Abstract
Introduction
Consolidation immunotherapy postchemoradiotherapy is standard for unresectable stage III non-small-cell lung cancer (NSCLC) per PACIFIC and GEMSTONE-301, but optimal integration with chemoradiotherapy is unclear, especially for large tumours. Induction immunotherapy before concurrent chemoradiotherapy (cCRT) may enhance tumour downstaging and immune synergy, while adaptive radiotherapy with strict lung constraints (V20 ≤20%) could reduce toxicity. This trial aims to evaluate the efficacy and safety of sintilimab with induction chemotherapy followed by adaptive radiotherapy and consolidation sintilimab in patients with unresectable stage III NSCLC.
Methods and analysis
This prospective, multicentre, single-arm phase II trial will enrol 35 patients with histologically or cytologically confirmed unresectable stage III NSCLC, without sensitising mutations, and Eastern Cooperative Oncology Group(ECOG) performance status 0–1. Patients will receive two cycles of induction sintilimab (200 mg, day 1, every 3 weeks) plus platinum-based doublet chemotherapy, followed by definitive cCRT with adaptive radiotherapy planning strictly limiting both lung V20 ≤20%. Radiotherapy dose can be delivered in three optional regimens based on tumour volume and distribution: (1) planning gross tumour volume (PGTV) 60–66 Gy/2.0–2.2 Gy/30F with planning target volume (PTV) 54 Gy/1.8 Gy/30F; (2) PGTV 54–66 Gy/2.0–2.2 Gy/30F without PTV irradiation or (3) PGTV 50 Gy/2.0 Gy/25F without PTV irradiation. During radiotherapy, patients will receive two additional cycles of sintilimab plus chemotherapy. Consolidation sintilimab will continue for up to 1 year or until disease progression/unacceptable toxicity.
Ethics and dissemination
This study was approved by the Institutional Ethics Committee of The Third Xiangya Hospital, Central South University (approval number: R25063; the approval letter is provided as online supplemental file 1). The study results will be disseminated through publication in peer-reviewed journals, presentations at national and international scientific conferences and communication to participants and the public via institutional channels and patient advocacy groups. Individual participant data will be available on reasonable request after study completion, subject to institutional and ethical approvals.
Trial registration number
Keywords: Clinical Trial, ONCOLOGY, Radiation oncology, Lung Diseases, Immunotherapy, Chest imaging
Introduction
The treatment paradigm for unresectable stage III non-small-cell lung cancer (NSCLC) was established by the PACIFIC trial, which defined concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab as the standard of care, demonstrating unprecedented survival benefits.1 However, 5%–30% of patients are unable to receive this pivotal consolidation therapy due to either disease progression or intolerable toxicity during the initial cCRT phase,2 highlighting a critical clinical gap and a fundamental limitation of the sequential PACIFIC regimen. This underscores the need for strategies that can bring the benefits of immunotherapy to a broader patient population and potentially improve outcomes for high-risk subgroups, such as those with bulky disease.
To address this, shifting immunotherapy earlier in the treatment sequence has been actively explored.3–5 The central hypothesis is that early immune activation could prime the tumour microenvironment, enhance systemic antitumour immunity, and potentially improve tumour control. However, the recent failures of the PACIFIC-26 and CheckMate 73L7 trials, which investigated the concurrent administration of immunotherapy with cCRT, underscore the complexity of this integration. These studies did not achieve superior outcomes compared with the standard PACIFIC sequence, with increased toxicity profiles being a major concern.6 These results refocus attention on a central scientific and clinical question: What is the optimal spatiotemporal integration of immunotherapy with definitive radiotherapy to maximise synergy while minimising antagonism and toxicity?
Induction chemoimmunotherapy followed by definitive radiotherapy (with or without concurrent chemotherapy) has emerged as a promising alternative strategy to potentially circumvent the limitations of the PACIFIC mode. Retrospective analyses from our institution and others, supported by encouraging preliminary data from phase II studies, suggest that this sequence may lead to improved tumour downstaging, higher response rates and potentially better survival outcomes compared with cCRT followed by consolidation.8–11 Conversely, other retrospective studies have reported no clear superiority,12 revealing a current state of equipoise. This discrepancy points to a potentially dualistic and context-dependent nature of ‘immune priming.’ On one hand, induction immunotherapy can reduce tumour volume (thereby enabling smaller, more conformal radiotherapy target volumes),13 enhance tumour antigen presentation and potentially induce a systemic immune response.14 On the other hand, activated and proliferating lymphocytes may become more susceptible to the cytotoxic effects of subsequent chemoradiation, leading to therapy-induced lymphopenia, which has been consistently associated with poorer outcomes in the immunotherapy era.15 16 This delicate balance suggests that the net benefit of induction immunotherapy may be significantly influenced by the design and parameters of the subsequent radiotherapy.
