Cadonilimab — a PD-1/CTLA-4 bispecific antibody for cervical cancer and other solid tumors
- Emmanuel Paredes
- Nov 1
- 6 min read
Cadonilimab is a humanized, tetravalent bispecific monoclonal antibody that simultaneously targets programmed cell-death protein-1 (PD-1) and cytotoxic T lymphocyte–associated protein-4 (CTLA-4). Designed to combine checkpoint blockade at two complementary immune checkpoints in a single molecule, cadonilimab was developed to harness the synergistic antitumor activity of dual checkpoint inhibition while improving safety and tolerability relative to separate PD-1 + CTLA-4 antibody combinations. Cadonilimab has advanced through early-phase clinical development and has regulatory approvals and marketing authorizations in China for selected indications.
Mechanism of Action
Cadonilimab binds both PD-1 and CTLA-4 on immune cells within the tumor microenvironment. PD-1 blockade reinvigorates exhausted tumor-specific T cells, while CTLA-4 blockade potentiates T-cell priming and expansion. The bispecific, tetravalent design concentrates dual blockade where PD-1 and CTLA-4 are co-expressed, aiming to enhance antitumor immunity with lower systemic exposure to CTLA-4 blockade than separate combination dosing. The molecule’s design (tetravalent architecture and modified Fc biology in many constructs) is intended to optimize tumor-localized activity and reduce Fc-mediated off-target effects.
Pharmacokinetics and Pharmacodynamics
PK: Early clinical pharmacokinetic (PK) data indicate dose-proportional exposure across tested dose ranges (various mg/kg regimens). Typical clinical dosing schedules evaluated include 6 mg/kg every 2 weeks (Q2W) and 15 mg/kg every 3 weeks (Q3W); these regimens produced measurable, sustained PD-1/CTLA-4 target engagement in trials.
PD: Pharmacodynamic effects include upregulation of peripheral and intratumoral T-cell activation markers and demonstration of objective tumor responses in multiple tumor types consistent with dual checkpoint inhibition.
Usual Dosing
Common clinical regimens used in trials / label (China): 6 mg/kg IV every 2 weeks (Q2W) has been used as a primary regimen; 15 mg/kg IV Q3W was also evaluated in studies. The approved/marketed dosing and exact instructions should be verified from the local prescribing information and clinical protocols.
Dosing in Renal and Hepatic Impairment
Limited formal guidance: As with most therapeutic antibodies, cadonilimab is not primarily renally excreted; formal, comprehensive dose-adjustment recommendations for renal or hepatic impairment are limited in public sources. When caring for patients with significant organ dysfunction, clinicians should consult the current product label and consider individualized monitoring. Clinical trial exclusion criteria and sponsor guidance should also be reviewed.
Administration
Route: Intravenous infusion.
Schedule: Typical regimens tested include 6 mg/kg IV Q2W or 15 mg/kg IV Q3W, given until disease progression, unacceptable toxicity, or per trial-specified duration. Premedication and infusion-related reaction precautions follow institutional practice for monoclonal antibodies. Check prescribing information for infusion duration and precautions.
Clinical Efficacy
Key clinical findings (selected):
Recurrent/metastatic cervical cancer (R/M CC): Cadonilimab monotherapy showed objective responses in platinum-resistant R/M cervical cancer (ORR ≈ 33% in some reports) and durable responses in a proportion of patients; single-arm and multicenter phase II studies supported regulatory approval in China for R/M cervical cancer after platinum therapy.
First-line R/M cervical cancer (combination): Randomized data and registrational trials of cadonilimab combined with chemotherapy ± bevacizumab as first-line therapy have reported clinically meaningful improvements in outcomes (PFS/OS) versus chemotherapy alone in recent pivotal data leading to regulatory approvals/market authorizations in China (company and regulatory announcements).COMPASSION-16
Other tumor types: Early-phase and basket/trial reports indicate activity in a variety of solid tumors (NSCLC, HCC, gastric/GEJ, biliary tract), particularly when combined with targeted agents (e.g., lenvatinib) or chemotherapy; confirmatory phase III trials are ongoing in multiple indications.
Safety Profile
Overall tolerability: Across Phase I/II studies, cadonilimab demonstrated an acceptable and manageable safety profile. The reported rates of Grade ≥3 treatment-related adverse events (TRAEs) and treatment discontinuations were generally lower than historical rates reported for separate PD-1 + CTLA-4 combination therapy in comparable small cohorts. Common TRAEs included immune-related events consistent with checkpoint inhibition (e.g., fatigue, rash, hepatitis, endocrine dysfunction), and CTLA-4–associated toxicities were observed but appeared less frequent/severe in some series.
Comparative safety signals: Early data and pooled comparisons suggest cadonilimab may have fewer high-grade immune-related AEs and lower discontinuation rates than published series of nivolumab + ipilimumab in similar populations; however, these observations are from non-randomized comparisons or limited cohort sizes and should be interpreted cautiously. Ongoing randomized trials are refining the comparative safety profile.
Indications and Current Regulatory Status
Cervical Cancer: Cadonilimab initially received approval in China for the treatment of relapsed or metastatic cervical cancer after progression on/after platinum therapy (June 2022). Subsequently, cadonilimab in combination with platinum-based chemotherapy ± bevacizumab has been authorized/approved for first-line treatment of persistent, recurrent, or metastatic cervical cancer in China; other indications (e.g., gastric/GEJ cancer combinations) are being pursued in registrational trials and local approvals. It was included in the 2022 Chinese Society of Clinical Oncology (CSCO) Guidelines for Cervical Cancer as a top recommendation for immunotherapy.
