Consolidation thoracic radiotherapy following quadruple induction with benmelstobart, anlotinib, and chemotherapy for extensive-stage small cell lung cancer: rationale and protocol of a phase II study
Study Protocol

Consolidation thoracic radiotherapy following quadruple induction with benmelstobart, anlotinib, and chemotherapy for extensive-stage small cell lung cancer: rationale and protocol of a phase II study

Yuntao Zhou1,2, Hui Zhu2, Siyi Yang2, Jialei Liu2, Miao Yu2, Jifeng Sun3, Chengwen Yang2, Yong Cui4, Ningbo Liu1,2

1Department of Radiotherapy, Beijing Friendship Hospital, Capital Medical University, Beijing, China; 2Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China; 3Department of Radiotherapy, Tianjin Cancer Hospital Airport Hospital, Tianjin, China; 4Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China

Contributions: (I) Conception and design: N Liu, Y Cui, Y Zhou; (II) Administrative support: Y Cui, N Liu; (III) Provision of study materials or patients: M Yu, J Sun; (IV) Collection and assembly of data: H Zhu, S Yang, J Liu; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Ningbo Liu, MD, PhD. Department of Radiotherapy, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China; Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. Email: liuningbo@tjmuch.com; Yong Cui, MD, PhD. Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China. Email: cywork1@sina.com.

Background: Extensive-stage small cell lung cancer (ES-SCLC) remains a highly aggressive malignancy with limited survival outcomes. While first-line immune checkpoint inhibitors combined with platinum-based chemotherapy have improved survival, the benefit is modest. Emerging evidence supports the integration of anti-angiogenic therapy and thoracic radiotherapy (TRT) to enhance systemic and local control. However, a comprehensive multimodal regimen combining chemotherapy, immunotherapy, anti-angiogenic therapy, and TRT has not been systematically evaluated. This study aims to assess the safety, feasibility, and preliminary efficacy of a multimodal treatment strategy involving induction with benmelstobart [an anti-programmed death-ligand 1 (PD-L1) antibody], platinum-etoposide chemotherapy, and anlotinib, followed by consolidation with benmelstobart, anlotinib, and sequential TRT in patients with untreated ES-SCLC.

Methods: This is a prospective, single-center, single-arm, phase II, open-label trial conducted at Tianjin Medical University Cancer Institute & Hospital. Twenty-five patients with histologically confirmed, treatment-naive ES-SCLC and measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 will be enrolled. The regimen consists of—induction phase: 4 cycles of benmelstobart (1,200 mg IV q21d), carboplatin (area under the curve 5) or cisplatin (75–80 mg/m2) on day 1, etoposide (100 mg/m2 IV days 1–3), and oral anlotinib (12 mg once daily, 2 weeks on/1 week off); consolidation phase: 2 cycles of benmelstobart, anlotinib, and TRT (25 Gy in 5 daily fractions of 5 Gy each, administered only during the first consolidation cycle); maintenance phase: benmelstobart plus anlotinib until progression, unacceptable toxicity, or clinical deterioration. The co-primary endpoints are progression-free survival (PFS) and incidence of grade ≥3 treatment-related adverse events (TRAEs). Secondary endpoints include objective response rate and overall survival. Safety will be evaluated in all treated patients.

Discussion: This trial will provide critical preliminary evidence on the safety, feasibility, and efficacy of integrating short-course TRT into a quadruple chemo-immuno-antiangiogenic backbone for ES-SCLC. The results are expected to inform the design of future multicenter, randomized phase III trials and potentially establish a novel multimodal paradigm for first-line management.

Trial Registration: ClinicalTrials.gov identifier: NCT07358676. Protocol version: version 1.0, April 03, 2025

Keywords: Extensive-stage small cell lung cancer (ES-SCLC); consolidative radiotherapy; benmelstobart; anlotinib; phase II clinical trial

Submitted Jan 27, 2026. Accepted for publication Apr 14, 2026. Published online May 15, 2026.