Therefore, the key to designing an effective therapeutic sequence lies not only in the order of modalities but also in optimising the radiotherapy component to preserve the advantages of immune priming while mitigating its potential drawbacks. Based on our prior retrospective findings,17 implementing a strict constraint on lung V20 (the volume of lung receiving 20 Gy) during radiotherapy planning may serve as a practical strategy with the potential to achieve this balance. This approach is grounded in radiobiological and clinical principles: limiting the low-dose bath to the lungs reduces the exposure of circulating lymphocytes to radiation, potentially preserving systemic immunity. Simultaneously, it is intended to mitigate the risk of severe radiation pneumonitis, a dose-limiting toxicity that can compromise treatment delivery and patient quality of life. Thus, adaptive radiotherapy with a rigorous lung V20 constraint is hypothesised to create a more permissive host environment for the efficacy of combined-modality immunotherapy.
Given the promising yet unconfirmed potential of this approach, prospective evaluation is warranted. We hypothesise that a comprehensive strategy comprising induction sintilimab (an anti-PD-1 antibody with established efficacy in NSCLC) plus platinum-based doublet chemotherapy, followed by definitive (sequential or concurrent) radiotherapy planned with a strict lung V20 constraint (≤20%), and subsequent consolidation sintilimab, will improve progression-free survival (PFS) for patients with unresectable stage III NSCLC. This approach aims to synergistically achieve deep tumour response, enhance the abscopal effect and minimise treatment-related toxicities, particularly pneumonitis and lymphopenia. The ART-LUNG 01 trial is a prospective, single-arm phase II study designed to test the efficacy and safety of this integrated treatment strategy.
Methods and analysis
Study design
The ART-LUNG 01 trial is a prospective, multicentre, single-arm, open-label phase II study designed to evaluate the efficacy and safety of an integrated treatment strategy for patients with unresectable stage III NSCLC. This strategy consists of induction chemoimmunotherapy, followed by definitive cCRT employing adaptive radiotherapy with a strict lung V20 constraint and culminating in consolidation immunotherapy. The study design is presented in figure 1. A total of 35 eligible patients will be enrolled across multiple centres in China. Following confirmation of unresectable status by a multidisciplinary team, patients will receive two cycles of induction therapy. This will be followed by adaptive radiotherapy planning and the cCRT phase. Eligible patients will then proceed to consolidation therapy for up to 1 year or until meeting discontinuation criteria.
Figure 1. Flowchart of the ART-LUNG 01 study. ALK, anaplastic lymphoma kinase; CCRT, concurrent chemoradiotherapy; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; ROS1, ROS proto-oncogene 1.
Patient recruitment began on 29 August 2025. With a planned 24-month accrual period, recruitment is expected to be completed by August 2027. The estimated primary completion date is December 2028, and the estimated overall study completion date is September 2030.
Research objectives
The primary objective is to assess PFS, defined as the time from the initiation of study treatment to the first documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause. Secondary objectives include evaluating the following endpoints: objective response rate (ORR), disease control rate, overall survival (OS), duration of response, in-field local control rate, out-of-field recurrence rate and the incidence and severity of adverse events. Exploratory objectives involve assessing health-related quality of life (HRQoL) using standardised questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 [EORTC QLQ-C30], Quality of Life Questionnaire-Lung Cancer 13 [QLQ-LC13], and EuroQol 5-Dimension 5-Level [EQ-5D-5L]) and investigating correlations between treatment response and multi-omics profiles derived from tumour tissue and blood samples.
STRENGTHS AND LIMITATIONS OF THIS STUDY.
A mandatory adaptive radiotherapy planning with a strict lung V20 ≤20% dose constraint is applied to all treatment plans, with three selectable dose-fractionation schemes chosen based on tumour volume and distribution.
The adaptive radiotherapy strategy incorporating postinduction re-planning and individualised dose selection is designed to optimise tumour coverage while minimising pulmonary toxicity and preserving systemic immune function.
Comprehensive biomarker analyses including genomics, proteomics and single-cell sequencing will be performed to explore predictive factors for treatment response and prognosis.
The single-arm design and relatively small sample size (n=35) may limit the generalisability of findings, and the lack of a randomised comparator arm precludes direct comparison with current standard-of-care regimens.
