Introduction: The Evolving Landscape of Refractory Solid Tumor Management
The management of advanced, recurrent, or refractory solid tumors remains one of the most significant challenges in modern oncology. Patients who have progressed after multiple lines of systemic treatment, including standard-of-care chemotherapy and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors, often face a dearth of evidence-based options. For these patients, the prognosis is typically poor, and the focus frequently shifts toward palliative care or clinical trials investigating novel therapeutic combinations.
In recent years, the combination of radiotherapy and immunotherapy has emerged as a compelling strategy to overcome treatment resistance. Specifically, Stereotactic Body Radiotherapy (SBRT) is hypothesized to act as more than just a local cytoreductive tool. By inducing immunogenic cell death, SBRT can release tumor-associated antigens and pro-inflammatory cytokines, effectively turning the tumor into an ‘in situ’ vaccine. When paired with immune checkpoint inhibitors, this can theoretically enhance systemic anti-tumor responses—a phenomenon often discussed in the context of the abscopal effect.
A recent Phase 1b study published in Cancer Communications explores this synergy using cadonilimab, a novel humanized immunoglobulin G1 (IgG1) bispecific antibody that simultaneously targets PD-1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). This study provides critical data on the safety and efficacy of this combination in a population of heavily pretreated patients with refractory solid tumors.
The Rationale for Cadonilimab and SBRT
Cadonilimab (AK104) represents a new generation of immunotherapy. Unlike the combination of two separate agents (such as nivolumab and ipilimumab), cadonilimab is designed to provide dual checkpoint blockade within a single molecule. This bispecific approach aims to enhance dose-dependent binding to lymphocytes infiltrating the tumor microenvironment, potentially offering superior efficacy with a more manageable safety profile compared to traditional combination therapies. By blocking both PD-1 and CTLA-4, cadonilimab addresses two distinct pathways of immune evasion, promoting both the activation of T-cells in the lymph nodes and the restoration of effector function within the tumor itself.
SBRT complements this by delivering high-precision, ablative doses of radiation to specific lesions. In the refractory setting, where tumor burden is often high and symptomatic, SBRT provides rapid local control. The integration of SBRT with cadonilimab seeks to leverage the ‘priming’ effect of radiation to sensitize cold tumors to dual checkpoint blockade.
Study Design and Patient Population
This Phase 1b study was a single-center, open-label trial conducted to evaluate the safety and clinical activity of SBRT plus cadonilimab. The study enrolled 63 patients between August 2022 and September 2023. To be eligible, patients had to have advanced solid tumors that had progressed after at least two prior lines of systemic therapy. Notably, the study population was heavily pretreated, with a median of 3.0 prior treatment lines (range 2.0-4.0). Furthermore, 46.0% of the cohort had previously received PD-1/PD-L1 therapy, representing a ‘hard-to-treat’ group with established resistance to monotherapy checkpoint inhibition.
The primary malignancies represented were non-small cell lung cancer (NSCLC) at 36.5% and soft tissue sarcoma at 12.7%. The intervention involved SBRT targeted at high-burden or symptomatic lesions, combined with intravenous cadonilimab administered at a dose of 6 mg/kg every two weeks. The primary endpoint was safety, with secondary endpoints including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and local control (LC).
Safety Results: Manageable Toxicity in a Vulnerable Cohort
Safety is a paramount concern when combining high-dose radiotherapy with dual checkpoint blockade. In this study, treatment-related adverse events (TRAEs) occurred in 38.1% (24/63) of patients. Crucially, the incidence of high-grade toxicity was remarkably low; Grade 3 TRAEs were reported in only 3.2% (2/63) of the participants, and no Grade 4 or 5 TRAEs were observed.
The most common adverse events included:
- Pain: 12.7%
- Elevated transaminases (AST/ALT): 12.7%
- Pneumonia: 6.4%
- Fatigue: 6.4%
- Nausea: 4.8%
- Fever: 4.8%
The low rate of severe immune-related adverse events (irAEs) is particularly noteworthy. Standard combinations of PD-1 and CTLA-4 inhibitors are often limited by high rates of colitis or endocrine toxicities. The bispecific structure of cadonilimab may contribute to this improved safety profile by focusing immune activation more specifically within the tumor microenvironment rather than systemically.
