Nature Communications | Efficacy of TIGIT and PD-1 Combination Blockade in Refractory Biliary Tract Cancer and ctDNA Dynamic Monitoring

This study provides early clinical evidence for a TIGIT/PD-1 dual blockade strategy in patients with biliary tract cancer who are resistant to immunotherapy, suggesting that TIGIT inhibition may restore anti-tumor immune activity, offering direct guidance for research into resistance mechanisms of immune checkpoint inhibitors and the design of subsequent combination therapies.

 

Literature Overview

The article titled 'Domvanalimab plus zimberelimab in unresectable and immunotherapy refractory biliary tract cancers: a phase 2 trial,' published in Nature Communications, systematically investigates the efficacy and safety of combining the anti-TIGIT antibody domvanalimab with the anti-PD-1 antibody zimberelimab in patients with advanced biliary tract cancer (BTC) who have developed resistance to PD-1/L1 inhibitors. Through a prospective phase 2 basket trial design, the study focuses on a refractory population, filling a critical gap in post-immunotherapy treatment strategies, and integrates ctDNA dynamic analysis to explore resistance mechanisms.

Background Knowledge

Biliary tract cancer (BTC) is a highly heterogeneous and aggressive malignancy with a poor prognosis. Its incidence is rising globally, and most patients are diagnosed at an advanced, inoperable stage. Although first-line chemotherapy combined with PD-1/L1 inhibitors has shown some survival benefit, overall response rates remain limited, and nearly all patients eventually progress, developing resistance to immunotherapy. This highlights the urgent need to develop novel immunotherapeutic combinations to overcome resistance.

Currently, TIGIT is an emerging immune checkpoint following PD-1 and CTLA-4. Its high expression on T cells and NK cells is closely associated with T cell exhaustion and tumor immune escape. In BTC, high expression of TIGIT and its ligand PVR is often linked to poor prognosis, suggesting that the TIGIT signaling pathway is a promising therapeutic target. However, clinical results of anti-TIGIT monotherapy or combination therapies in solid tumors have been inconsistent, with some phase III trials failing to meet primary endpoints, leaving its independent contribution unclear. Additionally, the lack of effective biomarkers for patient selection limits the precision application of TIGIT-targeted therapies. This study addresses this gap by testing the Fc-silenced anti-TIGIT antibody domvanalimab in combination with zimberelimab specifically in BTC patients with confirmed PD-1/L1 resistance, directly evaluating whether dual blockade can overcome adaptive resistance. Furthermore, ctDNA dynamics are used as a real-time monitoring tool for treatment response and resistance mechanisms, providing a foundation for future mechanistic and translational research.

 

 

Research Methods and Experiments

The study employed a single-arm, multicenter phase 2 basket trial (LIVERTI), enrolling 29 patients with histologically confirmed, unresectable or recurrent BTC who had progressed on prior PD-1/L1 inhibitor therapy. All patients received intravenous infusions of domvanalimab (1200 mg) and zimberelimab (360 mg) every 21 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed confirmed objective response rate (ORR), with secondary endpoints including disease control rate (DCR), progression-free survival (PFS), safety, and overall survival. A key aspect of the trial design was the strict enrollment of only PD-1/L1-resistant patients, thereby excluding those who previously responded to immunotherapy and allowing a clearer assessment of the independent role of TIGIT blockade.

To explore potential biomarkers, the study prospectively collected plasma samples at baseline and after the second cycle for ctDNA sequencing using an 83-gene panel. The relationship between baseline mutation allele frequency (VAF), tumor mutational burden (TMB), and treatment efficacy was evaluated, and ctDNA dynamics during treatment were tracked to examine the association between early molecular response and radiographic outcomes. Additionally, ctDNA sequencing was performed on samples collected at disease progression to identify acquired resistance-related genetic alterations, offering insights into resistance mechanisms.

Key Conclusions and Perspectives

• Among 29 evaluable patients, the confirmed ORR was 10.3% (3 partial responses), with a DCR of 44.8%, indicating modest anti-tumor activity of TIGIT and PD-1 dual blockade in refractory BTC, suggesting that dual checkpoint inhibition may reinvigorate exhausted T cells.
• The median duration of response (DoR) was 13.6 months, indicating durable responses, supporting the possibility that TIGIT-targeted therapy may induce long-term immune memory and informing future maintenance immunotherapy strategies.
• Treatment-related adverse events occurred in 36.4% of patients, primarily grade 1–2 pruritus and rash, with no grade ≥3 treatment-related serious adverse events, indicating that the combination of domvanalimab and zimberelimab is well tolerated and supports its safety in future combination regimens.
• Low baseline TMB was significantly associated with longer PFS (HR 0.35), whereas high baseline ctDNA levels showed no significant association, suggesting TMB may serve as a predictive biomarker, though its mechanism differs from traditional PD-1 inhibitors and requires further validation.
• Early ctDNA reduction (>30%) was significantly associated with improved PFS (HR 0.25), indicating that ctDNA dynamics can serve as an early predictor of treatment efficacy, guiding personalized therapeutic decisions.
• At progression, ctDNA analysis revealed acquired mutations in the RAS signaling, receptor tyrosine kinase, and DNA damage response pathways, suggesting that activation of the RAS pathway may be a key resistance mechanism to anti-TIGIT therapy, providing a rationale for combining TIGIT inhibitors with MEK/ERK inhibitors.

Research Significance and Prospects

This study provides critical clinical evidence for the application of TIGIT-targeted therapy in BTC, particularly demonstrating durable responses even in the context of prior immunotherapy resistance, suggesting its potential to overcome adaptive resistance. Although the ORR did not meet the predefined threshold, the favorable safety profile and durable responses support further exploration of TIGIT-based combination strategies, such as with chemotherapy, targeted agents, or other immune checkpoint inhibitors.

The study represents the first systematic use of ctDNA dynamics to monitor response to anti-TIGIT therapy, demonstrating that early ctDNA changes can predict PFS, highlighting the value of liquid biopsy in real-time efficacy assessment. This finding promotes a shift from traditional radiographic evaluation to molecular-level precision monitoring, offering novel endpoints for future clinical trial designs.

Resistance mechanism analysis revealed acquired alterations in RAS, RTK, and DDR pathways, indicating that tumors may evade TIGIT blockade by activating pro-survival signals. This provides clear directions for developing combination therapies to overcome resistance, such as pairing TIGIT inhibitors with MEK inhibitors, which could be validated in preclinical models.

 

 

Conclusion

This study establishes the preliminary efficacy and safety of TIGIT/PD-1 dual blockade in PD-1-resistant biliary tract cancer, offering a new therapeutic direction for this refractory population. Although the objective response rate is modest, the durability of responses and favorable tolerability support its use as a backbone for future combination strategies. By integrating ctDNA dynamic analysis, the study not only reveals a strong association between early molecular response and clinical outcomes but also provides a real-time monitoring tool for personalized treatment decisions. More importantly, the exploration of resistance mechanisms points to the activation of signaling pathways such as RAS, offering clear intervention targets to overcome anti-TIGIT resistance. From bench to bedside, this study builds a comprehensive framework for precision immunotherapy in biliary tract cancer—spanning mechanistic investigation, efficacy evaluation, and resistance intervention—paving the way for next-generation combination immunotherapies and ultimately improving long-term patient survival.

 

David Hsiehchen, John H Lohrey, Radhika Kainthla, Chul Ahn, and Hao Zhu. Domvanalimab plus zimberelimab in unresectable and immunotherapy refractory biliary tract cancers: a phase 2 trial. Nature Communications.