Heterogeneous Radioimmunotherapy for Bulky Tumors: A Phase 1 Trial for Advanced Non-Small Cell Lung Cancer

Abstract

Purpose

Inoperable bulky tumors remain challenging to treat with chemotherapy, radiation therapy (RT), or immune checkpoint inhibitors. We developed a novel heterogeneous RT technique with an eclipse-shaped dose distribution (EclipseRT, ERT) by embedding partial-tumor stereotactic body RT (immunogenic) within a low-dose RT (immunomodulatory) field targeting the gross tumor volume. In our previous study, we demonstrated that ERT plus anti–programmed cell death protein 1 (αPD-1) (iERT) activated the natural killer/DC/CD8⁺ T-cell axis, triggering potent antitumor immunity against bulky tumors in mouse tumor models. Here, we report a phase 1 trial to evaluate the safety and feasibility of iERT for advanced non-small cell lung cancer (NSCLC).

Methods and Materials

This phase 1 trial (NCT05615142, iERT-01) employed a 3 + 3 dose-escalation design. Patients with stage IV NSCLC and bulky tumors (>5 cm) who had failed standard therapy, were ineligible for standard therapy, or declined standard therapy were enrolled. iERT was delivered in 1 to 3 fractions of 10 Gy stereotactic body RT plus 2 Gy low-dose RT with anti–programmed cell death protein 1 (αPD-1). The primary endpoint of the iERT-01 trial was safety and tolerability. Key secondary endpoints included objective response rate, progression-free survival, and overall survival.

Results

A total of 9 patients with bulky NSCLC were included. The median follow-up was 22.3 months. iERT was well tolerated, with no dose-limiting toxicities observed. Overall, 7 of 9 patients (77.8%) experienced at least 1 adverse event, and 7 of 9 (77.8%) experienced treatment-related adverse events, all of which were grade 1 or 2. Moreover, it demonstrated encouraging antitumor activity, achieving an objective response rate of 55.6% (5 of 9), with a median progression-free survival of 12.6 months and a median overall survival of 26.4 months.

Conclusions

iERT demonstrated favorable safety and feasibility in this phase 1 trial for advanced bulky NSCLC. Larger-cohort studies with optimized dose regimens are still warranted to further validate the novel strategy.

Introduction

Bulky solid tumors (>5 cm) represent a major therapeutic challenge and are commonly associated with poor clinical outcomes.^1,2 These tumors are characterized by rapid growth and pronounced intratumoral hypoxia, which together confer intrinsic resistance to systemic chemotherapy and conventional fractionated radiation therapy (RT; 1.8-2.0 Gy per fraction).^1,2 Although RT dose escalation may partially overcome this resistance, its clinical application is often constrained by the close proximity of surrounding organs at risk (OARs), which increases the likelihood of severe treatment-related adverse events (TRAEs; grade 3 or higher).3, 4, 5 In addition, bulky tumors are characterized by an unfavorable tumor microenvironment (TME), marked by low infiltration of effector cells, eg, natural killer (NK) and T cells, and antigen-presenting cells, along with an enrichment of immunosuppressive cell populations such as regulatory T cells.^1,2 Consequently, bulky tumors exhibit poor responsiveness to immune checkpoint inhibitors (ICIs).^1,2

Low-dose radiation therapy (LDRT) with a fraction dose ≤2 Gy and a total dose of less than 10 Gy can reprogram the TME by polarizing macrophages to the M1 phenotype and increasing tumor infiltration by NK cells, NK group 2D⁺ CD4⁺ T cells, and CD8⁺ T cells.6, 7, 8, 9 Our results and those of others have shown that LDRT can markedly potentiate the RT-induced abscopal effect by recruiting CD8⁺⁷ and/or CD4⁺ T cells⁸ via the induction of the T lymphocyte chemoattractant CXCL10 in LDRT-irradiated abscopal tumors. However, LDRT is not tumoricidal, and its efficacy may be limited when used alone in bulky tumors.

