhance angiogenic signaling, including vascular endothelial growth factor (VEGF)-mediated tumor neovascularization. Conversely, VEGF/vascular endothelial growth factor receptor (VEGFR) signaling contributes to angiogenesis, vascular permeability, hypoxia, and a tumor-supportive microenvironment, which may limit the depth and durability of response to EGFR inhibition. Therefore, simultaneous blockade of EGFR-driven tumor-cell signaling and angiogenesis may suppress both tumor-intrinsic growth pathways and tumor-supportive vascular remodeling (8). Vorolanib was selected as the antiangiogenic partner because it is an orally available multi-target TKI with activity against VEGFR and platelet-derived growth factor receptor (PDGFR) signaling, providing a feasible fully oral combination strategy with befotertinib in the neoadjuvant setting. Therefore, this investigator-initiated trial is designed to evaluate whether neoadjuvant befotertinib plus vorolanib could improve pathological regression while preserving surgical feasibility and maintaining manageable toxicity in NSCLC patients with resectable stage II–IIIB EGFR-mutant disease. We present this article in accordance with the SPIRIT reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0382/rc).

Methods

Study design and setting

This is a prospective, single-center, open-label, single-arm phase I/II clinical trial sponsored by Zhejiang Cancer Hospital, which has been registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, identifier: ChiCTR2500103324). Eligible patients have histologically confirmed, clinically resectable stage II–IIIB NSCLC harboring sensitizing EGFR mutations (exon 19 deletion and/or exon 21 L858R mutations). The study consists of a phase I dose-escalation component followed by a phase II expansion component. This investigator-initiated clinical trial will be conducted in accordance with Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Zhejiang Cancer Hospital (approval number: IRB-2024-1227). Written informed consent will be obtained from all participants prior to enrollment.

Study endpoints

Primary endpoints

• Phase I: to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of neoadjuvant befotertinib plus vorolanib in patients with resectable stage II–IIIB EGFR-mutant NSCLC.
• Phase II: to evaluate the MPR rate following neoadjuvant therapy.

Secondary endpoints

To evaluate pCR, R0 resection rate, objective response rate (ORR), disease control rate (DCR), safety and tolerability of the regimen, disease-free survival (DFS), and overall survival (OS). Surgical feasibility outcomes include completion of planned surgery, interval from last study dose to surgery, delay to surgery, conversion to unresectability, surgical approach, extent of resection, completeness of resection, perioperative complications, postoperative hospital stay, and 30-day and 90-day postoperative mortality.

Study population

Eligibility criteria are listed in Table 1. Baseline evaluation includes prior treatment history, Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, physical examination, complete blood count, urinalysis, blood biochemistry, coagulation profile, tumor markers, pulmonary function testing, 12-lead electrocardiography, and pregnancy testing when applicable. Radiographic staging includes brain magnetic resonance imaging, contrast-enhanced chest and abdominal computed tomography (CT), and whole-body bone scintigraphy; positron emission tomography (PET)-CT may be performed when clinically indicated. Clinical staging follows the American Joint Committee on Cancer (AJCC) 8th edition. Baseline disease characteristics, including clinical stage, primary tumor size, nodal status, EGFR mutation subtype, and planned surgical approach, will be prospectively documented. Given the heterogeneity of resectable stage II–IIIB disease, final eligibility and resectability will be confirmed by multidisciplinary review before enrollment. Clinical nodal staging is predefined according to the AJCC 8th edition and the International Association for the Study of Lung Cancer (IASLC) lymph node map. Radiographically suspicious lymph nodes are defined as nodes with a short-axis diameter greater than 10 mm on contrast-enhanced CT and/or abnormal fluorodeoxyglucose uptake on PET-CT when PET-CT is performed. cN1 disease is defined as suspected involvement of ipsilateral peribronchial, hilar, or intrapulmonary lymph nodes. Because cN1 disease is often difficult to confirm pathologically before surgery, CT- and/or PET-CT-based radiographic criteria are accepted for cN1 classification. cN2 disease is defined as suspected involvement of ipsilateral mediastinal and/or subcarinal lymph nodes. For patients with suspected cN2 disease on CT or PET-CT, invasive mediastinal staging using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or other clinically appropriate procedures is recommended whenever feasible. Final clinical staging eligibility is confirmed after multidisciplinary review.

