Cadonilimab induction and consolidation for unresectable stage III non-small cell lung cancer patients receiving concurrent chemoradiation: safety run-in results of a prospective, phase II trial

Introduction

Approximately 30% of newly diagnosed non-small cell lung cancer (NSCLC) cases are classified as stage III. Despite the established standard of durvalumab consolidation following concurrent chemoradiotherapy (cCRT) for unresectable stage III NSCLC, long-term survival remains suboptimal, with the 5-year progression-free survival (PFS) remains modest at 33.1% (1,2). A critical clinical challenge is that approximately 30% of patients undergoing cCRT fail to initiate durvalumab consolidation, primarily due to disease progression or intolerable toxicities (3). This underscores the necessity of earlier systemic intervention to optimize therapeutic delivery and maximize overall efficacy.

While several key trials exploring immunotherapy concurrently with cCRT have largely reported negative results (4,5), induction immunotherapy followed by cCRT holds significant potential, supported by a growing body of evidence (6,7). First, there is a robust biological rationale for induction immunotherapy. The efficacy of immunotherapy is highly dependent on an intact and functional systemic immune system, including tumor-draining lymph nodes, which may be compromised by cCRT (8-10). Additionally, induction immunotherapy may enhance radiosensitivity by favorably remodeling the tumor microenvironment (11). For stage III NSCLC patients, despite the promising survival outcomes demonstrated by induction programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) monotherapy in prospective clinical trials (12,13), disease progression, particularly distant metastasis, remains a significant challenge. Novel treatment regimens capable of achieving higher response rates in unselected patient populations urgently need to be established.

To address this therapeutic gap, dual checkpoint blockade offers a compelling strategy. Cadonilimab (AK104), a bispecific antibody targeting both PD-1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4), is engineered to form stable multivalent bonds with T cells co-expressing these immune checkpoints in the tumor microenvironment. This targeted mechanism enhances its concentration in tumor tissues while limiting its distribution to normal tissues, thereby potentially reducing systemic adverse events (AEs). Promising results of cadonilimab treatment in advanced NSCLC have been reported (14,15). Notably, a multicenter, open-label, single-arm, phase II trial (the LungCadX study) evaluated cadonilimab combined with chemotherapy as a first-line treatment for PD-L1 negative advanced NSCLC. Among the first 46 evaluable patients, the investigator-assessed objective response rate (ORR) was 60.9%, while the disease control rate (DCR) reached 100.0% (15). However, the safety and efficacy of cadonilimab in stage III NSCLC remain unexplored.

Thus, we conducted a prospective, single-arm, phase II trial assessing the safety and efficacy of cadonilimab as both induction and consolidation therapy in unresectable stage III NSCLC. A safety run-in phase was conducted to determine the tolerability of this novel treatment strategy by monitoring dose-limiting toxicities (DLTs) in the first 20 enrolled patients; herein, we report the results. We present this article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0122/rc).

Methods

Study design and participants

This prospective, phase II, single-arm study is being conducted at Fudan University Shanghai Cancer Center (FUSCC) (Figure 1). The trial was approved by the Institutional Review Board of the FUSCC (No. 2404294-8-2504B) and registered with ClinicalTrials.gov on June 7, 2024 (NCT06448910). The trial was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All patients provided written informed consent.

Figure 1 Study design. The per-protocol treatment comprised three phases: (I) induction therapy with two cycles of cadonilimab plus chemotherapy, (II) standard cCRT, and (III) cadonilimab consolidation therapy. Consolidation therapy was maintained for up to 1 year or until disease progression, unacceptable toxicity, death, or withdrawal of consent. PFS1 was calculated from enrollment to disease progression or death due to any cause. PFS2 was calculated from the completion of cCRT to disease progression or death due to any cause. ALK, anaplastic lymphoma kinase; AUC, area under the curve; cCRT, concurrent chemoradiotherapy; d, day; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ITT, intention-to-treat; IV, intravenously; NSCLC, non-small cell lung cancer; PFS, progression-free survival; Q3W, once every 3 weeks; ROS1, c-ros oncogene 1; RT, radiotherapy.