doi: 10.21037/tlcr-2026-1-0114

Introduction

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with a dismal prognosis. Approximately two-thirds of patients are diagnosed with extensive-stage SCLC (ES-SCLC), and the 5-year survival rate remains only 3–5% (1). In recent years, immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy have significantly improved survival outcomes in ES-SCLC, establishing a new standard of care for first-line treatment (2-6). However, despite this historic advance, the improvement in median overall survival (OS) remains modest, typically limited to 2–4 months, reflecting the intrinsic limitations of systemic therapy alone (2-4,7-9). Recent efforts to further intensify first-line treatment, including maintenance lurbinectedin plus atezolizumab (IMforte) and the addition of the DLL3-targeting T-cell engager tarlatamab to first-line chemoimmunotherapy (DeLLphi-303), have demonstrated meaningful survival benefits (10,11). Nevertheless, even with enhanced systemic disease control in the first-line setting, intrathoracic progression remains a predominant pattern of treatment failure, underscoring the critical importance of integrating thoracic radiotherapy (TRT) to improve local control and maximize the overall benefit of first-line multimodal treatment strategies.

Previous attempts to incorporate cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or other ICIs into chemo-immunotherapy regimens have failed to yield positive results in multiple phase III trials (12-14). Meanwhile, anti-angiogenic therapy has emerged as a promising approach in ES-SCLC. Several phase II studies have demonstrated that sequential maintenance with anti-angiogenic therapy following initial chemo-immunotherapy can provide additional survival benefits (15,16). The phase III BEAT-SC trial showed that the quadruplet regimen of atezolizumab, bevacizumab, and chemotherapy significantly prolonged progression-free survival (PFS) compared to the triplet regimen: 5.7 vs. 4.4 months [P=0.006, hazard ratio (HR) =0.70] (17). Similarly, results from the ETER701 study indicated that the combination of benmelstobart, anlotinib, and chemotherapy in first-line ES-SCLC achieved a median PFS (mPFS) of 6.9 months in the quadruplet arm vs. 4.2 months in the standard chemotherapy group, with median OS (mOS) of 19.3 vs. 11.9 months, respectively, highlighting the promising potential of combining chemotherapy, immunotherapy, and anti-angiogenic therapy (18). In limited-stage SCLC (LS-SCLC), benmelstobart combined with anlotinib also showed encouraging clinical activity and a manageable safety profile among patients who had not experienced disease progression following initial first-line therapy. With a median follow-up of 15.13 months, the 12-month PFS rate was 86.7% [95% confidence interval (CI): 71.1–100.0%], the 12-month OS rate was 100%, and the disease control rate (DCR) reached 100% (19).

Radiotherapy, as a cornerstone of local therapy, plays a critical role in the comprehensive management of SCLC. Prior evidence has shown that consolidative TRT reduces the risk of local recurrence and improves survival (20). In the era of immunotherapy, the immunomodulatory properties of radiotherapy have attracted growing interest. Multiple prospective studies suggest that integrating TRT—either sequentially or concurrently—into systemic immunotherapy-based regimens may enhance antitumor efficacy, with acceptable safety profiles and potential synergistic effects (21-24).

While quadruplet regimens combining chemotherapy, immunotherapy, and anti-angiogenic agents have demonstrated early clinical promise, and accumulating data support the integration of TRT, a comprehensive multimodal strategy integrating platinum-based chemotherapy, immunotherapy, anti-angiogenic therapy, and TRT has not been prospectively evaluated in ES-SCLC. This study aims to assess the safety, feasibility, and preliminary efficacy of induction therapy with benmelstobart, chemotherapy, and anlotinib followed by consolidation with benmelstobart, anlotinib, and TRT in patients with ES-SCLC, providing a rationale for future individualized, multimodal treatment strategies.

Trial design

This is a prospective, single-center, single-arm, phase II, open-label clinical trial enrolling patients with untreated ES-SCLC who are suitable for first-line platinum-based chemotherapy and immunotherapy. This trial aims to evaluate the safety and efficacy of induction therapy with benmelstobart plus chemotherapy and anlotinib, followed by sequential consolidation therapy with benmelstobart, anlotinib, and TRT in patients with ES-SCLC (Figure 1). A summary of scheduled assessments is presented in Table S1.

Figure 1 Trial flowchart. d, day; ECOG, Eastern Cooperative Oncology Group; ES-SCLC, extensive-stage small cell lung cancer; PD, progressive disease; PS, performance status.