Participants
Detailed inclusion and exclusion criteria are presented in online supplemental table 1. Eligible patients must be aged 18–75 years with an ECOG performance status of 0 or 1 and histologically confirmed, unresectable stage III NSCLC. Key inclusion criteria include the absence of sensitising driver gene mutations, no prior systemic antitumour therapy or thoracic radiotherapy, at least one measurable lesion and adequate organ function. Patients must provide tumour tissue samples for biomarker analysis and, if applicable, use effective contraception. Major exclusion criteria include the presence of a small-cell carcinoma component, active autoimmune disease requiring systemic treatment, a history of non-infectious pneumonitis requiring steroids, uncontrolled infection, active hepatitis B or C, significant cardiovascular disease, recent major surgery and any condition that, in the investigator’s judgement, poses an undue risk or interferes with study compliance. All participants will provide written informed consent before any study-specific procedures are performed (online supplemental file 2).
Treatments
The treatment protocol comprises three distinct phases: induction therapy, cCRT and consolidation therapy. The complete treatment schema is illustrated in figure 1.
Induction phase (cycles 1–2)
All eligible patients receive two cycles of induction therapy. Each 21-day cycle consists of sintilimab 200 mg administered intravenously on day 1, combined with platinum-based doublet chemotherapy. The chemotherapy regimen is selected based on histological subtype:
For non-adenocarcinoma: nab-paclitaxel 100 mg/m² on days 1, 8 and 15, OR paclitaxel 135–175 mg/m² on day 1, OR liposomal paclitaxel 135–175 mg/m² on day 1, plus either cisplatin 75 mg/m² on day 1 or carboplatin area under the curve (AUC)=5 on day 1.
For adenocarcinoma: pemetrexed 500 mg/m² on day 1, plus either cisplatin 75 mg/m² on day 1 or carboplatin AUC=5 on day 1.
Pemetrexed is administered with mandatory folic acid and vitamin B12 supplementation and dexamethasone premedication as per standard institutional practice.
Concurrent chemoradiotherapy phase (cycles 3–4)
Following the two induction cycles, patients undergo a simulation CT scan for adaptive radiotherapy planning. Radiotherapy is delivered concurrently with two additional cycles (cycles 3 and 4) of sintilimab and the same platinum-based doublet chemotherapy as used during the induction phase. If radiotherapy extends beyond cycle 4, cycle 5 consists of sintilimab alone.
Radiotherapy planning and delivery: radiotherapy target volumes are defined according to the International Commission on Radiation Units and Measurements (ICRU) Reports 62 and 83:
Gross tumour volume (GTV): defined as the primary tumour and involved positive lymph nodes.
Planning GTV (PGTV): created by adding a 0.5 cm margin to the GTV.
Clinical target volume (CTV): defined by expanding the GTV with histology-specific margins: 0.6 cm for squamous cell carcinoma and 0.8 cm for adenocarcinoma. For positive lymph nodes, CTV expansion is 0.3 cm for nodes with a short axis <2 cm and 0.5 cm for nodes with a short axis ≥2 cm. The CTV is manually edited to respect anatomical barriers.
Planning target volume (PTV): generated by adding a 0.5 cm margin to the CTV.
Organs at risk, including the lungs, heart, oesophagus and spinal cord, are delineated according to the Radiation Therapy Oncology Group (RTOG) 1106 atlas. A mandatory dose constraint of V20≤20% for the total lung (both lungs combined) must be strictly adhered to in all treatment plans.
To achieve this lung V20 constraint and accommodate variations in tumour volume and distribution, physicians may select one of the following three dose-fractionation schemes (figure 2):
Figure 2. Schematic representation of the three adaptive radiotherapy dose-fractionation schemes. To meet the mandatory lung V20 ≤20% constraint, one of three regimens is selected based on tumour volume and distribution: Model 1: PGTV (60–66 Gy/2.0–2.2 Gy per fraction) with PTV (54 Gy/1.8 Gy per fraction) over 30 fractions; Model 2: PGTV only (54–66 Gy/2.0–2.2 Gy per fraction over 30 fractions), without elective nodal irradiation; Model 3: Hypofractionated PGTV only (50 Gy/2.0 Gy per fraction over 25 fractions), without elective nodal irradiation. If lung V20 remains >20% even with the most sparing hypofractionated PGTV-only regimen, the patient is discontinued from protocol treatment and may receive salvage systemic therapy (immunotherapy or chemotherapy) or palliative radiotherapy (eg, 45 Gy/3 Gy/15 fractions) at the investigator’s discretion. cCRT, concurrent chemoradiotherapy; PGTV, planning gross tumour volume; PTV, planning target volume.
