A bispecific antibody, cadonilimab, that hits both targets is being developed to treat various cancers by Hong Kong-based biotech Akeso.1
The symmetric tetravalent antibody has similar biologic activity to a combination of two separate antibodies, while also having higher binding avidity in a high-density PD-1 and CTLA-4 setting than in a low-density PD-1 setting (compared with monospecific anti-PD-1 antibodies).
It does not bind to Fc receptors, resulting in lower toxicities being observed in the clinic. An open label Phase Ib/II trial of the antibody as a monotherapy has been done in patients with unresectable advanced solid tumours in China.2
Subjects had previously (unsuccessfully) completed at least one systemic therapy but had not received any treatment targeting PD-1, PD-L1 or CTLA-4.
In the dose escalation part, 83 patients were given 6 mg/kg or 10 mg/kg intravenously every 2 weeks and, in the dose expansion part, 6 mg/kg and a fixed dose of 450 mg every 2 weeks.
Then, in the Phase II part, 6 mg/kg was given every 2 weeks to three disease cohorts: cervical cancer (111 patients), oesophageal squamous cell carcinoma (22 patients) and hepatocellular carcinoma (24 patients).
There were no dose limiting toxicities during dose escalation. Grade 3 or 4 treatment-related adverse events occurred in 28% of patients in all parts of the trial, with the most common being anaemia, increased lipase, decreased bodyweight or appetite and reduced neutrophils.
In the Phase II part, the objective response rate was 32% for cervical cancer, 18% for oesophageal cancer and 17% for liver cancer. Initial results of a Phase III trial in which the antibody was dosed in combination with platinum-based chemotherapy, either with or without bevacizumab, have been reported via press release.
At a prespecified interim analysis by an independent data monitoring committee, it met one of its primary endpoints: progression-free survival for the first line treatment of recurrent or metastatic cervical cancer for the antibody compared with a placebo in all patients (regardless of their PD-L1 status).
Initial indications also suggested an improvement in overall survival, the other primary endpoint, although these data were insufficiently mature at that early stage.
The trial continues. Safety data were consistent with previous clinical results.
References
- X. Pang, et al., MAbs 15, 2180794 (2023).
- X. Gao, et al., Lancet Oncol. 24, 1134 (2023).