Objectives

The co-primary endpoints are PFS and the incidence of grade ≥3 treatment-related adverse events (TRAEs). Secondary endpoints include objective response rate (ORR) and OS, with detailed definitions provided in Table 1. We present this article in accordance with the SPIRIT reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0114/rc).

Table 1

Objectives

Endpoint Definition
PFS (primary) The time from the date of study enrollment to the first documented date of disease progression as assessed by the investigator according to RECIST v1.1 criteria, or death due to any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), or the appearance of new lesions (including unequivocal progression of non-target lesions). Patients who have not progressed or died at the time of data cutoff will be censored at their last tumor assessment date. For more detailed information, please refer to Appendix 1
Incidence of Grade ≥3 TRAEs (primary) The proportion of patients who experience any AE of grade 3 or higher, as defined by the CTCAE version 5.0, that is considered by the investigator to be at least possibly related to any component of the study treatment regimen (including benmelstobart, chemotherapy, anlotinib, or TRT). This includes events occurring during the induction, consolidation, or maintenance phases, as well as within 30 days after the last dose of any study drug or completion of radiotherapy. The incidence will be summarized overall and by specific event type. Treatment-relatedness is defined as a causal relationship judged as “possible”, “probable”, or “definite” by the investigator
ORR (secondary) The proportion of patients who achieve a confirmed CR or PR as per RECIST v1.1 criteria during treatment. CR is defined as the disappearance of all target and non-target lesions, with no new lesions and sustained resolution of any pathological lymph nodes. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Response must be confirmed by a subsequent imaging assessment at least 4 weeks after the initial response. ORR will be calculated as the number of patients with CR or PR divided by the total number of evaluable patients
OS (secondary) The time from the date of study enrollment to the date of death due to any cause. Patients who are still alive at the time of data analysis will be censored at the date of their last follow-up contact

AEs, adverse events; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; TRAEs, treatment-related adverse events; TRT, thoracic radiotherapy.

Methods

Participants

Patients will be recruited from Tianjin Medical University Cancer Institute & Hospital. A total of 25 participants are expected to be enrolled over a 12-month recruitment period, with all enrolled patients followed for at least 12 months after completion of radiotherapy. The first patient is anticipated to be enrolled on October 1, 2025, and the last patient is expected to be enrolled by October 1, 2026. The anticipated date for the last study visit or data collection is October 1, 2027.

Baseline staging imaging requirements: prior to enrollment, all patients must undergo mandatory baseline staging with the following imaging assessments: (I) contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis; (II) contrast-enhanced magnetic resonance imaging (MRI) of the brain; (III) ultrasound or CT evaluation of the cervical and supraclavicular lymph node regions; and (IV) whole-body bone scintigraphy. Whole-body 18F-fluorodeoxyglucose positron emission tomography-CT (18F-FDG PET-CT) is recommended for comprehensive disease assessment but is not mandatory for study eligibility.

Inclusion and exclusion criteria

Inclusion and exclusion criteria are detailed in Table 2.

