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

Abstract

Background: Cadonilimab is a humanized immunoglobulin G1 bispecific antibody targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) combined with cadonilimab in patients with advanced recurrent or refractory solid tumors.

Methods: Patients with advanced solid tumors who progressed after at least two lines of systemic treatment, including immunotherapy, and were eligible for SBRT were enrolled. SBRT was administered to patients with high-burden/symptomatic lesions in combination with intravenous cadonilimab (6 mg/kg, once every 2 weeks). The primary endpoint was safety.

Results: Sixty-three patients were enrolled from August 28, 2022, to September 14, 2023 (median follow-up: 9.1 months). The median prior treatment line was 3.0 (range 2.0-4.0). Approximately 46.0% (29/63) of patients had received prior PD-1/PD-L1 therapy, 36.5% (23/63) and 12.7% (8/63) of patients had non-small cell lung cancer and soft tissue sarcoma. Treatment-related adverse events (TRAEs) occurred in 38.1% (24/63) of patients, with grade 3 TRAEs reported in 3.2% (2/63). The most common TRAEs included pain (12.7%), elevated transaminases (12.7%), pneumonia (6.4%), fatigue (6.4%), nausea (4.8%), and fever (4.8%). The objective response rate (ORR) was 23.8% (95% confidence interval [CI], 14.0%-36.2%). The median progression-free survival (PFS) was 7.2 months (95% CI, 6.3-8.2 months), and the median overall survival (OS) was 10.0 months (95% CI, 7.7-12.4 months). The 6-month and 12-month local control rates were 98.4% and 93.0%, respectively. In a subgroup analysis of 23 non-small cell lung cancer patients, the ORR was 17.4% (95% CI, 5.0%-38.8%), the median PFS was 6.9 months (95% CI, 4.7-9.1 months), and the median OS was 9.1 months (95% CI, 7.3-10.9 months). Multivariate analysis indicated that receiving ≥6 cycles of cadonilimab and having an Eastern Cooperative Oncology Group performance status score of 0-1 were significantly associated with improved PFS and OS (P < 0.05).

Conclusions: SBRT in combination with cadonilimab demonstrated manageable toxicity and promising efficacy in heavily pretreated patients with refractory solid tumors.

Trial registration: This study was retrospectively registered at ClinicalTrials.gov (NCT05915481) on August 20, 2022.

Keywords

Cadonilimab / immunotherapy / refractory solid tumors / safety / stereotactic body radiotherapy

References

[1] Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22(2): 198–211.

[2] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015; 373(1): 23–34.

[3] Sangro B, Chan SL, Kelley RK, Lau G, Kudo M, Sukeepaisarnjaroen W, et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024; 35(5): 448–57.

[4] Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023; 20(3): 181–95.

[5] Gao X, Xu N, Li Z, Shen L, Ji K, Zheng Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. Lancet Oncol. 2023; 24(10): 1134–46.

[6] Frentzas S, Gan HK, Cosman R, Coward J, Tran B, Millward M, et al. A phase 1a/1b first-in-human study (COMPASSION-01) evaluating cadonilimab in patients with advanced solid tumors. Cell Rep Med. 2023; 4(11): 101242.

[7] Shen L, Zhang Y, Li Z, Zhang X, Gao X, Liu B, et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med. 2025; 31(4): 1163–70.

[8] Liang G, Gu S, Guo Y, Li H, Liu J, Liu J, et al. The efficacy and safety of transarterial chemoembolization combined with cadonilimab and lenvatinib for unresectable hepatocellular carcinoma: A phase II clinical trial. Presented at: ASCO Meeting; 2024;Chicago, IL. Abstract No.478.

[9] Chen B, Yao W, Li X, Lin G, Chu Q, Liu H, et al. A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer. Brit J Cancer. 2024; 130(3): 450–6.

[10] Chen Q-Y, Guo S-S, Luo Y, Qu S, Wu D-H, Chen X-Z, et al. Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study. Oral onco. 2024; 151: 106723.

[11] Chen Y, Gao M, Huang Z, Yu J, Meng X. SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges. J Hematol Oncol. 2020; 13(1): 105.

[12] Cheng SH, Tu KY, Lee HH. The dynamic duo: A narrative review on the synergy between stereotactic body radiotherapy and immunotherapy in lung cancer treatment (Review). Oncol Rep. 2024; 52(1): 96.

[13] Juloori A, Bestvina CM, Pointer KB, Pitroda SP, Abazeed ME, Katipally RR, et al. OA22.03 The Addition of Multisite SBRT to Ipilimumab and Nivolumab in First Line Metastatic NSCLC: The COSINR Trial. Presented at: WCLC Meeting; 2023; Singapore, SG. Abstract No.OA22.03.

[14] Chen QY, Guo SS, Luo Y, Qu S, Wu DH, Chen XZ, et al. Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study. Oral Oncol. 2024; 151: 106723.

[15] Sangro B, Chan SL, Kelley RK, Lau G, Kudo M, Sukeepaisarnjaroen W, et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024; 35(5): 448–57.

[16] Zhao Y, Ma Y, Fan Y, Zhou J, Yang N, Yu Q, et al. A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non-small-cell lung cancer (AK104-202 study). Lung Cancer. 2023; 184: 107355.

[17] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228–47.

[18] Maintenance and Support Services Organization. Introductory Guide MedDRA Version 23.0. 2020.

[19] U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017.

[20] Bezjak A, Paulus R, Gaspar LE, Timmerman RD, Straube WL, Ryan WF, et al. Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/RTOG 0813 Trial. J Clin Oncol. 2019; 37(15): 1316–25.

[21] Theelen W, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts J, et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019; 5(9): 1276–82.

[22] Welsh J, Menon H, Chen D, Verma V, Tang C, Altan M, et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial. J immunother cancer. 2020; 8(2): e001001.

[23] Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol. 2018; 36(16): 1611–8.

[24] He K, Hong DS, Tang C, Sezen D, Cox L, Maleki A, et al. Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease. Radiother Oncol. 2023; 183: 109618.

[25] Welsh JW, Tang C, de Groot P, Naing A, Hess KR, Heymach JV, et al. Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses. Cancer Immunol Res. 2019; 7(12): 1903–9.

[26] Foster CC, Fleming GF, Karrison TG, Liao CY, Desai AV, Moroney JW, et al. Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors. Clin Cancer Res. 2021; 27(20): 5510–8.

[27] Paz-Ares L, Goto Y, Wan-Teck Lim D, Halmos B, Chul Cho B, Cobo M, et al. Canakinumab in combination with docetaxel compared with docetaxel alone for the treatment of advanced non-small cell lung cancer following platinum-based doublet chemotherapy and immunotherapy (CANOPY-2): A multicenter, randomized, double-blind, phase 3 trial. Lung Cancer. 2024; 189: 107451.

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2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.