Multicenter phase 1 trial of linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors

Immune checkpoint inhibitor (ICI) therapies have shown favorable outcomes in oncology, but many cancers are unresponsive or develop resistance that involves transforming growth factor-β1 (TGFβ1). Linavonkibart is a first-in-class fully human selective anti-latent TGFβ1 antibody. The multicenter phase 1 DRAGON trial evaluated linavonkibart and pembrolizumab in ICI-resistant advanced solid tumors. The primary endpoints were safety and tolerability of linavonkibart alone and in combination with pembrolizumab. Secondary objectives included evaluation of linavonkibart pharmacokinetics, assessment of anti-linavonkibart antibody development, and measurement of antitumor activity. All primary and secondary objectives were met. Linavonkibart had a manageable safety profile, and combined therapy with pembrolizumab was generally consistent with that of pembrolizumab monotherapy, with dermatological reactions the only additional risk factor. Among 78 patients, the combination demonstrated confirmed objective response rates of 20.0%, 18.2%, 9.1%, and 9.1% in anti-PD-1-resistant patients with clear cell renal cell cancer, melanoma, head and neck squamous cell cacer, and urothelial cancer, respectively. Biomarker data provided proof of mechanism. The authors conclude that the combination of linavonkibart and pembrolizumab showed acceptable safety and promising activity in patients with ICI-resistant advanced solid tumors.