The key inclusion criteria were as follows: age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, pathologically or histologically confirmed untreated stage III NSCLC according to the American Joint Committee on Cancer staging manual (8th edition), absence of common actionable sensitizing driver alterations [including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and C-Ros oncogene 1 (ROS1)], at least one measurable lesion per the Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST 1.1), and a tumor deemed unresectable by the multidisciplinary treatment board of FUSCC. The exclusion criteria included a history of or concurrent secondary malignancy, pregnancy or breastfeeding, and any general condition that might affect compliance or the ability to provide informed consent. Full eligibility criteria are detailed in the study protocol, which is provided in the supplementary material 1 (available at https://cdn.amegroups.cn/static/public/tlcr-2026-1-0122-1.docx).

Treatment

Enrolled patients initially received two cycles of induction therapy consisting of cadonilimab plus platinum-etoposide chemotherapy every 3 weeks. Cadonilimab was administered at 10 mg/kg intravenously (IV) on day 1. The induction chemotherapy regimen comprised etoposide (100 mg/m² IV on days 1–3) combined with either carboplatin [area under the curve (AUC) =5, IV on day 1] or cisplatin (25 mg/m² IV on days 1–3). The etoposide-platinum regimen was selected as a widely used cCRT backbone in unresectable stage III NSCLC.

Following induction therapy, the patients received standard cCRT, comprising definitive thoracic radiotherapy (60%±10% Gy over 30 fractions) administered concurrently with chemotherapy. Radiotherapy was delivered via intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Dose constraints for organs at risk were applied in accordance with the study protocol. For the lungs, the constraints were lung V20 (percentage of lung volume receiving at least 20 Gy) <35% (with lung V20 >40% defined as a major deviation), mean lung dose <20 Gy, and lung V5 (percentage of lung volume receiving at least 5 Gy) <65%. For the heart, the constraints were mean heart dose ≤25 Gy and heart V50 (percentage of heart volume receiving at least 50 Gy) <25%. To ensure treatment consistency, the concurrent chemotherapy was consistent with the regimen used in induction therapy (i.e., carboplatin/cisplatin plus etoposide). During cCRT, chemotherapy doses were modified to accommodate concurrent thoracic radiotherapy. Etoposide was administered at 50 mg/m² IV on days 43–47 and 71–75, and platinum was given as either cisplatin 50 mg/m² IV on days 43, 50, 71, and 78 or weekly carboplatin at an AUC of 2.

Consolidation therapy with cadonilimab was initiated within 6 weeks after completion of cCRT. Cadonilimab was administered at 10 mg/kg every 21 days for up to 1 year, or until disease progression, unacceptable toxicity, or withdrawal of consent. Detailed information on radiation dose-fractionation, chemotherapy regimens, dose specifications, and the overall treatment process is provided in the study protocol (supplementary material 1 available at https://cdn.amegroups.cn/static/public/tlcr-2026-1-0122-1.docx).

Endpoints

The primary endpoints were PFS1 and PFS2, defined as the 1-year PFS rate in the modified intention-to-treat (mITT) population and in patients eligible for cadonilimab consolidation, respectively.

The mITT population comprised patients who received at least one dose of induction cadonilimab, with PFS1 calculated from the time of informed consent to fully capture early clinical events, consistent with the methodology of the AFT-16 study (10). The consolidation candidates were defined as patients who completed cCRT without disease progression or unresolved toxicities, with PFS2 calculated from the completion of cCRT in this subgroup. These definitions generally align with those used in the PACIFIC study (1). The secondary endpoints included ORR, DCR, overall survival (OS), the proportion of patients receiving consolidation therapy, and treatment-related AEs (TRAEs) assessed using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). Notably, the World Health Organization-Uppsala Monitoring Centre system for standardized case causality assessment was applied to determine causality. Additionally, baseline tissue samples and serial peripheral blood samples were collected for biomarker analyses. Detailed information regarding the definitions and calculation of these endpoints is provided in the study protocol (supplementary material 1 available at https://cdn.amegroups.cn/static/public/tlcr-2026-1-0122-1.docx).

Assessments and safety run-in

For patients in the mITT population, treatment visits included physical examinations, laboratory assessments, AE collection, and regular radiographic follow-up. Tumor responses were evaluated according to the RECIST version 1.1. Radiographic evaluations were conducted initially at the end of the induction therapy to determine the objective response to the induction regimen; within 4 to 6 weeks following the completion of cCRT to evaluate the response and confirm eligibility for consolidation; and every 9 weeks thereafter during the consolidation therapy phase. The data cut-off date was June 30, 2025.