Table 2

Inclusion and exclusion criteria for proposed study

Item Description
Key inclusion criteria 1. Histologically confirmed ES-SCLC (VALG staging)
2. No prior systemic therapy for ES-SCLC
3. Presence of measurable lesions as defined by RECIST 1.1; lesions previously irradiated may be considered measurable only if there is clear evidence of progression after radiotherapy, and such irradiated lesions are not the only target lesions
4. Age between 18 and 75 years, inclusive
5. ECOG PS: 0–2
6. Life expectancy of ≥3 months
7. Adequate hematologic and organ function, meeting the following criteria:
7.1 Hematology (without blood or blood product transfusion, and without use of G-CSF or other hematopoietic growth factors for correction within 14 days):
7.1.1. ANC ≥1.5×109/L (1,500/mm3);
7.1.2. PLT ≥100×109/L (100,000/mm3);
7.1.3. HB ≥80 g/L
7.2 Renal function:
7.2.1. Calculated CrCl ≥50 mL/min
7.2.2. Urine protein <2+ or 24-hour (h) urine protein <1.0 g
7.3 Liver function:
7.3.1. Serum TBil ≤1.5 × ULN
7.3.2. AST and ALT ≤2.5 × ULN
7.3.3. Serum ALB ≥28 g/L
7.4 Coagulation function:
7.4.1. INR and APTT ≤1.5 × ULN
7.5 Cardiac function:
7.5.1. LVEF ≥50%
8. Female patients must meet one of the following conditions:
8.1 Postmenopausal (defined as at least 1 year of amenorrhea with no confirmed cause other than menopause), or
8.2 Surgically sterile (bilateral oophorectomy and/or hysterectomy), or
8.3 Of childbearing potential, but must meet the following criteria:
8.3.1. A negative serum pregnancy test within 3 days prior to study drug administration, and
8.3.2. Agreement to use contraception with a failure rate of <1% per year or to remain abstinent (avoid heterosexual intercourse) from the time of informed consent signing through at least 6 months after the last dose of study drug (contraceptive methods with <1% annual failure rate include bilateral tubal ligation, male sterilization, correctly used ovulation-inhibiting hormonal contraceptives, hormone-releasing intrauterine devices, copper intrauterine devices, or condoms), and
8.3.3. Not breastfeeding
9. Male patients must meet the following: agreement to remain abstinent (avoid heterosexual intercourse); or use contraception as follows: male patients with female partners of childbearing potential or pregnant partners must remain abstinent or use condoms during the study treatment period and for at least 6 months after the last dose of study drug to prevent potential drug exposure to the embryo. Periodic abstinence (e.g., calendar, ovulation, basal body temperature, post-ovulation methods) and withdrawal are not acceptable contraceptive methods
10. The subject is willing to participate in this study, has signed the informed consent form, has good compliance, and is willing to comply with follow-up visits
Key exclusion criteria 1. Symptomatic brain metastases. Patients with brain metastases are eligible if they have been treated and clinically stable for at least 1 month, and have not used steroids or anticonvulsants for at least 1 month prior to entering the study
2. Patients who have previously received TRT for limited-stage SCLC. Patients with pre-existing grade ≥2 interstitial lung disease, uncontrolled malignant pleural/pericardial effusion, ECOG PS >2 at TRT planning, or prior thoracic radiation are excluded from receiving consolidation TRT
3. Prior use of antiangiogenic drugs such as anlotinib, apatinib, bevacizumab, or immune checkpoint inhibitors targeting PD-1, PD-L1, etc.
4. Presence of any condition that could affect oral medication intake (e.g., inability to swallow, gastrointestinal resection, chronic diarrhea, and intestinal obstruction)
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage
6. Radiographic evidence of tumor invasion into major blood vessels or, in the investigator’s judgment, a high likelihood of such invasion leading to life-threatening hemorrhage during the study period
7. History of significant bleeding tendency or coagulopathy, including but not limited to: clinically significant hemoptysis (more than one tablespoon per day) within 3 months prior to enrollment; or significant clinical bleeding symptoms or tendencies within 4 weeks prior to randomization, such as gastrointestinal bleeding, hemorrhagic gastric ulcer (including gastrointestinal perforation and/or fistula; however, if the gastrointestinal perforation or fistula has been surgically removed, the patient may be eligible), unhealed wounds, ulcers, or fractures
8. Major surgical treatment, open biopsy, or significant traumatic injury within 28 days prior to randomization
9. Arterial/venous thrombotic events within 6 months prior to randomization, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis, and pulmonary embolism
10. Active autoimmune disease requiring systemic treatment (e.g., use of disease-modifying drugs, corticosteroids, or immunosuppressive agents) within 2 years prior to the first dose of study drug
11. Any other condition that, in the opinion of the investigator, increases the risk associated with participation in the study or study drug administration and makes the patient unsuitable for inclusion in the study

ALB, albumin; ALT, alanine aminotransferase; ANC, absolute neutrophil count; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; ES-SCLC, extensive-stage small cell lung cancer; G-CSF, granulocyte colony-stimulating factor; HB, hemoglobin; INR, international normalized ratio; LVEF, left ventricular ejection fraction; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PLT, platelet count; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; TBil, total bilirubin; TRT, thoracic radiotherapy; VALG, Veterans Administration Lung Study Group.

Interventions

Interventions are detailed in Table 3.