Efficacy Outcomes: Surprising Responses in Late-Line Therapy
Despite the refractory nature of the tumors, the combination demonstrated robust clinical activity. The Objective Response Rate (ORR) for the entire cohort was 23.8% (95% CI, 14.0%-36.2%). In the context of third-line or later therapy, where ORRs often hover in the single digits or low teens, these results are highly encouraging.
Survival Data
The median progression-free survival (PFS) was 7.2 months (95% CI, 6.3-8.2 months), and the median overall survival (OS) reached 10.0 months (95% CI, 7.7-12.4 months). These metrics suggest that the combination can provide a meaningful period of disease stabilization for patients who have exhausted standard options.
Local Control
The efficacy of SBRT was confirmed by the local control rates. The 6-month local control rate was 98.4%, and the 12-month rate remained high at 93.0%. This indicates that the radiotherapy component was highly effective at stabilizing the targeted lesions, providing symptomatic relief and preventing local progression.
Subgroup Insights: Focus on Non-Small Cell Lung Cancer
In a pre-specified subgroup analysis of 23 patients with NSCLC, the combination remained active. The ORR was 17.4% (95% CI, 5.0%-38.8%), with a median PFS of 6.9 months and a median OS of 9.1 months. Given that many of these patients had already failed prior immunotherapy, the ability of cadonilimab plus SBRT to re-induce a response suggests a potential strategy for overcoming acquired resistance to PD-1 blockade in lung cancer.
Prognostic Factors and Clinical Implications
Multivariate analysis identified two significant predictors of improved outcomes. Patients who received at least 6 cycles of cadonilimab and those with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 experienced significantly better PFS and OS (P < 0.05). This highlights the importance of patient selection and the potential benefit of sustained treatment in those who tolerate the initial cycles well.
Expert Commentary and Mechanistic Insights
The success of this Phase 1b trial underscores the potential of ‘dual-targeting’ immunotherapy. By combining PD-1 and CTLA-4 inhibition into a single molecule, cadonilimab appears to bypass some of the toxicity hurdles associated with combination bolus injections. When SBRT is added to the mix, it likely acts as a catalyst. Radiotherapy can increase the expression of MHC class I molecules and facilitate the infiltration of CD8+ T-cells into ‘cold’ tumors, which may explain why nearly a quarter of these heavily pretreated patients responded to the therapy.
However, clinicians must remain cautious. While the Grade 3 TRAE rate was low, the presence of treatment-related pneumonia (6.4%) reminds us that combining thoracic SBRT with immunotherapy requires careful radiation planning to minimize lung V20 doses and close monitoring for pneumonitis.
Conclusion
The combination of SBRT and cadonilimab represents a promising therapeutic avenue for patients with refractory solid tumors who have failed multiple lines of systemic treatment. With a manageable toxicity profile and an ORR of 23.8%, this regimen offers a potential bridge for patients who otherwise have limited therapeutic prospects. Future Phase 2 and 3 trials are warranted to further define the optimal sequencing of radiation and bispecific antibodies and to identify biomarkers that can predict which patients will derive the greatest benefit from this synergistic approach.
Trial Registration and Funding
This study was retrospectively registered at ClinicalTrials.gov (NCT05915481) on August 20, 2022. The research was supported by institutional grants and contributing pharmaceutical partners involved in the development of cadonilimab.
References
1. Xiao Y, Wang Y, Li J, et al. Stereotactic body radiotherapy plus cadonilimab (PD-1/CTLA-4 bispecific antibody) as third-line or beyond therapy for refractory solid tumors: A phase 1b study. Cancer Commun (Lond). 2025;45(10):1235-1246. doi:10.1002/cac2.70051.
2. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017.
3. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256-265.