Novel immunotherapy demonstrates early potential to overcome resistance to immune checkpoint therapy: Study

“This is a very exciting trial because we’ve been trying to effectively target this protein, called transforming growth factor-beta 1, for a long time,” Yap said. “We’ve known that it helps tumors evade the immune system and develop resistance to immunotherapies but, until now, attempts to target it have failed. This is potentially a significant step in helping patients overcome resistance and benefit further from immunotherapies.”

What is the significance of this clinical trial of linavonkibart?

Despite the tremendous impact that immunotherapies like pembrolizumab have had, many cancers are either unresponsive or develop treatment resistance. Research has found that often this resistance involves a protein called transforming growth factor-beta 1 (TGFβ1).

There have been previous efforts to develop therapies targeting TGFβ1, but most initial treatments also blocked TGFβ2 and TGFβ3, instead of just selectively blocking TGFβ1. Researchers found that TGFβ2 and TGFβ3 are essential for normal body functions, and so previous efforts were met with significant dose-limiting toxicities.

Linavonkibart is a first-in-class selective immunotherapy that aims to overcome resistance by targeting and preventing activation of only TGFβ1. Linavonkibart attaches itself to the protein in its “off” position, which then makes it unable to switch “on.”

Linavonkibart also is a “fully human” antibody, meaning it is built exclusively from structures found naturally in the human body. This should make it safer and less likely to initiate an immune response against it, and the initial clinical data support this theory.

What were the key data of this trial?

This Phase I DRAGON trial was divided into three parts:

• Single-agent dose escalation arm (19 patients with a median age of 66 and four prior lines of therapy)

• Combination dose escalation arm (15 patients, median age of 65 and four prior lines) with linavonkibart combined with pembrolizumab

• Combination dose expansion arm (78 patients, median age of 65 and three prior lines)

The safety profile was manageable overall, and the combination therapy showed side effects consistent with the safety profile of pembrolizumab as a monotherapy, with only dermatological reactions identified as an additional risk. No grade four or five or dose-limiting toxicities were observed in either dose escalation cohort. In the dose expansion cohort, the most common adverse effect at grade three or higher was rash, with only four patients experiencing any grade four adverse effects.

In the dose expansion cohort of 78 heavily pre-treated patients who were progressing on prior immune checkpoint therapy, physicians observed multiple objective responses. Especially notable was a 20% objective response rate in patients with heavily pretreated advanced clear cell renal cell cancer. Interestingly, the exploratory biomarker studies have uncovered a potential patient selection strategy for that subgroup to enrich for patient benefit. Responses also were observed in melanoma, head and neck squamous cell cancer, and urothelial cancer.

What is the next step for linavonkibart?

According to Yap, there are multiple next steps to assess linavonkibart, including investigating whether it may be even more effective as an earlier-line treatment.

“It’s notable that our Phase I trial involved a very heavily pretreated population with a prognosis of just over three months,” Yap said. “We believe that this linavonkibart combination will be even more effective when given in earlier treatment settings, before significant resistance to immunotherapy has developed.”

Reference:

Yap, T.A., Sweis, R.F., Vaishampayan, U. et al. Linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors: a phase 1 trial. Nat Med (2026). https://doi.org/10.1038/s41591-025-04157-w