Gastric Cancer: Cadonilimab is a Category I (Level 1A) recommendation for first-line immunotherapy in the Chinese Society of Clinical Oncology (CSCO) Gastric Cancer Guidelines. It is approved for use in combination with chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma.
Patient Selection and Clinical Considerations
Who may benefit: Patients with PD-1–sensitive tumors and those for whom dual checkpoint blockade is desirable (e.g., cervical cancer) are principal candidates. Cadonilimab has demonstrated activity regardless of PD-L1 status in some trials, but patient selection should be guided by indication, trial evidence, tumor histology, prior therapies, and comorbidities.
Practical considerations: Evaluate prior immune-related toxicity history, autoimmune disease, organ dysfunction, and potential need for combination partners (chemotherapy, anti-angiogenics, targeted agents). Monitor for immune-related adverse events per institutional protocols.
How Cadonilimab Compares with Other Immune Checkpoint Inhibitors (ICIs)
Dual-targeting in one molecule: Unlike single-target PD-1 inhibitors (e.g., pembrolizumab, nivolumab) or separate PD-1 + CTLA-4 combination therapy (e.g., nivolumab + ipilimumab), cadonilimab integrates both PD-1 and CTLA-4 blockade into a single bispecific antibody. This design aims to attain the efficacy advantages of dual checkpoint inhibition while potentially reducing systemic CTLA-4 exposure and associated high-grade immune toxicities.
Clinical advantages suggested by early data: Phase I/II data and company-reported comparisons indicate cadonilimab can achieve robust antitumor activity with lower rates of grade ≥3 TRAEs, fewer treatment discontinuations, and fewer treatment-related deaths than historical reports of separate PD-1 + CTLA-4 combination treatment in small cohorts. These findings suggest a potentially improved therapeutic index (similar or improved efficacy with better tolerability), especially relevant in tumor types where CTLA-4 add-on provides incremental benefit. However, definitive superiority requires head-to-head randomized comparisons; many such trials are ongoing.
Feature / metric | Cadonilimab (AK104) (COMPASSION-03 / phase 1b–2) | Nivolumab + Ipilimumab (CheckMate program — exemplar data) |
Indication / trial population | Advanced unresectable solid tumours; phase 2 cervical cancer cohort reported separately. | Advanced melanoma (CheckMate-067) — front-line; other indications also studied. |
Key trial(s) | COMPASSION-03 (multicentre phase 1b/2; Lancet Oncology 2023). | CheckMate-067 (phase 3 NEJM 2015/2017), other combination trials. |
Objective response rate (ORR) | Cervical cancer cohort (phase 2): 32.3% (32/99; 95% CI 23.3–42.5). Other cohorts: HCC, ESCC lower. | CheckMate-067 (melanoma): ~58% ORR for combination (reported ~55–60% in long-term updates). |
Median PFS | Not reported as a single pooled median across all cohorts in abstract; activity signal reported in cohort-specific analyses. | CheckMate-067 (melanoma): median PFS ≈ 11.5 months (nivolumab + ipilimumab). |
Median OS | Phase 2 cohorts still maturing; durable responses described in subset analyses. | CheckMate-067 (melanoma): long-term OS benefit vs ipilimumab; median OS not reached for combination at reported follow-up. |
Grade ≥3 treatment-related adverse events (TRAEs) | 28% grade 3–4 TRAEs across 240 patients (COMPASSION-03). 17 (7%) discontinued due to TRAEs; 54 (23%) experienced serious TRAEs. (Phase 1b–2 pooled safety). | ~59% grade 3–4 TRAEs in the nivolumab + ipilimumab arm (CheckMate-067 melanoma). High rates of immune-related high-grade events and more frequent discontinuations vs single agent. |
Treatment discontinuation due to TRAE | ~7% discontinued due to TRAE (COMPASSION-03). | Higher discontinuation rates reported in CheckMate-067 (combination vs monotherapy; e.g., discontinuation rates substantially higher with combination). |
Comments | Bispecific PD-1/CTLA-4 antibody intended to concentrate dual blockade and potentially reduce systemic CTLA-4 toxicity; promising ORR in cervical cancer cohort with lower reported high-grade TRAE rate vs historical separate-agent combinations (non-randomized). | Established combination with proven efficacy (notably in melanoma, RCC subsets), but substantial high-grade toxicity burden widely reported and requiring active management and monitoring. |
Conclusions
Cadonilimab is a first-in-class PD-1/CTLA-4 bispecific antibody that combines dual immune-checkpoint blockade within a single agent. Early and mid-phase clinical data demonstrate meaningful antitumor activity across multiple tumor types and a tolerability profile that may be more favorable than historic PD-1 + CTLA-4 combination regimens. Regulatory approvals in China for cervical cancer and emerging registrational trials in other indications reflect its clinical promise. While early comparative data suggest cadonilimab may offer efficacy comparable to dual-agent combinations with potentially fewer high-grade toxicities, robust head-to-head randomized data will be needed to establish formal superiority over existing immune checkpoint inhibitors and combination regimens. Clinicians should consult up-to-date local labels, trial results, and guidelines when considering cadonilimab use.
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