Stereotactic body radiation therapy (SBRT), which delivers highly ablative doses per fraction (5-30 Gy), has revolutionized the treatment of localized and oligometastatic disease by overcoming radioresistance and promoting immunogenic remodeling of TME. In addition to direct tumor cell killing, SBRT can induce vascular disruption and immunogenic cell death, thereby stimulating tumor-specific CD8⁺ T-cell responses and triggering abscopal effects.10, 11, 12 However, its application in bulky solid tumors is constrained by normal tissue tolerance and is therefore typically limited to lesions ≤5 cm. Moreover, the longstanding emphasis on dose homogeneity, while appropriate for small curable tumors, may be suboptimal for large incurable lesions, where the therapeutic objective may shift from maximal local tumor cell killing toward systemic immune activation.^13,14

To overcome this challenge, we developed a heterogeneous RT strategy termed eclipse radiation therapy (EclipseRT, ERT), named for its eclipse-like dose distribution.¹⁵ In preclinical studies, we demonstrated that ERT delivers SBRT to intratumoral subvolumes to promote T-cell priming through immunogenic cell death and antigen release, whereas irradiating the whole-tumor volume with LDRT to reprogram the TME and enhance T-cell recruitment via chemokine induction.¹⁵ We hypothesized that combining ERT with ICIs would elicit potent antitumor immunity, a strategy we term immuno-ERT (iERT).¹⁵

In mice bearing bulky tumors, we demonstrated that iERT exerts potent antitumor activity. The SBRT component activates type I interferon signaling, which promotes the intratumoral accumulation of XCL1⁺ NK cells. These NK cells secrete X-C motif chemokine ligand 1 (XCL1) to recruit X-C motif chemokine receptor 1⁺ (XCR1⁺) conventional type 1 dendritic cells, a specialized DC subset required for antigen presentation and effective CD8⁺ T-cell priming, thereby contributing critically to the therapeutic efficacy of iERT. Meanwhile, the LDRT component further remodels the TME by enhancing the infiltration of NK cells and CD8⁺ T cells, collectively amplifying systemic antitumor immunity.¹⁵

To investigate the clinical feasibility of this strategy, a phase 1 trial was initiated in patients with bulky non-small cell lung cancer (NSCLC). Herein, we report the results of this trial.

Methods and Materials

The phase 1 trial protocol (Eclipse01) was approved by the Ethics Committee of West China Hospital, Sichuan University, and registered on ClinicalTrials.gov (NCT05615142). It was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before the commencement of treatment. Key inclusion criteria were age ≥18 years old, Eastern Cooperative Oncology Group 0 to 2, stage IV NSCLC (American Joint Committee on Cancer eighth edition), tumor size >5 cm, failure of standard therapy, unsuitability for standard treatment, or refusal of chemotherapy. Key exclusion criteria included driver gene positivity (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], and ROS proto-oncogene 1, receptor tyrosine kinase [ROS1]) or unknown driver gene status, and active central nervous system metastases. Patients in the dose escalation received LDRT + partial SBRT in 3 cohorts with increasing dose levels: LDRT 2 Gy/1 fraction + SBRT 10 Gy/1 fraction in dose level 1; LDRT 4 Gy/2 fractions + SBRT 20 Gy/2 fractions in dose level 2; LDRT 6 Gy/3 fractions + SBRT 30 Gy/3 fractions in dose level 3. First, 3 patients were enrolled at the lowest dose level group: LDRT 2Gy/1fraction + SBRT 10Gy/1fraction. If a dose-limiting toxicity (DLT) occurred in 1 of these 3 patients, up to 3 additional patients would be enrolled. Dose escalation would cease if more than 1 DLT was observed in a cohort of 6 or fewer patients, designating that dose level as nontolerated. DLT was evaluated as at least possibly related to LDRT and/or programmed cell death protein 1 (PD-1) inhibitors, occurring within ≤28 days from the start of RT, including during the RT, the end of RT, and events confirmed as DLT during the observation of the first cycle of PD-1 inhibitor use.

The gross tumor volume for LDRT (GTV_LDRT) and OARs was defined and contoured using computed tomography (CT), 2-deoxy-2-[fluorine-18]fluoro-D-glucose (¹⁸F-FDG) positron emission tomography (PET)/CT, bronchoscopy, or mediastinoscopy. The GTV_LDRT was expanded by 5 to 10 mm to establish the planning target volume for LDRT (PTV_LDRT).