Table 3

Interventions

Phase Description
Induction therapy phase The induction therapy phase consists of 4 cycles, with each 21 days as one treatment cycle:
Benmelstobart monoclonal antibody injection, 1,200 mg per dose, once every 21 days, intravenous infusion
Injection of carboplatin, on day 1, AUC 5 mg/mL/min, intravenous infusion (maximum usage dose is 750 mg); or cisplatin, on day 1, 75–80 mg/m2, intravenous infusion
Etoposide for injection, continuous administration on days 1, 2, and 3, 100 mg/m2, intravenous infusion
Anlotinib hydrochloride capsules, 12 mg per dose, continuous use for 2 weeks followed by a 1-week break, oral administration
Consolidation therapy phase For patients who have not progressed after induction therapy (including CR, PR, or SD), they will receive consolidation therapy with benmelstobart monoclonal antibody combined with anlotinib + TRT, for a total of 2 cycles, with each 21 days as one treatment cycle:
Consolidation radiotherapy, 5 Gy × 5 fractions, field irradiation (only the first cycle)
Benmelstobart monoclonal antibody injection, 1,200 mg per dose, once every 21 days, intravenous infusion
Anlotinib hydrochloride capsules, 12 mg per dose, continuous use for 2 weeks followed by a 1-week break, oral administration
Maintenance therapy phase For patients who have not progressed after consolidation therapy (including CR, PR, or SD), they will receive maintenance therapy with benmelstobart monoclonal antibody combined with anlotinib until loss of clinical benefit, unacceptable toxicity, efficacy evaluation as PD, or the investigator deems it inappropriate to continue medication:
Benmelstobart monoclonal antibody injection, 1,200 mg per dose, once every 21 days, intravenous infusion
Anlotinib hydrochloride capsules, 12 mg per dose, continuous use for 2 weeks followed by a 1-week break, oral administration

AUC, area under the curve; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TRT, thoracic radiotherapy.

Radiation therapy planning and delivery

TRT will be administered during days 1–5 of the first consolidation cycle following induction therapy. Treatment planning will commence with a dedicated simulation CT scan. The gross tumor volume (GTV), defined as the residual primary tumor and involved lymph nodes on the post-induction CT, will be contoured, and a planning GTV (PGTV) will be generated by applying a uniform 5-mm isotropic expansion to account for respiratory motion and setup uncertainties. TRT will be delivered using intensity-modulated radiotherapy or volumetric-modulated arc therapy, with motion management (e.g., active breathing control) and daily image guidance applied at the treating radiation oncologist’s discretion. The prescribed dose is 25 Gy in 5 daily fractions of 5 Gy. Detailed organ-at-risk dose constraints per Timmerman guidelines are detailed in Appendix 2 (25). Prophylactic cranial irradiation will not be recommended; instead, brain MRI surveillance is performed every 3 months during the first 2 years and every 6 months thereafter.

Criteria for study discontinuation/withdrawal

Provided in Appendix 3.

Concomitant and prohibited medications/treatments

Provided in Appendix 4.

Statistical methods

Sample size

This single-arm, open-label, phase II exploratory study is designed to evaluate the safety, feasibility, and preliminary efficacy of a multimodal regimen incorporating chemotherapy, immunotherapy, anti-angiogenic therapy, and TRT in patients with ES-SCLC. Given the exploratory nature of the study and the absence of a concurrent control arm, the sample size is not based on formal hypothesis testing. Instead, enrollment of 25 patients is considered sufficient to provide a preliminary estimate of PFS and to characterize the safety profile of the combination strategy. Contemporary first-line chemo-immunotherapy trials in ES-SCLC have reported a mPFS of approximately 5–7 months. With an expected approximately 20 PFS events, this sample size allows a reasonably precise estimation of mPFS and facilitates comparison with historical benchmarks to identify potential signals of clinical activity. The findings of this study are intended to be hypothesis-generating and to inform the design of future randomized trials, rather than to establish definitive evidence of superiority over current standard-of-care treatments.

Primary analysis

The primary analysis will be conducted on the full analysis set (FAS), which comprises all enrolled patients who have received at least one dose of the study treatment and meet the protocol eligibility criteria.

