1. Classification and Current Status of BTC
Since 2010, experts have classified intrahepatic cholangiocarcinoma (ICC) as part of BTC and established an independent staging system. According to the 2022 CSCO guidelines for biliary tract malignancies, BTC primarily includes gallbladder cancer (GBC) and cholangiocarcinoma (CCA), with CCA further divided into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC).
The incidence and mortality rates of BTC have been rising, with the disease often presenting silently and exhibiting high malignancy. The median overall survival (OS) is less than 12 months, and approximately 70% of patients are diagnosed at an advanced stage. The five-year survival rate for first-line chemotherapy is only 5%–15%, highlighting the urgent need for new treatment strategies. In China, BTC poses an even greater burden due to low early detection rates and poor treatment outcomes. According to data from the National Cancer Center, in 2016, there were 56,000 new cases of gallbladder cancer and 41,000 related deaths.
The only curative option for primary gallbladder cancer and ICC remains radical (R0) resection. However, the resectability rate at initial diagnosis is low, and recurrence rates are high. As a result, systemic therapy is the primary treatment option for unresectable BTC. In cases of recurrence or distant metastases, a comprehensive evaluation and multidisciplinary discussion (MDT) are required to determine the most appropriate systemic treatment approach.
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2. The New Era of First-Line Immunotherapy for Advanced BTC
In the past, systemic treatment for advanced BTC was limited to chemotherapy, which provided modest benefits, with a median OS of less than one year. BTC tumors secrete immunosuppressive molecules, creating an immunosuppressive microenvironment. Immune checkpoint inhibitors (ICIs) work by blocking immune checkpoint-ligand interactions, thereby reversing immune evasion and re-activating antitumor immunity. However, ICI monotherapy has shown limited efficacy in BTC.
Chemotherapy may enhance immunotherapy responses by upregulating checkpoint expression, inducing immunogenic cell death, and modifying immune cell infiltration. As a result, chemoimmunotherapy has become a major breakthrough in BTC treatment. The TOPAZ-1 study marked a significant turning point, replacing the 12-year dominance of GemCis chemotherapy as the standard of care and ushering in a new era of first-line chemoimmunotherapy for advanced BTC.
TOPAZ-1 Study: Durvalumab Becomes the First and Only ICI to Demonstrate OS and PFS Benefit in BTC
TOPAZ-1 is a global, randomized, double-blind, Phase III trial (NCT03875235).
At three years of follow-up, durvalumab plus GemCis achieved a median OS of 12.9 months, with the three-year OS rate more than doubling compared to chemotherapy alone (14.6% vs. 6.9%) and a 26% reduction in the risk of death (HR 0.74).
Subgroup analysis revealed that patients with initially unresectable BTC had an OS HR of 0.84, while postoperative recurrent patients had an OS HR of 0.56, reflecting a 44% reduction in mortality risk. This raises a critical question: Should IO therapy be integrated into adjuvant treatment for resectable BTC patients, rather than waiting for recurrence? Further research is needed to explore this approach.
Regarding PFS, durvalumab plus chemotherapy achieved a median PFS of 7.2 months compared to 5.7 months in the control group (HR 0.75, P=0.001). The one-year PFS rate was nearly twice as high as chemotherapy alone (16.0% vs. 6.6%), demonstrating a long-term survival benefit.
Additionally, durvalumab plus chemotherapy exhibited a high response rate, rapid onset of action, and durable responses, with an ORR of 26.7%, a 43% improvement over chemotherapy alone.
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3. Real-World Validation: Italian Study Confirms OS and PFS Benefits of Durvalumab Plus Chemotherapy
This study represents the first real-world validation of the TOPAZ-1 regimen, enrolling 563 patients with unresectable, locally advanced, or metastatic BTC. The study compared durvalumab plus cisplatin/gemcitabine versus chemotherapy alone. Results demonstrated that adding durvalumab significantly improved OS (14.8 vs. 11.2 months, P=0.0002) and PFS (8.3 vs. 6.0 months, P<0.0001) in a real-world setting, reinforcing TOPAZ-1 findings.