PGTV with PTV: PGTV receives 60–66 Gy in 2.0–2.2 Gy per fraction, and PTV receives 54 Gy in 1.8 Gy per fraction over 30 fractions.
PGTV only (without PTV): PGTV receives 54–66 Gy in 2.0–2.2 Gy per fraction over 30 fractions, without elective nodal irradiation (no PTV).
Hypofractionated PGTV only (without PTV): PGTV receives 50 Gy in 2.0 Gy per fraction over 25 fractions, without elective nodal irradiation.
If, after evaluation with the hypofractionated PGTV-only scheme (50 Gy/2.0 Gy/25 fractions), the lung V20 constraint cannot be achieved, the patient will be discontinued from the protocol treatment. Subsequent management may include systemic therapy (immunotherapy or chemotherapy) or palliative radiotherapy (eg, 45 Gy/3 Gy/15 fractions) at the investigator’s discretion.
All radiotherapy is delivered using intensity-modulated radiotherapy or volumetric modulated arc therapy techniques with daily image guidance (cone-beam CT) to ensure accurate patient positioning.
Consolidation phase
Within 4 weeks after the completion of radiotherapy, patients who have not experienced disease progression or unacceptable toxicity begin consolidation therapy with sintilimab monotherapy. Sintilimab 200 mg is administered intravenously every 3 weeks. The first dose of consolidation is considered the start of maintenance therapy, which continues for up to 1 year or until disease progression, unacceptable toxicity or withdrawal of consent, whichever occurs first.
Assessment
Tumour response will be assessed by contrast-enhanced CT (and brain MRI) per RECIST v1.1 at screening, postinduction, post-cCRT, every 6 weeks during consolidation and regularly during follow-up. Safety will be monitored continuously, with adverse events graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Regular laboratory tests, cardiac markers, thyroid function and pulmonary function tests will be performed. HRQoL questionnaires will be administered at key timepoints. For biomarker research, tumour tissue (for genomics), serial blood samples (for ctDNA, immune profiling) and stool samples (for microbiome) will be collected at predefined intervals.
Statistical considerations and analysis
The sample size was calculated based on the primary endpoint of PFS. Assuming an improvement in median PFS from a historical reference of 12 months (based on standard consolidation therapy) to 24 months with the study regimen, a one-sample log-rank test with a two-sided alpha of 0.05 and 80% power, a 24-month accrual and 24-month follow-up period requires 31 evaluable patients. Accounting for a 10% dropout rate, the total sample size is set at 35. The primary analysis will be performed on the full analysis set. PFS and OS will be estimated using the Kaplan-Meier method. Secondary efficacy endpoints like ORR will be presented with their 95% CIs. Safety will be analysed descriptively in the safety set. Subgroup analyses are planned for exploratory purposes. Statistical analyses will be conducted using R or SPSS software.
Monitoring
An independent data monitoring committee is not planned for this phase II study. Trial conduct, including protocol compliance, data quality and patient safety, will be monitored by the sponsor or designated contract research organisation through regular site monitoring visits. Source data verification will be performed to ensure the accuracy of the data recorded in the electronic case report forms.
Disease monitoring
Disease monitoring will be performed according to a predefined schedule using standardised imaging modalities. Contrast-enhanced CT of the chest and upper abdomen is the primary imaging modality for tumour response assessment, performed at screening, after the induction phase, after cCRT, every 6 weeks during consolidation therapy and every 3 months in the first year and every 6 months thereafter during the follow-up period following completion of immunotherapy maintenance, until disease progression or study completion. Brain MRI will be performed at screening and whenever clinically indicated to detect central nervous system metastases. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) will be obtained at baseline where available and may be repeated when clinically indicated to evaluate metabolic response and to guide biopsy decisions.
Image-guided biopsy (eg, CT- or ultrasound-guided percutaneous biopsy) will be incorporated when clinically indicated to confirm suspected disease progression, to distinguish true progression from pseudoprogression or treatment-related changes and to obtain tissue for translational biomarker analyses. All biopsy decisions will be made by the multidisciplinary tumour board. When imaging findings are equivocal or suggestive of pseudoprogression, repeat imaging at a 4–6 week interval will be performed before declaring progression; if progression remains uncertain, image-guided biopsy will be considered to establish a definitive diagnosis.
