Introduction: The Challenge of Conversion in Pancreatic Cancer
The management of borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) remains one of the most formidable challenges in surgical oncology. While radical surgical resection offers the only potential for long-term survival, the majority of patients present with tumors that involve critical peripancreatic vasculature, precluding immediate surgery. Historically, neoadjuvant or conversion therapy using multi-agent chemotherapy, such as FOLFIRINOX or albumin-bound (nab)-paclitaxel plus gemcitabine (AG), has been the standard of care. However, R0 resection rates and overall survival remain suboptimal. In recent years, the integration of immune checkpoint inhibitors and radiotherapy has emerged as a promising strategy to enhance local control and systemic efficacy. The THAG trial—evaluating tislelizumab, hypofractionated radiotherapy, and AG—represents a significant step forward in optimizing conversion therapy for this high-risk population.
Study Design and Methodology
This prospective Phase II trial (ChiCTR2000032955, NCT05634564) was designed to evaluate the efficacy and safety of the THAG regimen in patients with treatment-naive BRPC or LAPC. A total of 56 patients were enrolled, including 17 (30.4%) with BRPC and 39 (69.6%) with LAPC.
The THAG Protocol
The treatment sequence was carefully structured to leverage the synergistic effects of the three modalities. Patients received tislelizumab (an anti-PD-1 antibody) combined with AG chemotherapy in 21-day cycles. For those who did not show disease progression, hypofractionated radiotherapy was administered concurrently during the third chemotherapy cycle. After completing four cycles, a multidisciplinary team (MDT) performed a rigorous assessment to determine eligibility for radical surgery.
Biomarker Monitoring
A distinctive feature of this study was the use of dynamic biomolecular profiling. The researchers utilized liquid biopsies to monitor circulating tumor DNA (ctDNA) and analyzed baseline inflammatory markers, specifically Interleukin-6 (IL-6), to identify predictors of treatment response and survival.
Clinical Efficacy: Survival and Response Rates
The primary findings of the trial provide strong evidence for the clinical activity of the THAG regimen. The objective response rate (ORR) was 51.8% (95% CI 38.0-65.3%), indicating that over half of the participants achieved significant tumor shrinkage.
Survival Outcomes
The median progression-free survival (mPFS) was 13.2 months (95% CI 11.6-19.4 months), and the median overall survival (mOS) for the entire cohort was 21.3 months (95% CI 18.8-NR). These figures compare favorably with historical benchmarks for LAPC and BRPC, where mOS often ranges between 12 and 18 months with standard chemotherapy alone.
Surgical Conversion and Success
The ultimate goal of conversion therapy is successful radical resection. In this trial, 30 patients reached the clinical criteria for resectability, and 22 patients (39.3% of the total cohort) ultimately underwent surgery. Among these, the R0 resection rate (no cancer cells at the margin) reached an impressive 90.9% (95% CI 70.8-98.9%). Crucially, the mOS for patients who underwent surgery was significantly extended to 34.0 months (95% CI 20.1-NR), highlighting the profound survival benefit associated with successful surgical conversion.
Safety Profile and Adverse Events
While the THAG regimen is intensive, the safety profile was deemed manageable within the context of aggressive pancreatic cancer treatment. Grade 3 or higher adverse events (AEs) occurred in 58.9% of the patients (33/56). Common toxicities were consistent with those expected from AG chemotherapy and radiotherapy, including hematologic toxicities and fatigue. The addition of tislelizumab did not appear to result in an unexpected increase in severe immune-related adverse events, suggesting that the combination is tolerable for patients with a sufficient performance status.
Precision Medicine: The Role of IL-6 and ctDNA
One of the most impactful aspects of the study is the identification of biomarkers that can guide clinical decision-making.
Interleukin-6 (IL-6)
The study found that baseline IL-6 levels were highly predictive of outcomes. Specifically, patients with baseline IL-6 levels greater than 5 pg/ml exhibited better PFS. This suggests that the inflammatory milieu of the tumor microenvironment may influence how the cancer responds to the combination of immunotherapy and radiotherapy.
ctDNA Kinetics
Dynamic monitoring of ctDNA proved to be a powerful prognostic tool. Patients who achieved ctDNA clearance during treatment demonstrated superior survival compared to those with persistent ctDNA. This reinforces the utility of liquid biopsies as a non-invasive ‘molecular barometer’ to assess the effectiveness of neoadjuvant therapy and potentially select patients who are most likely to benefit from surgery.
Expert Commentary and Clinical Implications
The THAG trial addresses a critical unmet need in pancreatic cancer care. By combining the cytotoxic power of AG, the local control of hypofractionated radiotherapy, and the potential for a sustained immune response through tislelizumab, this regimen achieves a high R0 resection rate even in LAPC patients.
Mechanistic Synergy
The biological plausibility of THAG lies in the concept of ‘radio-immunotherapy.’ Hypofractionated radiotherapy can induce immunogenic cell death, releasing tumor antigens and modulating the tumor microenvironment, which in turn enhances the efficacy of PD-1 inhibitors like tislelizumab. When added to the standard-of-care AG chemotherapy, this triple-threat approach maximizes the chances of downstaging the tumor.
Limitations and Future Directions
While these results are encouraging, the study is a Phase II trial with a relatively small sample size. Further validation in randomized Phase III trials is necessary to confirm whether THAG should become a new standard for conversion therapy. Additionally, the high rate of Grade 3+ AEs necessitates careful patient selection and expert supportive care.
Conclusion
The THAG regimen represents a potent conversion therapy option for patients with BRPC and LAPC. With a 90.9% R0 resection rate among operated patients and a median overall survival of 34 months in the surgical group, the study provides a compelling argument for the integration of immunotherapy and radiotherapy into neoadjuvant protocols. Furthermore, the use of IL-6 and ctDNA monitoring paves the way for a more personalized approach to treating one of the most lethal malignancies.
Funding and Clinical Trial Information
This study was registered under ChiCTR2000032955 and NCT05634564. The research was supported by various clinical research funds dedicated to advancing gastrointestinal oncology.
References
Ni J, Sun Y, Cheng H, et al. Tislelizumab and hypofractionated radiotherapy plus nab-paclitaxel/gemcitabine as conversion therapy for BRPC/LAPC: A Phase II trial with dynamic biomarker monitoring. Clin Cancer Res. 2025 Dec 1. doi: 10.1158/1078-0432.CCR-25-2461. PMID: 41324566.