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4. KEYNOTE-966 Study: Further Validation of First-Line Chemoimmunotherapy in BTC
KEYNOTE-966 is a randomized, double-blind, Phase III trial investigating pembrolizumab plus GP chemotherapy in first-line BTC. At the 2024 ASCO Annual Meeting, its three-year survival data was presented. After 36.6 months of follow-up, pembrolizumab plus GP achieved a median OS of 12.7 vs. 10.9 months in the control group (HR 0.86, nominal P=0.0099). However, PFS and ORR showed no statistically significant differences. The median time to response (TTR) was 2.8 months.
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5. Comparing TOPAZ-1 and KEYNOTE-966: Key Considerations
Both TOPAZ-1 and KEYNOTE-966 were randomized, double-blind, Phase III trials conducted in advanced BTC patients, with similar study designs and patient inclusion criteria. However, some key differences emerged in secondary and exploratory endpoints.
In KEYNOTE-966, the three-year OS rate was similar between the experimental and control arms, and OS HR increased over time (0.83 at the two-year follow-up vs. 0.86 at three years). Additionally, KEYNOTE-966 showed no significant differences in PFS and ORR. The median time to response (TTR) was 2.8 months, compared to 1.6 months in TOPAZ-1, suggesting differences in tumor response kinetics between the two regimens.
The speed of immune response is crucial in both medical and surgical oncology. In the context of advanced BTC, how do differences in ICI onset of action influence first-line, conversion, and neoadjuvant therapy strategies? What impact do these differences have on patient prognosis? Addressing these questions is critical to optimizing BTC treatment pathways and warrants further research.
Another important consideration is the choice of immune checkpoint inhibitors. PD-L1 inhibitors differ from PD-1 inhibitors in that they simultaneously bind PD-L1 on tumor cells and antigen-presenting cells, leading to stronger immune activation while preserving PD-L2’s physiological function. Studies indicate that PD-1 inhibitors are associated with a higher incidence of grade ≥3 adverse events compared to PD-L1 inhibitors (OR 1.58; 95% CI: 1.00–2.54). Based on this, PD-L1 inhibitors may offer an overall advantage in terms of both efficacy and safety.
3. Exploration of Chemoimmunotherapy Strategies for Advanced BTC
The foundation of first-line treatment for advanced BTC is chemoimmunotherapy, and in recent years, research in this field has expanded rapidly, exploring various combinations such as IO + chemotherapy, IO + chemotherapy + TKIs, IO + HAIC + TKIs, IO + chemotherapy + anti-VEGF, dual-IO + chemotherapy, and IO + TKIs.
TopDouble Study: Evaluating Durvalumab Plus Gemcitabine-Based Chemotherapy in Chinese BTC Patients
Durvalumab plus GC has become the standard first-line treatment for advanced BTC according to treatment guidelines. However, other gemcitabine-based chemotherapy regimens are also commonly used in clinical practice. The TopDouble study, a Phase IIIb, single-arm, multicenter trial, was conducted in a Chinese patient population to evaluate the efficacy of durvalumab combined with different gemcitabine-based regimens. As of January 2024, the study had enrolled 112 patients (GEMOX group: 45 patients, GS group: 49 patients, GC group: 18 patients), with a median follow-up of 3.02 months. Preliminary safety analysis showed that D + GC was the best tolerated, while D + GEMOX and D + GS were also manageable.
ALLEN Regimen: Exploring the Potential of Durvalumab Plus Albumin-Bound Paclitaxel and Lenvatinib
A Phase II, open-label, single-arm study conducted by Zhifang Li’s team at the Chinese PLA General Hospital enrolled 16 patients with unresectable BTC between September 2021 and September 2023, with 14 patients receiving at least two cycles of treatment included in the efficacy analysis. With a median follow-up of 6.8 months, the median patient age was 59.0 years. The study reported an objective response rate (ORR) of 35.7% and a disease control rate (DCR) of 100%, with a median PFS of 7.3 months (95% CI: 4.9–8.2). These promising results suggest that durvalumab-based combination therapies may offer significant antitumor activity in unresectable BTC, warranting further investigation in larger patient populations.
