Global Registrational Trial for Cadonilimab in PD-1–Resistant HCC to Launch

Akeso, Inc has announced the initiation of a global, multicenter registrational trial to evaluate its bispecific antibody, cadonilimab (AK104), in combination with lenvatinib (Lenvima) for the treatment of advanced hepatocellular carcinoma (HCC) in patients who have developed resistance to prior PD-1 checkpoint inhibitor therapy.¹

The trial, designated COMPASSION-36/AK104-225, addresses a critical unmet clinical need for second-line treatment options in a population with limited therapeutic alternatives. This phase 2 randomized study is designed to compare the efficacy of the cadonilimab-lenvatinib combination against lenvatinib monotherapy.

"We are excited to initiate cadonilimab's first international multicenter registrational trial, a pivotal step in addressing the global challenge of cancer immunotherapy resistance. This study represents a key milestone in Akeso's global strategy to address the substantial clinical unmet needs in oncology,” said Yu Xia, MD, founder, chairperson, president, and CEO of Akeso, in a press release.

The approval to proceed with this trial by both the US FDA and China’s National Medical Products Administration marks a significant step forward for the development of cadonilimab, a bispecific antibody which simultaneously targets both PD-1 and CTLA-4. The rationale for this dual-immunotherapy approach is rooted in the hypothesis that blocking both checkpoints may offer a synergistic effect, potentially overcoming the resistance mechanisms that lead to disease progression on single-agent immune checkpoint inhibitors. The patient population for this trial is particularly challenging, as all participants will have previously been treated with the standard-of-care first-line combination of atezolizumab (Tecentriq) and bevacizumab (Avastin).

Cadonilimab's clinical development program has yielded promising results across multiple tumor types. The bispecific antibody is the first of its kind to receive global and China-specific regulatory approval for cancer immunotherapy. Prior data presented at the 2023 European Society for Medical Oncology (ESMO) Congress highlighted the potential of the cadonilimab-lenvatinib combination as a first-line treatment for advanced HCC, showing superior antitumor activity compared to existing therapies. Additionally, a study presented at the 2023 ESMO Asia Congress demonstrated a 100% disease control rate when cadonilimab was combined with FOLFOX-HAIC as a neoadjuvant therapy for resectable multinodular HCC. These preliminary findings provide a strong foundation for the current registrational trial, which seeks to validate the agent's potential in a more advanced, treatment-resistant setting.

Cadonilimab is being investigated in several other disease states. Data presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium demonstrated cadonilimab’s benefits in rectal cancer. The open-label, single-arm phase 2 NeoCaCRT trial (NCT05792735) found that neoadjuvant short-course radiation therapy followed by cadonilimab and chemotherapy led to positive pathologic complete responses (pCRs) and demonstrated an acceptable safety profile in patients with mismatch repair-proficient or microsatellite-stable locally advanced rectal cancer.²

At the October 20, 2024, data cutoff, with a median follow-up of 9.7 months, the pCR rate was 37.0% (95% CI, 19.4%–57.6%); the clinical major pathological response rate was 55.6% (95% CI, 35.3%–74.5%); and the clinical CR was 22.2% (95% CI, 8.6%–42.2%), and among those who achieved a clinical CR, 83.3% received local excisions.

Additionally, data presented from the phase 3 COMPASSION-16 at the 2025 ASCO Annual Meeting showed that overall survival (OS) and progression-free survival (PFS) benefits observed with the addition of cadonilimab to first-line standard therapy in patients with persistent, recurrent, or metastatic cervical cancer.³

Previously reported interim analyses from the COMPASSION-16 study demonstrated statistically significant improvements in both PFS and OS, with a median PFS of 13.3 months with cadonilimab vs 8.2 months with placebo (HR, 0.62; P <.0001) and a median OS not yet reached vs 22.8 months (HR, 0.64; P =.0011).

REFERENCES:

1. Akeso Announces Approval to Initiate Global Registrational Trial of Cadonilimab (PD-1/CTLA-4) for PD-1 Treatment-Resistant Hepatocellular Carcinoma. News release. Akeso Inc. August 4, 2025. Accessed August 6, 2025. https://tinyurl.com/bdef62se

2. He W, Huang J, Liao G, et al. Short-course radiation (SCRT) followed by 6 cycles of cadonilimab plus mFOLFOX6 as neoadjuvant therapy for patients with locally advanced rectal cancer (LARC): A multicenter, single arm phase 2 trial (NeoCaCRT). J Clin Oncol. 2025;43(4):LBA210. doi:10.1200/JCO.2025.43.4_suppl.LBA210

3. Sun Y, Yang H, Lou H. Cadonilimab plus platinum-based chemotherapy ± bevacizumab for persistent, recurrent, or metastatic cervical cancer: Subgroup analyses of COMPASSION-16. J Clin Oncol. 2025;43(suppl 17):5509. doi: 10.1200/JCO.2025.43.16_suppl.5509.