Given that the safety profile of cadonilimab for induction and consolidation therapy in stage III NSCLC patients receiving cCRT has not been evaluated, a safety run-in phase was implemented to ensure no excessive severe TRAEs occurred in the treated patients. In this study, DLT was defined by the following three conditions (excluding asymptomatic biochemical abnormalities): grade 3 non-hematologic toxicity lasting more than seven consecutive days, grade 4 non-hematologic toxicity, and grade 5 AEs where a treatment-related cause could not be ruled out. To minimize the risk of excessive toxic reactions associated with the experimental treatment, toxicity was closely monitored in the first 20 patients receiving trial therapy. If seven or more of these 20 patients experienced any of the specified DLTs within 90 days of completing cCRT, the trial was to immediately cease enrolling or treating new participants. The research team was then to analyze the data and additional details to determine whether the treatment protocol needed to be revised to lower the DLT rate or if the trial should be terminated altogether. This toxicity monitoring strategy was underpinned by statistical criteria. A DLT rate of 25% or lower was considered acceptable, whereas a rate of 45% or higher was deemed unacceptable. If the actual DLT rate was 25%, the likelihood of terminating the trial during the safety run-in phase was 0.1018. However, if the DLT rate was 30%, this probability increased significantly to 0.7480. Additionally, the trial was to be halted immediately if more than four treatment-related deaths occur among the first 20 monitored patients within the first 90 days of treatment, triggering a thorough investigation.

Statistical analysis

This study employed a one-stage binomial exact test. The first primary endpoint was the 1-year PFS1 rate in the mITT population. Historical control data from large phase III clinical trials, such as the RTOG0617 study, reported a 1-year PFS rate of no more than 50% (16).

Guided by the efficacy signal from the AFT-16 study (12), the alternative hypothesis was defined as an increase in the 12-month PFS rate from 50% to 66%, corresponding to a 40% reduction in the risk of disease progression or death [hazard ratio (HR) =0.60]. The required sample size was calculated using a one-sample log-rank test with a one-sided α level of 0.05 and 80% power, assuming 12 months of accrual followed by 12 months of additional follow-up. Under these assumptions, 37 eligible patients were required. To account for an anticipated 10% loss to follow-up, the planned enrollment was 41 patients. The second primary endpoint was the 1-year PFS2 rate among patients who proceeded to consolidation. Prior data indicated that approximately 70% of patients initiating cCRT were able to receive consolidation immunotherapy (3). Therefore, among the 41 enrolled patients, at least 28 were expected to be eligible for consolidation and included in the PFS2 analysis. For sample size planning, the reference 1-year PFS2 rate was set at 56.0%, using the 1-year PFS rate reported in the durvalumab arm of the PACIFIC trial as a pragmatic historical benchmark for outcomes in patients receiving standard-of-care consolidation after cCRT (2). With 28 evaluable patients, 80% power was expected to detect an improvement in the 1-year PFS2 rate from 56.0% to 74.5% at a one-sided α level of 0.05.

The study employed a fixed-sequence testing approach. First, the difference for the first primary endpoint was assessed, and based on that result, the difference for the second primary endpoint was evaluated, while controlling the overall type I error rate at the one-sided level of 0.05. The TRAEs and DLTs observed in the first 20 patients enrolled in the safety run-in phase of the trial were categorized by type, grade, frequency, and proportion. Follow-up was calculated from the date of enrollment to the date of disease progression or, for patients without progression, the date of last follow-up. These patients were evaluated using the same schedule and criteria applied to subsequent participants. Demographic variables were summarized as medians and ranges for continuous data, and as frequencies and percentages for categorical data. The statistical analyses were conducted using SPSS 21.0 (SPSS, Chicago, IL, USA) and R version 3.5.1 (The R Foundation for Statistical Computing).