  • PFS: PFS is defined as the time from the first dose of study treatment to the first documented disease progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) criteria or death from any cause, whichever occurs first. Patients who have not experienced an event at the time of analysis will be censored at their last valid tumor assessment date. PFS will be estimated using the Kaplan-Meier method, and the mPFS with its corresponding 95% CI will be reported.
  • Incidence of Grade ≥3 TRAEs: the frequency and proportion of patients experiencing grade ≥3 TRAEs will be summarized using descriptive statistics (number and percentage). TRAEs are defined as any adverse event judged by the investigator to be at least possibly related to any component of the study regimen (benmelstobart, platinum-etoposide chemotherapy, anlotinib, or TRT) and graded according to CTCAE version 5.0.

The primary analysis will be performed once a sufficient number of PFS events have accrued to allow stable estimation of the median, or at the conclusion of the study, whichever occurs first.

Secondary analysis

The secondary analyses will be performed on the FAS and, where applicable, the safety set (all patients who received at least one dose of study treatment). The secondary endpoints include ORR and OS.

  • ORR: ORR is defined as the proportion of patients who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. The exact binomial method will be used to calculate the 95% CI for ORR. Response assessments will be based on investigator evaluations and confirmed by independent radiological review when available.
  • OS: OS will be defined as the time from the date of enrollment to the date of death due to any cause. Patients who are still alive at the time of analysis will be censored at their last known follow-up date. OS will be estimated using the Kaplan-Meier method, and results will be presented with 95% CIs.

All secondary analyses will be exploratory in nature and will not be adjusted for multiple comparisons. Statistical analyses will be performed using R (version 4.5.2). Results will be reported as part of the final study report and may be presented at scientific conferences or published in peer-reviewed journals.

Safety

The safety of the study regimen will be evaluated in all patients who receive at least one dose of any study treatment (safety set). Safety assessments will include the monitoring and documentation of all adverse events (AEs), serious AEs (SAEs), treatment-emergent AEs (TEAEs), and TRAEs throughout the study period and up to 30 days after the last dose of study drugs (or longer for specific events such as immune-related or delayed toxicities, as clinically indicated). Table S1 summarizes the study procedures.

AEs will be coded using the Medical Dictionary for Regulatory Activities, version 27.0, and graded according to the National Cancer Institute’s CTCAE, version 5.0. Special attention will be paid to immune-related AEs (irAEs), including pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and other organ-specific toxicities, as well as hematologic, renal, hepatic, cardiac, and neurological toxicities.

The incidence, severity, timing, duration, and relationship to study treatment of all AEs will be summarized using descriptive statistics (frequency and percentage). The proportion of patients experiencing grade ≥3 AEs and SAEs will be reported. Any SAEs and AEs leading to dose modification, interruption, or discontinuation of study treatment will be summarized and reviewed by the investigator.

All patients will undergo regular safety evaluations, including physical examinations, vital signs, 12-lead ECGs, and clinical laboratory tests (hematology, chemistry, coagulation, and urinalysis), performed at scheduled visits as per the study protocol. Left ventricular ejection fraction will be monitored periodically to assess cardiac function.

The overall safety profile of the combination regimen—benmelstobart plus chemotherapy, anlotinib, and TRT—will be characterized to assess tolerability and inform future clinical development. Safety data will be reviewed regularly by the investigator and sponsor, and unanticipated problems involving risks to subjects or others will be reported promptly to the ethics committee and regulatory authorities in accordance with Good Clinical Practice (GCP) guidelines.

Oversight and monitoring

Provided in Appendix 5.

Ethical statement

The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Human Research Ethics Committee (HREC) of Tianjin Medical University Cancer Institute & Hospital (approval No. E20260033) and registered with ClinicalTrials.gov (Identifier: NCT07358676). Written informed consent will be obtained from all individual participants prior to enrollment and study procedures. Each investigator delegated to perform the informed consent process must have completed appropriate training and attended trial initiation sessions, and their authorization will be documented in the study delegation log in accordance with GCP guidelines.

Discussion

SCLC is typically defined as an “immunologically cold” tumor, characterized by high heterogeneity and an immunosuppressive tumor microenvironment (TME) (26,27). Although the incorporation of ICIs into first-line chemotherapy has consistently improved OS in ES-SCLC, the magnitude of benefit remains modest, highlighting the intrinsic limitations of systemic therapy alone and the urgent need for more effective multimodal treatment strategies.