Treatment plan

One neoadjuvant cycle is defined as 21 days, and patients will receive two cycles (42 days in total). The 6-week neoadjuvant duration was selected to balance preliminary antitumor activity with surgical feasibility and perioperative safety. Because this is an early phase I/II study evaluating a novel fully oral combination regimen that includes the antiangiogenic agent vorolanib, a relatively conservative treatment duration was chosen to avoid unnecessary delay of curative-intent surgery and to reduce potential perioperative risks. The 21-day cycle length also allows tolerability and dose-limiting toxicities (DLTs) to be assessed in phase I before dose escalation or expansion. Befotertinib is initiated at 75 mg orally once daily for the first 21 days. If tolerated, the dose is increased to 100 mg once daily from day 22. Vorolanib is administered orally once daily according to the dose level assigned in phase I or the RP2D selected for phase II. Phase I uses a 3+3 design. Dose level A consists of befotertinib escalation from 75 mg once daily to 100 mg once daily after 21 days, combined with vorolanib 100 mg once daily. Dose level B uses the same befotertinib schedule combined with vorolanib 200 mg once daily. Each dose level enrolls at least 3 patients and up to 6 patients. Dose escalation, expansion, and study continuation are governed by the occurrence of DLTs, with the MTD/RP2D selected on the basis of observed tolerability. Phase II consists of a two-stage single-arm expansion. In stage 1, 10 patients are treated at the RP2D. After review of safety and preliminary efficacy, the study proceeds to stage 2, in which 17 additional patients are enrolled. Thus, 27 patients are planned for phase II.

Tumor response is evaluated by contrast-enhanced chest CT within 28 days after completion of neoadjuvant treatment according to RECIST version 1.1. Patients without disease progression who remain candidates for resection undergo standard preoperative assessment and radical surgery 4–6 weeks after the last study dose. This interval is selected as a conservative perioperative safety measure because the regimen includes vorolanib, an antiangiogenic agent with potential perioperative risks, including bleeding and wound-healing complications. In the current protocol, befotertinib and vorolanib are discontinued according to the same neoadjuvant treatment schedule to maintain protocol consistency and safety monitoring. Systematic mediastinal lymph node dissection is required according to tumor laterality. Surgical feasibility outcomes will be prospectively recorded, including completion of planned surgery, interval from the last study dose to surgery, delay beyond the protocol-specified 4–6-week surgical window, conversion to unresectability after neoadjuvant therapy, surgical approach, extent of resection, completeness of resection, perioperative complications, postoperative hospital stay, and 30-day and 90-day postoperative mortality. Completeness of resection will be categorized as R0, R1, or R2. These outcomes will be summarized descriptively. Resected specimens will undergo centralized pathological review for pathological response assessment, including MPR and pCR (Figure 1). Pathological response will be independently evaluated by two experienced thoracic pathologists who are blinded to radiographic response and clinical treatment information whenever feasible. Discrepancies will be resolved by consensus discussion or adjudicated by a third senior pathologist. MPR is defined as 10% or less residual viable tumor cells in the resected primary tumor. pCR is defined as the absence of residual viable tumor cells in both the primary tumor and resected lymph nodes. The percentages of residual viable tumor, necrosis, and stromal or treatment-related changes will be recorded using predefined standardized criteria for pathological regression assessment after neoadjuvant therapy.

Figure 1 Study flowchart of the investigator-initiated phase I/II trial of neoadjuvant befotertinib plus vorolanib in NSCLC patients with resectable stage II–IIIB EGFR-mutant disease. CT, computed tomography; EGFR, epidermal growth factor receptor; MPR, major pathological response; NSCLC, non-small cell lung cancer; pCR, pathological complete response; RP2D, recommended phase II dose; TKI, tyrosine kinase inhibitor.

