Dual Targeting of TGFβ1 and PD-1 Is Safe and Tolerable in Solid Tumors

While immunotherapy has revolutionized cancer treatment, clinical benefit is limited in most patients because of primary or acquired resistance. Transforming growth factor beta (TGFβ), a pleiotropic cytokine, has been implicated in resistance to immune checkpoint inhibitors, consistent with the known function of TGFβ in rewiring the tumor microenvironment into an immunosuppressive milieu. Preclinical studies demonstrating the antitumor efficacy of TGFβ inhibition in combination with anti–PD-1 therapy have prompted the clinical investigation of this combination in patients. Linavonkibart is a first-in-class, fully human, monoclonal antibody that specifically recognizes latent TGFβ1 but not TGFβ2 or TGFβ3. Yap, Sweis, and colleagues initiated the phase I DRAGON trial to test the safety and tolerability of linavonkibart alone or in combination with the anti–PD-1 antibody pembrolizumab. This multicenter trial enrolled patients with metastatic or locally advanced solid tumors, with or without prior anti–PD-(L)1 therapy, and involved three parts: a single-agent linavonkibart dose escalation (part A1, n = 19), a linavonkibart plus pembrolizumab dose escalation (part A2, n = 15), and a combined dose expansion (part B, n = 78). The primary objective of safety and tolerability of linavonkibart alone or in combination was met, with no dose-limiting toxicities or grade 4 or 5 treatment-related adverse events observed in either of the dose escalation cohorts. The maximum tolerated dose was not reached, and dose expansion proceeded with a recommended dose of 1,500 mg linavonkibart once every three weeks and 200 mg pembrolizumab once every three weeks. In the dose expansion cohort, the confirmed objective response rate was 20.0% for patients with clear-cell renal cell carcinoma (ccRCC), 18.2% for melanoma, 9.1% for head and neck squamous cell carcinoma, and 9.1% for urothelial cancer. Notably, one patient with ccRCC achieved a complete response. Exploratory analyses of samples after treatment versus baseline indicated that the combination increased CD8+ T-cell infiltration and specifically increased CD8+ T-cell activation in patients who had a response, supporting a treatment-induced inflammatory tumor microenvironment. Moreover, analysis of baseline biopsy samples suggested that elevated TGFB1 levels in a baseline biopsy might point to patients likely to respond to the combination. Together, these clinical findings from the DRAGON phase I trial provide evidence of the safety and tolerability of linavonkibart alone or in combination with pembrolizumab in the treatment of patients with solid tumors.Yap TA, Sweis RF, Vaishampayan U, Kilari D, Gainor JF, McKean M, et al. Linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors: a phase 1 trial. Nat Med 2026 Jan 13 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.