The GTV for SBRT (GTV_SBRT) or internal target volume (ITV) for SBRT (ITV_SBRT) was selected within GTV_LDRT, focusing on the tumor center while avoiding (1) necrosis; (2) pulmonary atelectasis; and (3) regions located in close proximity to the bronchial tree or mediastinal structures. The GTV_SBRT should be positioned away from the tumor edge to create an intratumoral dose fall-off region and reduce unnecessary high-dose exposure to adjacent normal tissues. For patients undergoing 4-dimensional simulation, the ITV_SBRT was required to remain within the tumor throughout respiratory motion. In principle, the target diameter is ≤3 cm, and the target volume (GTV_SBRT or ITV_SBRT) is ≤14.1 cm³. The investigators were allowed to set more than 1 GTV_SBRT or ITV_SBRT depending on tumor size. The use of ¹⁸F-FDG-PET/CT for simulation is encouraged.

More than 1 GTV_SBRT or ITV_SBRT can be selected for large or irregular tumors, as was done in patient no. 8 (Table E1). The spacing between subvolumes was individualized according to tumor geometry, respiratory motion, and nearby OAR, rather than being defined by a fixed distance.

SBRT and LDRT were delivered concurrently, with ERT at dose levels 2 and 3 administered on consecutive days. SBRT plans should meet the compliance criteria of Radiation Therapy Oncology Group (RTOG) 0915.

PD-1 inhibitors, with or without chemotherapy and other agents (as decided by the principal investigator), were administered within 7 days following ERT. Optional PD-1 inhibitors, including sintilimab, nivolumab, tislelizumab, camrelizumab, and pembrolizumab, were administered intravenously. PD-1 inhibitors were given as recommended in the instruction manual until disease progression, unacceptable toxicities, the patient withdrew informed consent, or PD-1 inhibitor treatment reached a maximum of up to 24 months.

TRAEs were defined as adverse events (AEs) related to ERT, ICI, chemotherapy, or other anticancer agents. AEs were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Tumor responses, including complete response, partial response (PR), stable disease, and progressive disease, were assessed by CT imaging using the Response Evaluation Criteria in Solid Tumors version 1.1. The objective response rate (ORR) was calculated as the proportion of complete response plus PR. The primary endpoint was safety and tolerability, and the key secondary endpoints included ORR, PFS, and overall survival (OS).

Statistical analysis

Time-to-event data were analyzed using the Kaplan-Meier method to estimate the survival function, plot survival curves, and estimate the median time to event along with its 95% CI.

Results

A phase 1 trial was conducted to investigate the safety and tolerability of iERT (± chemotherapy or other systemic therapy) in patients with stage IV NSCLC with tumor size >5 cm (typical size unsuitable for whole-tumor SBRT) who had failed standard therapy, or who were unsuitable for standard treatment, or refused chemotherapy (Eclipse01 trial, NCT05615142; Fig. 1A). Between June 2022 and April 2024, 9 patients were enrolled for treatment (dose escalation: LDRT 2 Gy/1 fraction + SBRT 10 Gy/1 fraction, n = 3; LDRT 4 Gy/2 fractions + SBRT 20 Gy/2 fractions, n = 3; and LDRT 6 Gy/3 fractions + SBRT 30 Gy/3 fractions, n = 3), and 3 patients withdrew (Fig. 1B).

Figure 1.

Scheme and enrollment for iERT-001 trial. (A) Scheme of study design for the phase 1 clinical trial (NCT05615142) to evaluate iERT in patients with stage IV NSCLC with tumors >5 cm who have failed standard therapy, or who are unsuitable for standard treatment, or who refuse chemotherapy. Patients received escalating doses of SBRT (10 Gy, 20 Gy, and 30 Gy) combined with LDRT (2 Gy, 4 Gy, and 6 Gy), followed by PD-1 inhibitors. The primary endpoint was safety and tolerability, whereas secondary endpoints included ORR, PFS, and OS. (B) Flow chart of patient enrollment for NCT05615142. Nine patients were enrolled, and 3 patients per group were treated at 3 different dose levels, with 3 exclusions.

Abbreviations: αPD-1 = anti–programmed cell death protein 1; ALK = anaplastic lymphoma kinase; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology Group; iERT = immuno-ERT; NSCLC = non-small cell lung cancer; LDRT = low-dose radiation; ORR = overall response rate; OS = overall survival; PD-1 = programmed cell death protein 1; PFS = progression-free survival; Q3W = every 3 weeks; RT = radiation therapy; SBRT = stereotactic body radiation therapy.