Durvalumab Plus Lenvatinib and Hepatic Arterial Infusion Chemotherapy (HAIC) for Unresectable ICC
Previous research from Sun Yat-sen University Cancer Center demonstrated that oxaliplatin + leucovorin + 5-FU (FOLFOX) HAIC provided clinical benefit for unresectable ICC. The team further explored the combination of durvalumab + lenvatinib + FOLFOX-HAIC in treatment-naïve patients with unresectable ICC.
A total of 28 eligible patients were enrolled, and the study reported objective response rates (ORR) of 65.2% (mRECIST) and 39.1% (RECIST 1.1). Additionally, the median PFS of 11.9 months was the longest PFS reported for any triplet therapy in ICC to date, with a favorable safety profile. These findings suggest that durvalumab combined with HAIC and lenvatinib may represent an optimal treatment strategy for unresectable ICC.
IMbrave151 Study: Evaluating Atezolizumab + Bevacizumab + GemCis for BTC
IMbrave151 is a randomized, controlled Phase II trial, and the first study to evaluate PD-L1/anti-VEGF therapy combined with chemotherapy as first-line treatment for advanced BTC.
Results showed that adding bevacizumab to atezolizumab + CisGem slightly improved PFS (8.3 vs. 7.9 months, HR = 0.67) but did not result in a significant OS benefit (14.9 vs. 14.6 months, HR = 0.97). Furthermore, ORR and DCR did not show significant improvements, suggesting that further optimization of this regimen is needed.
ZSAB-TOP Study: Investigating the Potential of Dual-IO + Chemotherapy in BTC
The ZSAB-TOP study is evaluating tislelizumab (PD-1 inhibitor) + ociperlimab (TIGIT inhibitor) + GemCis as first-line therapy for unresectable advanced BTC. This is the first clinical trial in BTC exploring a PD-1 inhibitor combined with a TIGIT inhibitor and chemotherapy.
At 8 months of follow-up, the study reported a confirmed ORR (cORR) of 48.8% (P = 0.0009), reaching statistical significance, and a DCR of 82.9%. Subgroup analysis showed cORR rates of 34.4% in ICC, 100.0% in GBC, and 100.0% in ECC. Notably, patients with TIGIT-positive tumors demonstrated higher response rates, with cORR reaching 69.2% in the TIGIT+/PD-L1+ group and 66.7% in the TIGIT+/PD-L1− group.
The median PFS was 7.7 months, while median OS had not yet been reached, with a 6-month OS rate of 86.2%. No new safety concerns were observed, and the overall safety profile was manageable.
Additionally, the ADJUBIL trial is currently investigating durvalumab + tremelimumab (CTLA-4 inhibitor) combined with capecitabine as adjuvant therapy for BTC.
Regorafenib Plus Durvalumab (MEDI4736) for Chemotherapy-Refractory Advanced BTC
Small-molecule inhibitors like regorafenib can modulate the tumor microenvironment and enhance the efficacy of immunotherapy when combined with ICIs like durvalumab.
A Phase I/II trial, led by Raed Moh’d Taiseer Al-Rajabi, is currently recruiting patients to evaluate the safety and efficacy of regorafenib + durvalumab (MEDI4736) in chemotherapy-refractory BTC.
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Conclusion
The treatment landscape for advanced BTC has fully transitioned into the immunotherapy era, but unmet clinical needs remain. A wide array of “immunotherapy plus” strategies are being explored, and optimizing combination regimens to maximize patient benefit remains the key focus of future BTC research. Chemoimmunotherapy continues to be the dominant first-line approach, and refining these regimens will be crucial in improving BTC outcomes.