Anti-angiogenic therapy has emerged as a promising approach to enhance the efficacy of immunotherapy in ES-SCLC. Mechanistically, the aggressive growth and metastasis of SCLC are highly dependent on angiogenesis, and overexpression of vascular endothelial growth factor (VEGF) is closely associated with poor prognosis (28-30). Preclinical evidence indicates that the anti-angiogenic agent anlotinib not only directly inhibits tumor cell proliferation and migration but also promotes tumor vessel normalization, thereby improving tissue perfusion, alleviating hypoxia, and enhancing radiosensitivity (31-34). Additionally, anlotinib can promote infiltration of CD8+ T cells and natural killer (NK) cells into the TME, rebalance immune cell subsets, and enhance immune activation, providing a strong mechanistic rationale for its synergistic combination with ICIs and radiotherapy, and enabling potentiated antitumor effects (35,36). Notably, anlotinib has been shown to downregulate programmed death-ligand 1 (PD-L1) expression on tumor micro-conduit endothelial cells—specifically blood endothelial cells and lymphatic endothelial cells (LECs)—by inhibiting the VEGFR1-PI3K-AKT and VEGFR3 signaling pathways, respectively, thereby dismantling an endothelial “immune barrier” that restricts CD8+ T cell function and potentiating the antitumor efficacy of benmelstobart (37).

Despite improved systemic disease control achieved with intensified systemic regimens, intrathoracic progression remains a dominant pattern of failure in ES-SCLC. Residual primary tumors and regional lymph nodes often progress rapidly and significantly contribute to poor clinical outcomes (38). TRT, as a local treatment modality, has long been shown to reduce locoregional recurrence and improve survival in selected patients. In the immunotherapy era, the role of radiotherapy has gained renewed interest due to its immunomodulatory properties. Radiotherapy can induce immunogenic cell death, activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, promote type I interferon responses, enhance antigen presentation, and remodel the TME by increasing inflammatory cytokine release. In addition, radiotherapy can upregulate immune checkpoint molecules and death receptors on tumor cells, thereby increasing tumor immunogenicity and sensitizing tumors to ICIs (39,40).

However, the optimal timing, dosage, and fractionation of radiotherapy remain under active investigation. In the induction phase, several studies have evaluated the potential of concurrent short-course radiotherapy to enhance efficacy. The MATCH study showed that adding low-dose radiotherapy (LDRT, 3 Gy × 5 fractions) to atezolizumab plus chemotherapy resulted in a mPFS of 6.9 months (23,41). The LEAD study, using durvalumab plus chemotherapy with concurrent LDRT (3 Gy × 5 fractions), extended mPFS to 8.3 months (42). Another prospective trial administered moderate-to-high dose palliative radiotherapy (30–45 Gy/10–15 fractions) during the combination phase of chemo-immunotherapy, achieving a mPFS of 8.6 months, suggesting that early integration of radiotherapy may enhance systemic antitumor effects (21).

In the maintenance phase, TRT has also shown clinical value. The SAKK 15/19 study reported that patients receiving TRT (3 Gy × 13 fractions) after durvalumab plus chemotherapy had a mPFS of 6.4 months, a 12-month PFS rate of 16.4%, and a mOS of 15.8 months, without increasing the incidence of grade 3–4 AEs (43). A prospective phase II study further confirmed that sequential TRT (≥30 Gy/10 fractions or ≥50 Gy/25 fractions) following atezolizumab plus chemotherapy, with continued atezolizumab maintenance, yielded a mPFS of 10.1 months and a mOS of 21.4 months (22). Additionally, a multicenter retrospective study demonstrated that patients receiving TRT had significantly longer mPFS (8.0 vs. 5.9 months, P=0.03) and mOS (22.7 vs. 14.7 months, P=0.02) compared to those who did not (44). Taken together, these data indicate that integrating radiotherapy—whether concurrently during induction or sequentially in maintenance—confers clinical benefits with an acceptable safety profile.