The median age at enrollment was 69 (59-85) years, and all patients were male, with 88.9% (8 of 9) of them having a smoking history (Table 1). There were 5 cases classified as lung adenocarcinoma and 4 cases as lung squamous cell carcinoma. A total of 33.3% (3 of 9) of patients had programmed death-ligand 1 (PD-L1) expression >50%. All patients received the iERT on the primary bulky tumor of the lung (Table E1).

Table 1.

Patients’ characteristics

Patient	Age	Sex	Smoking history	ECOG performance status	Histology	PD-L1 TPS (%)	Clinical stage	Metastasis sites	Number of metastasis sites	Prior treatment lines	Prior radiation therapy	Prior immunotherapy
P1	64	Male	Yes	2	ADC	75	IVA	Adrenal gland	1	0	None	None
P2	84	Male	Yes	2	SCC	20	IVA	Brain	1	0	None	None
P3	68	Male	Yes	1	SCC	1	IVB	Pleura, adrenal gland	2	2	None	Yes; tislelizumab
P4	75	Male	Yes	2	SCC	<1	IVB	Pleura, bone, celiac lymph nodes	3	0	None	None
P5	85	Male	No	0	ADC	<1	IVA	Lung	1	1	Left lower lung lobe lesion, 42 Gy/7f	Yes; sintilimab
P6	59	Male	Yes	0	ADC	<1	IVB	Lung, brain, axillary lymph nodes, pleura	4	2	None	Yes; tislelizumab
P7	69	Male	Yes	1	SCC	10	IVB	Axillary lymph nodes, bone	2	1	Left upper lung/mediastinal lesions, 14.4 Gy/8f	None
P8	74	Male	Yes	1	ADC	60	IVB	Cardiophrenic angle lymph nodes, lung, bone	3	0	None	None
P9	69	Male	Yes	2	ADC	60	IVA	Brain	1	1	Left upper lung lobe lesion, 60 Gy/30f	Yes; pembrolizumab

Abbreviations: ADC = adenocarcinoma; ECOG = Eastern Cooperative Oncology Group; PD-L1 = programmed death-ligand 1; SCC = squamous cell carcinoma; TPS = tumor proportion score.

Seven of 9 patients (77.8%) experienced at least 1 AE, and 7 of 9 patients (77.8%) experienced TRAEs, and 6 of 9 (66.7%) experienced immune-related adverse events (Fig. 2 and Table E2). No grade ≥3 TRAEs or treatment-related deaths occurred.

Figure 2.

TRAEs in the iERT-001 trial. (A) Heatmap showing the distribution of TRAEs by grade and category. Dark red stars indicate TRAEs. Dark circles indicate irAEs.

Abbreviations: irAEs = immune-related adverse events; iERT = immuno-ERT; TRAE = treatment-related adverse events.

At the latest data update (January 14, 2026), the median follow-up was 22.3 (7.5-43.1) months. The maximum change in tumor size from baseline for the irradiated lesion and overall measurable lesions is shown in Fig. 3A. The ORR was 55.6% (5 of 9) (Fig. 3A). Of the 9 patients, 3 had nonirradiated lesions (Table E1). A swimmer plot demonstrating the time to tumor response is shown in Fig. 3B. The estimated median PFS was 12.6 (95% CI, 0.9-not available [NA]) months, and the estimated median OS was 26.4 (95% CI, 7.5–NA) months (Fig. 3C).

Figure 3.

Waterfall plot, swimming plot, and survival curves in the iERT-001 trial. (A) Waterfall plot showing the maximum percentage change in irradiated target lesions (left) and overall target lesions (right) in response to treatment across the 3 dose groups: 2 Gy/1f + 10 Gy/1f (teal), 4 Gy/2f + 20 Gy/2f (pink), and 6 Gy/3f + 30 Gy/3f (orange). (B) Swimming plot showing treatment responses and their duration in patients. (C) PFS and OS curves demonstrated by the Kaplan-Meier method.

Abbreviations: ERT = eclipse radiation therapy; iERT = immuno-ERT; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease.