Postoperative adjuvant therapy is not mandated by the protocol and is left to investigator discretion according to the pathological findings, postoperative recovery, patient preference, and contemporary standards of care (2). Acceptable postoperative management may include adjuvant EGFR-TKI therapy, including befotertinib when clinically appropriate and available, chemotherapy, radiotherapy, or combinations thereof. All postoperative treatments will be prospectively documented in the case report forms, including treatment type, indication, regimen, dose, start and end dates, treatment duration, dose modification, treatment interruption or discontinuation, and major treatment-related toxicities. These data will be summarized descriptively and incorporated into exploratory survival analyses.

Safety assessments

Safety assessments are performed on day 1 of each treatment cycle during neoadjuvant therapy and again 30 (±7) days after the last protocol treatment. Adverse events are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Given the antiangiogenic activity of vorolanib, adverse events of special interest will be prospectively monitored, including bleeding, hypertension, proteinuria, thromboembolic events, wound-healing complications, and perioperative complications. Safety monitoring includes vital signs, blood pressure, physical examination, complete blood count, liver and renal function tests, coagulation profile, urinalysis, and assessment of bleeding symptoms and wound-healing status. Clinically significant toxicities will be managed according to protocol-defined dose interruption, dose modification, treatment discontinuation, and supportive-care rules.

Sample size and statistical analysis

The total planned enrollment is 36 patients, with a maximum of 39 depending on phase I dose-escalation requirements. Phase I is expected to enroll 6–12 patients (9,10). For phase II, the sample size is based on a historical MPR rate of 8.9% with neoadjuvant chemotherapy and a target MPR improvement to 30% with the study regimen (11). This historical rate is used only for sample-size estimation and preliminary signal detection in this single-arm phase II component, rather than as a formal comparator for confirmatory efficacy testing. Because no concurrent control group is included, efficacy outcomes will be interpreted descriptively and considered hypothesis-generating. Using a two-sided alpha of 0.05 and 80% power, and allowing for a 10% dropout rate, 27 patients are planned for the phase II portion. Safety analyses will include all patients who receive at least one dose of study treatment. Efficacy outcomes, including MPR, pCR, ORR, DCR, and the R0 resection rate, will be presented descriptively as numbers and proportions. Predefined exploratory subgroup analyses will be conducted according to clinical stage, nodal status, and EGFR mutation subtype. Clinical stage subgroups will include stage II, IIIA, and IIIB disease, or stage II versus stage III when appropriate due to limited sample size. Nodal status subgroups will include cN0–1 versus cN2 disease, and EGFR mutation subgroups will include exon 19 deletion versus exon 21 L858R mutation. MPR, pCR, R0 resection rate, ORR, DCR, surgical feasibility outcomes, DFS, and OS will be summarized descriptively within these subgroups. These analyses will be exploratory and not powered for formal subgroup comparisons. Continuous data will be reported as mean ± standard deviation or median with interquartile range, where appropriate. DFS and OS will be analyzed using the Kaplan-Meier approach. Postoperative treatment patterns, including receipt of adjuvant EGFR-TKI therapy such as befotertinib, chemotherapy, and/or radiotherapy, will be summarized descriptively. When the number of events permits, exploratory subgroup or sensitivity analyses will be conducted according to postoperative treatment exposure. DFS and OS will be interpreted as exploratory endpoints because postoperative adjuvant therapy is not protocol-mandated, although it will be recommended according to institutional multidisciplinary standards and contemporary standards of care. This design preserves clinical flexibility but may introduce heterogeneity into DFS and OS analyses. Therefore, postoperative treatment patterns will be prospectively documented, and long-term survival outcomes will be interpreted as exploratory and hypothesis-generating. After surgery, patients will undergo follow-up with chest CT and serum tumor marker assessment every 3 months for the first 2 years, every 6 months during years 3 to 5, and once yearly thereafter until recurrence, death, withdrawal of consent, loss to follow-up, or study closure.

Discussion

This study addresses an important unmet need in resectable EGFR-mutant NSCLC. Although neoadjuvant EGFR-TKI therapy has shown promising radiographic activity, surgical feasibility, and encouraging long-term outcomes in selected real-world series, pathological response remains limited compared with the magnitude of tumor shrinkage typically observed on imaging (6,8,12). Combining a third-generation EGFR-TKI with antiangiogenic therapy may deepen response by simultaneously suppressing tumor-cell proliferation and tumor-associated angiogenesis.

