Trials of the OX40 inhibitor rocatinlimab have been scrapped after the emergence of Kaposi sarcoma cases, raising broader safety questions about the entire drug class.

In March, Kyowa Kirin announced it was discontinuing rocatinlimab trials after identifying one confirmed and one suspected case of Kaposi sarcoma, alongside a previously confirmed case [link here]. The company said the findings suggested “a potential mechanistic link to OX40 pathway modulation”.

A separate January update from Sanofi reported that a patient with known risk factors who had received the OX40-ligand antibody amlitelimab developed cutaneous Kaposi sarcoma and discontinued treatment.

Across 13,700 patients enrolled in OX40-targeting clinical trial programs, Belgian dermatologists calculated at least three Kaposi sarcoma cases, a rate of 22 per 100,000 patients. They said this was roughly 14 times the background incidence of 1.53 per 100,000 person-years in a non-HIV population.

The findings “raise questions about a possible link between OX40 pathway modulation and KS development”, wrote Dr Erwin Suys, head of dermatology at AZ Groeninge hospital, Belgium, and colleagues in JEADV [link here].

Why might OX40 inhibition trigger KS?

While no PubMed-indexed publications had directly linked anti-OX40 or OX40L therapies to Kaposi sarcoma, prior case reports pointed to a connection between OX40 signalling and human herpesvirus 8 (HHV-8), which caused it.

A report of congenital OX40 deficiency in a child with aggressive Kaposi sarcoma offered one clue. Experimental data has also suggested OX40–OX40L engagement can inhibit HHV-8 lytic replication in endothelial cells, implying the pathway plays a role in controlling HHV-8 infection.

The authors noted that therapeutic OX40 inhibition may cause broad immunosuppression affecting both CD4+ and CD8+ T cells across all immune phenotypes, potentially leaving patients vulnerable to infections and impaired tumour surveillance.

“Taken together, the findings may be suggestive of a possible link between KS and OX40 pathway modulation, although the evidence remains inconclusive and insufficient to draw firm conclusions regarding causality,” they wrote.

The exact mechanism linking OX40 and HHV-8 control remained unknown, but the authors said it was essential to assess whether current evidence adequately addressed the potential risks of OX40 inhibition. They called for consideration of routine HHV-8 screening before initiating OX40-targeting therapies to identify at-risk patients.