Results

Patient characteristics and treatment

From July 22, 2024, to December 25, 2024, 20 patients were enrolled and treated (Figure 2). The patients’ baseline characteristics are summarized in Table 1. The study cohort consisted primarily of male smokers. The median age was 68 years, and 45% of patients were aged 70 years or older. Most patients had lung squamous cell carcinoma (SCC) and an ECOG performance status of 1. By the data cut-off date, 19 patients (95.0%) had completed induction therapy, while one patient (5.0%) discontinued after the first cycle due to possible immune-related colitis. All patients received cCRT, including the one patient who did not complete two cycles of induction therapy. Among the patients, 19 (95.0%) completed cCRT, and 17 (85.0%) received at least one cycle of cadonilimab consolidation therapy. At the data cutoff on June 30, 2025, the median (range) follow-up was 8.4 months (6.2–10.7 months). The treatment plans of thoracic radiation demonstrated rigorous adherence to normal tissue constraints (Table S1). For the lungs, the median [IQR] dose was 17.9 Gy (13.8–18.2 Gy), with a median (IQR) V20 of 19.1% (12.3–22.3%) and a median (IQR) V5 of 47.3% (37.9–57.9%). Cardiac exposure was also effectively minimized, with a median (IQR) dose of 16.0 Gy (11.6–20.4 Gy). These dosimetric profiles confirm that the radiotherapy delivery was optimized and consistent with the safety thresholds, providing a stable baseline for interpreting combined-modality toxicities.

Figure 2 CONSORT diagram. ^a, the patient did not proceed with the second cycle of induction chemoimmunotherapy due to possible immune-related colitis. Following recovery from the colitis event, the patient successfully underwent cCRT. Cado, cadonilimab; cCRT, concurrent chemoradiotherapy; Chemo, chemotherapy.

TRAEs and DLTs

TRAEs of any grade occurred in 20 (100.0%) patients, most commonly leukopenia (95.0%), anemia (80.0%), neutropenia (80.0%), pneumonitis (55.0%), and fatigue (50.0%) (Table 2). The majority of TRAEs were mild; however, grade 3-4 TRAEs and grade 3-4 non-hematological TRAEs occurred in 16 patients (80.0%) and 10 patients (50.0%), respectively. The TRAEs at different treatment stages are summarized in Table S2. Notably, four (20.0%) patients experienced DLTs, including two cases of pneumonitis (10.0%), one case of colitis (5.0%), and one case of grade 5 pneumonia (with treatment-related etiology not fully excluded). An exploratory subgroup safety analysis according to PD-L1 tumor cell expression (<1%, 1–49%, and ≥50%) was performed, and the detailed TRAE profiles by treatment phase are provided in Tables S3-S5.

Characteristics of patients with pneumonitis and pneumonia

Noninfectious pneumonitis occurred in 11 patients, with 9 grade 1–2 cases and 2 grade 3–4 cases. Pulmonary events were observed across different treatment phases, including none during induction therapy, 2 during cCRT, and 9 during consolidation therapy. Systemic corticosteroids were administered in 4 of the 11 patients, and antibiotics were used in 10 patients. Among evaluable patients, the median time to improvement or recovery was 16 days (range, 4–84 days). 3 patients improved to grade ≤1 or achieved complete resolution. Immunotherapy rechallenge after improvement was attempted in 6 patients. In the setting of multimodality treatment, precise attribution of noninfectious pulmonary events to a single cause may be challenging (1,17,18), and the above classification was based on the available clinical data and investigator assessment.

One patient developed fatal pneumonia during cadonilimab consolidation therapy (Figure 3). Microbiological testing supported Klebsiella pneumoniae infection. However, a contribution from treatment-related pneumonitis could not be completely excluded. Therefore, this event was classified as fatal pneumonia with an indeterminate contribution from treatment-related pneumonitis. This patient was an elderly man with pre-existing bullous emphysema and impaired diffusion capacity who developed acute respiratory deterioration after two cycles of consolidation cadonilimab and died despite high-flow oxygen, broad-spectrum antibiotics, high-dose corticosteroids, and intensive supportive care. A comprehensive review of clinical, pathological, and radiographic data determined the cause of death to be probable pneumonia, with treatment-related pneumonitis not fully excluded. This fatal grade 5 event underscores the substantial clinical risks associated with intensified therapy, particularly in elderly patients with pre-existing pulmonary comorbidities such as bullous emphysema and impaired diffusion capacity. While a multidisciplinary review determined the primary cause of death to be probable pneumonia, the contributory role of treatment-related pneumonitis could not be definitively excluded, reflecting a toxicity profile that, while within the acceptable spectrum for intensified regimens, vigilant clinical monitoring is very much needed.

Figure 3 Representative imaging of chest computed tomography at different clinical time points from the patient who died from a probable pneumonia. Red arrows show the location of the lung lesion in different scans. (A) Pre-treatment. (B) After two cycles of induction therapy. (C) After concurrent chemoradiotherapy. (D) During consolidation. cCRT, concurrent chemoradiotherapy.