The present trial has several notable design features. First, it prospectively evaluates a biomarker-defined population with potentially high sensitivity to targeted therapy. Second, the phase I/II design allows early dose optimization while preserving the ability to generate preliminary efficacy data. Third, the use of pathological response as the main phase II endpoint is clinically relevant in the neoadjuvant setting and may help bridge radiographic and surgical outcomes.

The study also has limitations. First, this is a single-arm, single-center trial with a modest sample size and no concurrent control group. The historical MPR assumption is used for sample-size estimation and signal-seeking purposes only, and any observed MPR or pCR benefit cannot be interpreted as definitive evidence of superiority over existing neoadjuvant strategies, including osimertinib-based therapy, chemotherapy, or chemoimmunotherapy. Therefore, pathological and survival outcomes from this study should be considered exploratory and hypothesis-generating, and future randomized multicenter trials will be required for comparative efficacy assessment. Another limitation is that both befotertinib and vorolanib are discontinued before surgery according to the same treatment schedule, with surgery planned 4–6 weeks after the last study dose. Although this interval was selected to prioritize perioperative safety in a regimen containing antiangiogenic therapy, withholding befotertinib during this period may reduce the duration of active EGFR inhibition before surgery. Future studies may explore differential discontinuation strategies, such as stopping vorolanib earlier while continuing EGFR-TKI therapy closer to surgery, provided that perioperative safety is carefully monitored. Third, the inclusion of resectable stage II–IIIB disease creates a heterogeneous study population with potential differences in baseline prognosis, tumor burden, nodal involvement, resectability, and pathological response. Although predefined exploratory subgroup analyses will be performed according to clinical stage, nodal status, and EGFR mutation subtype, the modest sample size limits the ability to draw definitive conclusions from these subgroup analyses. Nevertheless, the trial is expected to provide important feasibility and signal-seeking data to support future multicenter and potentially randomized studies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0382/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0382/prf

Funding: This work was supported by the Zhejiang Provincial Medical Health Science and Technology Project (No. 2025KY695); Natural Science Foundation of Zhejiang Province (No. LHDMY25H100001); and Qujiang District Life Oasis Public Service Center (No. XHJH-0013).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0382/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. This investigator-initiated clinical trial will be conducted in accordance with Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Zhejiang Cancer Hospital (approval number: IRB-2024-1227). Written informed consent will be obtained from all participants prior to enrollment.

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

References

1. Siegel RL, Kratzer TB, Wagle NS, et al. Cancer statistics, 2026. CA Cancer J Clin 2026;76:e70043. [Crossref] [PubMed]
2. Gao S, Li N, Wang S, et al. Lung Cancer in People's Republic of China. J Thorac Oncol 2020;15:1567-76. [Crossref] [PubMed]
3. Jiang W, Huang X, Tian J, Wu Y, et al. Revisiting The Dual Role of Radiotherapy in EGFR-mutant NSCLC: Implications for Therapeutic Combination Strategies. Oncol Commun 2026;1:5-7.
4. Blakely CM, Urisman A, Gubens MA, et al. Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study. J Clin Oncol 2024;42:3105-14. [Crossref] [PubMed]
5. Hosomi Y, Morita S, Sugawara S, et al. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol 2020;38:115-23. [Crossref] [PubMed]
6. Aoki M, Miyata R, Kamimura G, et al. Successful long-term outcome of neoadjuvant sequential targeted therapy and chemotherapy for stage III non-small cell lung carcinoma: 10 case series. Transl Lung Cancer Res 2024;13:3278-88. [Crossref] [PubMed]
7. He J, Tsuboi M, Weder W, et al. Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer. J Clin Oncol 2025;43:2875-87. [Crossref] [PubMed]
8. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625-35. [Crossref] [PubMed]
9. Liu M, Wang SJ, Ji Y. The i3+3 design for phase I clinical trials. J Biopharm Stat 2020;30:294-304. [Crossref] [PubMed]
10. Gao JJ, Pazdur R, Beaver JA. Reexamination of Patient Autonomy and Prior Therapies in Oncology Clinical Trial Eligibility Criteria. JAMA Oncol 2022;8:1-2. [Crossref] [PubMed]
11. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
12. 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]