← Return to [[Biliary Tract Cancer Clinical Trials]] ---- Phase III | SWOG randomized open-label trial | n=441 | Advanced biliary tract cancer | JCO 2025 **Shroff et al.** Published in Journal of Clinical Oncology, 2025 Enrollment: 2018–2021 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/39671534/) --- ### Essential Takeaway SWOG S1815 evaluated whether intensifying frontline therapy with **gemcitabine/cisplatin/nab-paclitaxel (GAP)** could improve outcomes compared with standard Gem/Cis in advanced biliary tract cancer. Although GAP improved response rates, it failed to improve overall survival and produced substantially greater toxicity. The trial reinforced Gem/Cis-based doublets — now typically combined with immunotherapy — rather than triplet cytotoxic escalation as the preferred frontline strategy in unselected BTC. --- ### Clinical Question Does adding nab-paclitaxel to gemcitabine/cisplatin improve survival in newly diagnosed advanced biliary tract cancer? --- ### Population Included: - Intrahepatic cholangiocarcinoma - Extrahepatic cholangiocarcinoma - Gallbladder carcinoma Disease status: - Locally advanced unresectable - Metastatic disease Excluded: - Ampullary carcinoma - Prior systemic therapy for advanced disease --- ### Study Design Randomized open-label phase III trial. #### Arm 1 — GAP - Gemcitabine - Cisplatin - Nab-paclitaxel #### Arm 2 — GC - Gemcitabine - Cisplatin Treatment continued until progression or unacceptable toxicity. --- ### Endpoints #### Primary Endpoint - Overall survival (OS) #### Secondary Endpoints - Progression-free survival (PFS) - Objective response rate (ORR) - Toxicity --- ### Key Results ### Overall Survival - 14.0 vs 13.6 months - HR 0.91 - p = 0.41 No significant OS improvement. --- ### Progression-Free Survival - 7.5 vs 6.3 months - HR 0.89 - p = 0.32 No significant PFS improvement. --- ### Objective Response Rate - 31% vs 21% - p = 0.03 Higher response rates with GAP did not translate into survival benefit. --- ### Toxicity GAP produced substantially greater toxicity, including: - neutropenia - thrombocytopenia - neuropathy - fatigue - GI toxicity Treatment-related deaths: - 7 with GAP - 1 with GC --- ### Subgroup Findings Exploratory analyses suggested possible greater benefit in: - gallbladder carcinoma - locally advanced disease However, these findings were hypothesis-generating only and not practice-changing. --- ### Interpretation SWOG S1815 was a negative trial. Despite encouraging phase II data and improved radiographic response rates, adding nab-paclitaxel to Gem/Cis did not improve survival and significantly increased toxicity. The study reinforced that future advances in BTC are more likely to come from: - immunotherapy - molecular targeting - biologic selection rather than broader cytotoxic intensification. --- ### Important Limitations #### Open-Label Design Potential bias in investigator-assessed responses. --- ### Heterogeneous Disease Population Combined: - ICC - EHCC - gallbladder carcinoma despite important biologic differences. --- ### Exploratory Subgroup Signals Subgroup findings were underpowered and should be interpreted cautiously. --- ### Relationship to Other BTC Trials #### ABC-02 Established: - Gem/Cis frontline standard #### TOPAZ-1 / KEYNOTE-966 Established: - chemoimmunotherapy with Gem/Cis + checkpoint inhibition #### SWOG S1815 Demonstrated that: - triplet cytotoxic escalation did not meaningfully improve survival --- ### Current Practice Relevance SWOG S1815 does not support routine frontline use of GAP in unselected advanced BTC. Current frontline standards remain: - Gem/Cis + durvalumab - Gem/Cis + pembrolizumab with increasing emphasis on molecularly targeted therapy and biomarker-driven treatment selection. --- ### Practice Impact SWOG S1815 demonstrated that increasing chemotherapy intensity alone is insufficient to substantially improve outcomes in advanced BTC and reinforced the modern shift toward immunotherapy and precision oncology approaches.