Discussion

In this safety run-in analysis, induction chemoimmunotherapy with cadonilimab followed by cCRT and consolidation cadonilimab demonstrated preliminary clinical feasibility with a safety profile generally consistent with intensified regimens in patients with unresectable stage III NSCLC. All 20 enrolled patients proceeded to cCRT, and 17 (85.0%) subsequently received consolidation immunotherapy. DLTs occurred in 4 patients (20.0%), and grade 3-4 non-hematologic TRAEs were observed in 10 patients (50.0%). These findings suggest that a PD-1/CTLA-4 bispecific antibody can be incorporated into an induction-based treatment strategy with manageable short-term toxicity, supporting continued evaluation in the ongoing phase II study. However, the observed pneumonitis events and grade 5 pulmonary event warrant cautious interpretation and close monitoring.

Previous studies have investigated the feasibility of induction immunotherapy or chemoimmunotherapy using PD-1/PD-L1 inhibitors (12,13,19,20). In the SPRINT study, locally advanced NSCLC patients with a PD-L1 tumor proportion score of ≥50% underwent three cycles of induction pembrolizumab, followed by risk-adapted thoracic radiotherapy and consolidation pembrolizumab. Among the 25 enrolled patients, definitive thoracic radiotherapy and consolidation pembrolizumab were administered to 24 patients (96.0%) and 21 patients (84.0%), respectively, resulting in a notable 1-year PFS rate of 76.0% (13). Additionally, in the AFT-16 study, unresectable stage III NSCLC patients received four cycles of induction atezolizumab, followed by standard cCRT and consolidation atezolizumab. Among the 62 enrolled patients, cCRT and consolidation atezolizumab were given to 44 patients (71.0%) and 35 patients (56.0%), respectively, resulting in a median PFS of 30.0 months (12). The therapeutic architecture of the current regimen aligns more closely with AFT-16 than with SPRINT. While the SPRINT trial utilized a biomarker-selected population (PD-L1 ≥50%) and adopted a risk-adapted approach that omitted concurrent chemotherapy for some patients (13), both AFT-16 and the present study retained a definitive cCRT within a broader, biomarker-agnostic population of unresectable stage III NSCLC (12). Moreover, a recent randomized phase II study (InTRist study) investigated the efficacy and safety of induction toripalimab/placebo plus chemotherapy, followed by cCRT and consolidation toripalimab in unresectable stage III NSCLC patients with bulky disease. Preliminary results from this trial indicated a significant improvement in PFS with induction toripalimab plus chemotherapy (n=27) compared to induction chemotherapy alone (n=25) [HR =0.25 (95% confidence interval: 0.07–0.90), P=0.03] (20).

To the best of our knowledge, the current study is the first prospective trial to evaluate the safety and efficacy of induction chemoimmunotherapy using a PD-1/CTLA-4 bispecific antibody. Among the first 20 patients, 20 (100.0%) received cCRT and 17 (85.0%) received consolidation immunotherapy, demonstrating the feasibility and tolerability of the current regimen. Notably, DLTs and grade 3–4 non-hematological TRAEs occurred in only four patients (20.0%) and 10 patients (50.0%), respectively. Our safety findings are consistent with previous studies evaluating cadonilimab in advanced NSCLC, as well as those exploring induction immunotherapy in stage III NSCLC (12-15,20). This safety profile appears broadly comparable to that reported in AFT-16, in which grade ≥3 TRAEs occurred in 48.4% of patients and grade ≥3 immune-related AEs occurred in 27.4%, including one grade 5 pneumonitis event (12). By comparison, SPRINT reported no grade 4–5 TRAEs. However, direct comparison should be interpreted cautiously because SPRINT enrolled only PD-L1-high patients and used thoracic radiotherapy without concurrent chemotherapy, both of which may influence toxicity risk and pulmonary event patterns (13). In addition, prior phase Ib/II experience in advanced NSCLC reported grade 3–4 TRAEs in 11.3% of patients receiving cadonilimab-based therapy, supporting the manageable toxicity profile of this bispecific platform outside the stage III setting (14).