In case 1 (P1, Fig. 4A), a 64-year-old man was diagnosed with lung adenocarcinoma (cT4N3M1b, IVA). This patient presented to the emergency department with severe airway obstruction, type 2 respiratory failure, and required noninvasive ventilator-assisted ventilation. A CT scan revealed a 10.5 × 7.0 cm tumor mass of the right lung compressing the airway. Biopsy specimens demonstrated positive PD-L1 expression (tumor proportion score [TPS], 72%) and driver-gene–negative. The patient received ERT containing SBRT at 10 Gy × 1 fraction (GTV_SBRT, 0.96 cm³) and LDRT at 2 Gy × 1 fraction (whole tumor, GTV_LDRT, 278.14 cm³) followed by pembrolizumab the next day (Fig. 4A, case 1). Dyspnea resolved 3 days after iERT. One month later, PR was confirmed. The patient was treated with pembrolizumab + pemetrexed as maintenance therapy, and the PR was maintained for 43.1 months (Fig. 4A).

Figure 4.

Representative cases treated with iERT. Representative CT images of patients treated with ERT, showing baseline scans, ERT dosimetry, and post-ERT scans of tumors treated with 1 (A for patient 1), 2 (B for patient 4), and 3 (C for patient 8) fractions of iERT. Pre-iERT ¹⁸F-FDG-PET/CT scans are shown, and the DVH shows the dose distribution for GTVs and normal tissue (D for patient 3).

Abbreviations: CT = computed tomography; DVH = dose-volume histogram; ERT = eclipse radiation therapy; iERT = immuno-ERT; ITV = internal target volume; ¹⁸F-FDG = 2-deoxy-2-[fluorine-18]fluoro-D-glucose; GTV = gross tumor volume; LDRT = low-dose radiation; PET/CT = positron emission tomography/computed tomography; PR = partial response; SBRT = stereotactic body radiation therapy.

Case 2 (P4, Fig. 4B) was a 75-year-old man with stage IVB (cT4N2M1c) squamous NSCLC and a PD-L1 TPS <1%. Chest CT showed an 8.1 × 5 cm right‑lower‑lobe mass. He received ERT: SBRT at 10 Gy × 2 fractions (GTV_SBRT 0.91 cm³) and LDRT at 2 Gy × 2 fractions (whole tumor, GTV_LDRT 134.81 cm³), together with albumin‑bound paclitaxel and sintilimab (αPD-1). The patient subsequently continued maintenance therapy with sintilimab. Two months after iERT, imaging confirmed PR, which persisted for 15.4 months.

Case 3 (P8, Fig. 4C) described a 74-year-old man who presented with left-sided chest pain and dyspnea. He was diagnosed with cT4N3M1c stage IVB lung adenocarcinoma, with a PD-L1 TPS of 60%. He received pembrolizumab plus ERT (SBRT: 10 Gy × 3 fractions, GTV 1.6 cm³; LDRT: 2 Gy × 3 fractions, whole‑tumor GTV 607.6 cm³ over 3 consecutive days), followed by pembrolizumab maintenance. Two months after iERT, imaging confirmed a PR, accompanied by marked symptom relief. The patient achieved a PFS of 13.6 months.

An example of pre-iERT ¹⁸F-FDG-PET/CT scans used for ERT treatment planning is presented in the second column of Fig. 4D, and the dose-volume histogram in Fig. 4D illustrates the dose distribution for GTVs and surrounding normal tissues. ¹⁸F-FDG-PET/CT can be applied to distinguish normal lung tissue (eg, pulmonary atelectasis) from tumor when setting the GTV_SBRT.

Discussion

Radioimmunotherapy trials have thus far shown only modest clinical benefit, largely because conventional RT trial designs fail to elicit robust and durable systemic antitumor immunity. Specifically, high-dose irradiation of tumor-draining lymph nodes can deplete T cells within tumor-draining lymph nodes, which are highly radiosensitive; repeated high-dose RT to tumors may eliminate newly recruited T cells activated by ICIs; in addition, excessive RT–associated toxicity can further compromise therapeutic efficacy.^16,17 There is therefore an urgent need to develop novel RT strategies tailored to effectively potentiate ICIs. Our preclinical studies demonstrated that iERT activates type I interferon signaling, thereby promoting NK-cell activation and downstream DC–CD8⁺ T-cell–mediated adaptive antitumor immunity.¹⁵ Consistent with these observations, independent preclinical studies from other groups have provided convergent support for the immunologic and therapeutic rationale of heterogeneous RT combined with ICIs.^18,19

Based on this rationale, we translated this novel strategy into the clinic, initiating the Eclipse01 trial as a proof-of-concept for heterogeneous RT combined with ICIs in NSCLC. In this phase 1 trial of 9 patients with NSCLC bulky tumors who had failed standard therapy, were unsuitable for standard treatment, or declined chemotherapy, ERT delivered as 1 to 3 fractions of 10 Gy plus 2 Gy in combination with PD-1 inhibitors was feasible and well tolerated, with no ≥grade 3 TRAEs, and demonstrated encouraging antitumor activity, with an median PFS of 12.6 (95% CI, 0.9–NA) and a median OS of 26.4 (95% CI, 26.4–NA) months.