Criteria for escalating or repeating imaging include: (1) new or worsening symptoms suggestive of disease progression; (2) equivocal findings on routine imaging requiring clarification; (3) clinical suspicion of pseudoprogression and (4) suspected distant metastases requiring characterisation. In these scenarios, additional CT, MRI or PET-CT will be performed at the investigator’s discretion, guided by the multidisciplinary team.
Safety outcomes will be monitored continuously and systematically recorded. All adverse events, including procedure-related adverse events associated with imaging or biopsy (eg, contrast-induced nephropathy, allergic reactions to contrast media, biopsy-site bleeding, pneumothorax or infection), will be captured using the electronic case report form, graded according to NCI CTCAE v5.0 and followed until resolution or stabilisation. Imaging- and biopsy-related complications will be specifically documented and analysed as part of the safety evaluation. Serious adverse events will be reported to the ethics committee and sponsor within the required regulatory timeframes.
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Ethics and dissemination
This study is conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines. The protocol, informed consent form and all study-related documents were approved by the Institutional Ethics Committee of The Third Xiangya Hospital, Central South University (approval number: R25063). Written informed consent will be obtained from all participants before any study-specific procedure is performed (online supplemental file 2). The trial is registered at ClinicalTrials.gov (NCT07138755). The results of this study will be disseminated through publication in a peer-reviewed journal and presentations at national and international scientific conferences. A plain-language summary of the findings will be shared with participants and the broader public through institutional communication channels and patient advocacy groups. Individual participant data will be made available on reasonable request after study completion, subject to institutional and ethical approvals and a data sharing agreement. There are no plans to make the full raw dataset publicly available. Authorship of any resulting publications will follow the International Committee of Medical Journal Editors (ICMJE) recommendations.
Discussion
The ART-LUNG 01 trial is designed to address the pivotal scientific question raised in the post-PACIFIC era: how to optimally sequence and integrate immunotherapy with definitive radiotherapy in unresectable stage III NSCLC. While the PACIFIC regimen established a standard, its limitation—that a significant subset of patients not suitable for consolidation therapy2—and the failure of concurrent immuno-chemoradiotherapy strategies (eg, PACIFIC-2, CheckMate 73L) due to toxicity,6 7 highlight the urgent need for novel, optimised integration strategies.
Our trial investigates induction chemoimmunotherapy followed by adaptive chemoradiotherapy in this setting. This sequence seeks to harness the potential advantages of immune priming, such as early systemic control, tumour downstaging (which may facilitate smaller, more conformal radiotherapy target volumes) and enhanced antigen presentation.13–15 However, it also explicitly acknowledges the inherent risk suggested by conflicting retrospective data: that activated lymphocytes may become more susceptible to subsequent chemoradiation. A key feature of the ART-LUNG 01 trial is its integrated approach, which is designed to mitigate this specific risk while aiming to preserve the potential benefits of immune priming.
The protocol mandates adaptive radiotherapy with a strict lung V20 ≤20% constraint, which is hypothesised to be a practical strategy to balance this dichotomy.18 By minimising the volume of lung parenchyma receiving low-dose radiation, this strategy aims to directly reduce the exposure of circulating lymphocytes to radiation, thereby potentially preserving systemic immune function and limiting the severity of radiation pneumonitis. This is intended to render the theoretical ‘immune-sensitising’ effect of prior immunotherapy less detrimental. The study evaluates a treatment sequence that incorporates a predefined dosimetric optimisation, with the aim of assessing the balance between synergy and toxicity in immuno-radiotherapy combinations.
The choice of sintilimab is supported by its established efficacy and safety profile.19–22 The inclusion of multiple, clinically guided radiotherapy dose-fractionation schedules (eg, simultaneous integrated boost or hypofractionated regimens without elective nodal irradiation) is based on tumour volume, tumour distribution and the mandatory lung V20 ≤20% constraint.
This trial has several limitations. Its single-arm, phase II design with a modest sample size precludes definitive efficacy comparisons against the standard of care and may underdetect rare adverse events. The heterogeneity in radiotherapy regimens, while pragmatic, must be considered when interpreting outcomes.
Supplementary material
Acknowledgements
The authors thank all participating patients, families and research staff. Sintilimab for this trial is provided by Innovent Biologics (Suzhou) Co., Ltd., which had no role in study design, data analysis or manuscript preparation.
Footnotes
Funding: This work was supported by Innovent Biologics (Suzhou) Co., Ltd., which provided sintilimab for the trial. The funder had no role in study design, data collection, analysis, interpretation of data or manuscript preparation. No additional specific grant from any other funding agency in the public, commercial or not-for-profit sectors was received.
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2026-120335).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
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