Pneumonitis represents a clinically significant toxicity requiring vigilant monitoring in stage III NSCLC patients undergoing cCRT combined with immunotherapy, with particular attention warranted for Asian populations (21,22). In the previous studies, the observed pulmonary safety profile has varied according to population selection and treatment regimen. Specifically, the incidence of grade 3–5 pneumonitis vary between studies, with 6.5% reported in the predominantly White population (77.4%) of the AFT-16 trial, and 11.1% reported in the exclusively Asian cohort of the InTRist study (12,20). The SPRINT study reported a relatively low incidence of grade 3–5 pneumonitis (4.0%), likely due to the use of induction monotherapy and the omission of concurrent chemotherapy in some patients (13). In the prospective AYAME study of the PACIFIC regimen in Japanese patients, interstitial lung disease of grades 3 and 5 occurred in 11.2% and 1.8%, respectively, highlighting that clinically significant lung toxicity remains a major issue in Asian populations even with the current standard post-cCRT consolidation approach (23). In the current study, the observed incidence of grade 3–4 pneumonitis (10.0%) is slightly higher. In addition, one patient (5.0%) died of probable pneumonia during consolidation therapy with cadonilimab, although treatment-related pneumonitis could not be entirely ruled out as a possible underlying cause. It may be attributed to the intensified dual-checkpoint blockade combined with chemotherapy. This suggests that while a bispecific antibody-based induction is feasible, it necessitates more rigorous pulmonary monitoring compared to PD-1/PD-L1 monotherapy induction paradigms.

To mitigate the incidence of pneumonitis, comprehensive optimization of radiotherapy procedures is imperative, including refinement of target volume delineation, dose-fractionation regimens, workflow management, and quality control measures. Novel radiotherapy approaches, including stereotactic body radiotherapy for primary lung tumors followed by concurrent mediastinal chemoradiotherapy, and accelerated hypo-fractionated radiotherapy, are currently under clinical investigation as potential strategies to mitigate pneumonitis risk in stage III NSCLC patients (24,25). Additionally, the development of advanced prediction models for radiation-induced and immune-related pneumonitis, incorporating artificial intelligence and other emerging technologies, represents a crucial area of research with significant clinical implications for this patient population (26,27).

Our study had several strengths. First, no study has previously assessed the safety and efficacy of induction chemoimmunotherapy using a PD-1/CTLA-4 bispecific antibody in stage III NSCLC. Although this study was a single-arm study, several previous clinical trials have investigated the efficacy of cCRT alone, cCRT plus consolidation immunotherapy, and induction immunotherapy (1,2,12,13,16,19,20), which may serve as reliable historical controls. Moreover, the data generated from serially collected biological samples can provide valuable information regarding the molecular mechanisms underlying the effective anti-tumor immune response induced by the trial regimen, which can be used to design improved combinational treatment strategies for unresectable stage III NSCLC. However, several limitations must be acknowledged. First, this study was conducted at a single high-volume academic center, and the generalizability of our findings requires validation in future multi-center, randomized controlled trials. Moreover, as an early-phase report, the median follow-up is insufficient to assess long-term survival endpoints or potential chronic immune-related toxicities. Finally, the findings of this study should be interpreted as preliminary and descriptive, as they are based on the predefined safety run-in cohort of an ongoing phase II trial, while the full study continues for subsequent efficacy evaluation.

Conclusions

In this safety run-in analysis, induction therapy with cadonilimab plus chemotherapy, followed by standard cCRT and consolidation cadonilimab, demonstrated a manageable safety profile and promising feasibility consistent with intensified regimens in patients with driver mutation-negative, unresectable stage III NSCLC. DLTs occurred in 4 of 20 patients (20.0%), grade 3–4 non-hematologic TRAEs occurred in 10 patients (50.0%), and grade 3–4 pneumonitis occurred in 2 patients (10.0%). One patient (5.0%) developed grade 5 pneumonia, with treatment-related pneumonitis not fully excluded. These findings support continued evaluation of this regimen in the ongoing phase II trial, with close monitoring of pulmonary toxicity.

Acknowledgments

We thank the patients and their families for participating in this study. We also thank the Akeso, Inc., for providing the corresponding drugs.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0122/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0122/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0122/prf

Funding: This study was supported by Key Clinical Specialty Project of Shanghai, National Natural Science Foundation of China (grant No. 82003230), the Chinese Society of Clinical Oncology (grant Nos. Y-MSDPU2022-0561 and Y-2020Sciclone) and Beijing Huakang Public Health Foundation (grant No. EXZL-GX-054).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0122/coif). All authors report the support from Akeso, Inc. for providing the corresponding drugs. The authors have no other 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 and its subsequent amendments. The study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (No. 2404294-8-2504B). Written informed consent was obtained from all patients.

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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(English Language Editor: L. Huleatt)