In a phase 1 trial with metastatic disease, multisite SBRT (up to 4 sites) combined with pembrolizumab proved safe and effective, with an ORR of 13.2% and a disease control rate of 44.1%.²⁰ Notably, partial-volume SBRT for bulky lesions (>65 cm³, n = 62) yielded a 1-year local failure rate (13.3%) comparable to that achieved with complete SBRT for smaller tumors (5.4%, n = 157).²¹ One key difference from the iERT strategy was that only a partial tumor was irradiated with SBRT without LDRT covering the entire tumor in this trial.²¹ However, partial SBRT may not be optimal, as we demonstrated in mice that partial SBRT + αPD-1 was less effective than iERT. This difference reflects the requirement for LDRT to inflame the TME and elicit optimal CD8⁺ T-cell responses, suggesting that ERT may represent a more effective partner for ICIs to treat bulky tumors.¹⁵

Spatially fractionated radiation therapy (SFRT), using 2-dimensional grid radiation therapy (GRID) or 3-dimensional lattice techniques, facilitates the delivery of ablative radiation doses (10-25 Gy × 1-5 fractions) to discrete intratumoral subvolumes, thereby inducing potent cytoreduction although maintaining an acceptable safety profile for bulky masses. Although retrospective data suggest that SFRT is an effective palliative RT strategy for large-volume solid tumors and sarcomas, these findings are limited by significant interstudy heterogeneity and the absence of prospective clinical validation.22, 23, 24, 25, 26 Although SFRT ensures complete target coverage, this approach carries a substantial risk of high-grade complications. In the reported series, ≥grade 3 toxicities included 2 nonhealing wounds/skin ulcers and 7 fistulas (bowel, esophageal, and bronchopleural).²⁷ Furthermore, excessive dosing in the valley regions may directly deplete newly infiltrated CD8+ T cells, potentially leading to a clinically significant immunosuppressive effect.²⁸ In the era of ICIs, SFRT plus ICIs has been reported in a few patients without systematic evaluation in standardized clinical studies. Our study first prospectively evaluated the combination of ERT and PD-1 inhibitors in a phase 1 trial.

In contrast to conventional SFRT, which distributes high-dose RT relatively uniformly across bulky tumors to maximize cytoreduction, ERT is designed as an immune-adaptive RT strategy based on biologically informed dose heterogeneity. Specifically, ERT integrates (1) a treatment objective that prioritizes optimal remodeling of the TME to better synergize with ICIs rather than maximal tumor debulking alone; (2) immunogenic SBRT delivered with intermediate dose fractionation (8-12 Gy) to activate innate immune cells (eg, NK cells and conventional DCs), thereby promoting the priming of adaptive antitumor T-cell responses10, 11, 12; (3) functional imaging, such as FDG and hypoxia PET in the future, to define biologically active intratumoral subvolumes for high-dose irradiation, including hypoxic regions that are resistant to conventional fractionated RT; and (4) LDRT delivered to the entire tumor volume, leveraging its immunomodulatory effects to promote the recruitment of antitumor immune cells, including NK cells and T cells.¹⁵ Based on this rationale, we conducted the prospective phase 1 trial to evaluate the safety and feasibility of ERT with PD-1 inhibitors. Notably, given the phase 1 design with a primary focus on feasibility and severe toxicities, the small sample size may preclude precise toxicity assessment and the identification of rare or delayed AEs.

In conclusion, we propose iERT, a novel strategy of immune-adaptive RT, combining LDRT, SBRT, and ICI therapy, to address the clinical challenge of bulky tumors and expand the indications of RT in the immunotherapy era. This strategy is safe, practical, and feasible, and a phase 2 randomized study is currently ongoing (NCT06121505).²⁹

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.