Despite these advances, the optimal dose and fractionation for consolidation TRT in the chemo-immunotherapy era have not been prospectively established. While 30 Gy in 10 fractions has historically been the most widely adopted regimen, our protocol employs a 25 Gy in 5 fractions schedule to prospectively evaluate its feasibility and efficacy (45). From a radiobiological perspective, the biological effective dose for 25 Gy/5 fractions is 37.5 Gy, which closely approximates the 39 Gy delivered by the conventional 30 Gy/10 fractions regimen, indicating comparable potential for local control of residual microscopic disease. Clinically, a condensed 5-day course substantially reduces treatment burden and hospital visits, minimizes interruptions to concurrent benmelstobart and anlotinib maintenance therapy, and enhances adherence in a population prone to rapid clinical deterioration. This hypofractionated approach therefore aligns with modern multimodal treatment paradigms that prioritize seamless integration with systemic maintenance therapy without compromising oncologic outcomes.

Safety is a critical consideration. In the ETER701 study, the incidence of grade ≥3 TRAEs was 93.1% in the benmelstobart plus anlotinib plus chemotherapy group vs. 87.0% in the chemotherapy-alone group, with hematologic toxicity and hypertension being the most common. Although the quadruple regimen was associated with relatively higher rates of dose reductions, treatment interruptions, and discontinuations, the rates specifically attributable to benmelstobart or anlotinib were only about 8.5%, and treatment discontinuation due to anlotinib-related AEs was as low as 1.2%, indicating that the regimen is generally manageable and safe (18). Moreover, multiple clinical studies suggest that the addition of TRT does not significantly increase the risk of AEs when combined with chemo-immunotherapy (46,47). By integrating TRT into this quadruple backbone, this study aims to comprehensively assess the safety profile of this multimodal approach, with the expectation that the findings will provide valuable clinical insights for optimizing ES-SCLC treatment.

Building on the promising efficacy of the quadruple backbone (chemotherapy, benmelstobart, and anlotinib), this study integrates short-course TRT (25 Gy in 5 fractions) specifically during the consolidation phase. To our knowledge, this is the first trial to harness this multimodal strategy, leveraging sustained immune activation from checkpoint inhibition, anti-angiogenic-induced vascular normalization, and radiotherapy-mediated immunomodulation to simultaneously enhance local control and potentiate systemic antitumor immunity. However, as a single-arm, single-center phase II trial (n=25), the findings are exploratory and inherently constrained by cross-trial heterogeneity in historical comparisons, a 12-month minimum follow-up that precludes evaluation of late toxicities and long-term survival, and the absence of prespecified predictive biomarker analyses. Despite these limitations, this protocol establishes a rigorous framework to systematically evaluate the safety, feasibility, and preliminary efficacy of the integrated approach. Ultimately, the generated evidence will directly inform the design of future multicenter, randomized phase III trials, potentially establishing a novel, multidimensional paradigm for first-line management of ES-SCLC.

Acknowledgments

We would like to express our sincere gratitude to all the patients who volunteered to participate in this study. During the preparation of this manuscript, the authors used DeepSeek (specifically the DeepSeek-V3.2 model by DeepSeek AI) for language polishing and formatting assistance. The AI was used to improve the readability and academic tone of the text. The authors reviewed and edited all content generated by the AI and take full responsibility for the final version of the manuscript.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0114/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0114/prf

Funding: This study was supported by National Natural Science Foundation of China (No. 82460580), Natural Science Foundation of Xinjiang Uygur Autonomous Region of China (No. 2023D01A55), and Tianjin Key Medical Discipline Construction Project (No. TJYXZDXK-3-004B).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0114/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 will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Human Research Ethics Committee (HREC) of Tianjin Medical University Cancer Institute & Hospital (approval No. E20260033) and registered with ClinicalTrials.gov (Identifier: NCT07358676). Written informed consent will be obtained from all individual participants prior to enrollment and study procedures.

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/.

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Cite this article as: Zhou Y, Zhu H, Yang S, Liu J, Yu M, Sun J, Yang C, Cui Y, Liu N. Consolidation thoracic radiotherapy following quadruple induction with benmelstobart, anlotinib, and chemotherapy for extensive-stage small cell lung cancer: rationale and protocol of a phase II study. Transl Lung Cancer Res 2026;15(6):181. doi: 10.21037/tlcr-2026-1-0114

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