This study is the first to report that linavonkibart, a novel antibody selectively inhibiting TGFβ1, in combination with pembrolizumab demonstrates manageable safety and significant antitumor activity in patients with immune checkpoint inhibitor resistance, particularly achieving a 20% objective response rate in renal cell carcinoma, and reveals a potential biomarker-guided patient selection strategy.
Literature Overview
The article titled 'Linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors: a phase 1 trial,' published in Nature Medicine, reviews and summarizes the findings of the DRAGON trial (NCT04291079), which evaluated the safety, pharmacokinetics, pharmacodynamics, predictive biomarkers, and efficacy of the novel antigen-activated TGFβ1 antibody linavonkibart as monotherapy or in combination with pembrolizumab in patients with advanced solid tumors resistant to immune checkpoint inhibitors. The results demonstrated that this combination therapy exhibited acceptable safety and preliminary antitumor activity across multiple refractory tumor types, with objective responses observed in ccRCC and melanoma, and provided mechanistic evidence and a potential patient selection strategy through longitudinal sample analysis. The study further supports TGFβ1 as a key target for overcoming resistance to immunotherapy. The entire section is coherent and logically structured, ending with a Chinese period.Background Knowledge
Immune checkpoint inhibitor (ICI) therapy has significantly improved survival outcomes in various cancers; however, only about 20–30% of patients respond to treatment, and most initial responders eventually develop acquired resistance. Primary and secondary resistance remain major unmet clinical challenges. Studies indicate that immune evasion mediated by the transforming growth factor-β (TGFβ) signaling pathway plays a crucial role in ICI resistance, where TGFβ induces an immunosuppressive tumor microenvironment, inhibits T-cell infiltration, and enhances Treg cell function. The TGFβ family includes three isoforms—TGFβ1, TGFβ2, and TGFβ3—with TGFβ1 being the predominantly expressed isoform in most tumors, and its high expression is associated with resistance to anti–PD-1 therapy. However, nonselective inhibition of all TGFβ isoforms or their receptors often leads to cardiac toxicity and bleeding risks, limiting clinical application. Therefore, selective inhibition of TGFβ1 represents a promising strategy to overcome ICI resistance while avoiding toxicity. Linavonkibart is a novel fully human IgG4 monoclonal antibody that specifically targets latent TGFβ1, preventing its activation, thereby enabling comprehensive inhibition of TGFβ1 in the tumor microenvironment while preserving the physiological functions of TGFβ2/3. This study was designed based on this mechanism to evaluate its safety and preliminary efficacy in ICI-resistant populations, filling a critical gap in the clinical translation of this targeted strategy.
Research Methods and Experiments
The DRAGON trial was a multicenter, open-label, phase 1 clinical study consisting of three parts: Part A1 involved dose escalation of linavonkibart monotherapy, Part A2 involved dose escalation of linavonkibart in combination with pembrolizumab, and Part B was the dose-expansion cohort for combination therapy. The study enrolled patients with histologically confirmed locally advanced or metastatic solid tumors who had either not responded to or progressed after prior anti–PD-(L)1 therapy. The primary endpoints were safety and tolerability, while secondary endpoints included pharmacokinetics, anti-drug antibodies, and antitumor activity. All patients received intravenous infusions of linavonkibart, with or without pembrolizumab, until disease progression or unacceptable toxicity occurred. A 3+3 design was used for dose escalation, and efficacy was assessed in the expansion cohorts. Longitudinal tumor and blood samples were analyzed using immunohistochemistry, flow cytometry, and molecular assays to explore predictive biomarkers and their association with response.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to demonstrate in humans that selective inhibition of TGFβ1 can overcome resistance to immune checkpoint inhibitors, and that combining linavonkibart with pembrolizumab is associated with acceptable safety and preliminary efficacy, particularly achieving a 20% objective response rate in ccRCC—outperforming existing rechallenge strategies. These findings provide a new therapeutic direction for ICI-resistant patients and validate the targeting value of TGFβ1 as a key resistance mechanism.
Biomarker analyses suggest that CD8+ T-cell infiltration, Treg levels, and TGFB1 expression may be used to predict response, supporting future enriched phase 2 trials. However, due to the small sample size, these findings require validation in larger cohorts. Additionally, this study lays the foundation for further exploration of linavonkibart in combination with other immunotherapies or targeted agents, potentially enhancing antitumor efficacy.
Conclusion
This study systematically evaluated the safety and efficacy of the selective anti–TGFβ1 antibody linavonkibart in combination with pembrolizumab in patients with advanced solid tumors resistant to immune checkpoint inhibitors through the phase 1 DRAGON trial. The results showed that the combination regimen was generally safe, with no unexpected toxicities, and the main adverse events were skin-related. In terms of efficacy, the combination therapy achieved objective responses in multiple tumor types, including a 20% objective response rate in ccRCC patients, with a median duration of response exceeding 10 months, demonstrating significant clinical potential. Biomarker analyses further indicated that baseline CD8+ T-cell infiltration, Treg cell levels, and TGFB1 expression were closely associated with treatment response, suggesting these markers may serve as potential tools for patient selection. In summary, this study not only confirms the feasibility of targeting TGFβ1 to overcome resistance to immunotherapy but also provides important evidence for subsequent precision immunotherapy strategies, supporting further validation of its clinical value in larger studies。
