← Return to [[Biliary Tract Cancer Clinical Trials]] ---- Phase III | Global randomized double-blind placebo-controlled trial | n=685 | Advanced biliary tract cancer | NEJM Evidence 2022 **Oh et al.** Published in NEJM Evidence, 2022 Enrollment: 2019–2020 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/38319896/) --- ### Essential Takeaway TOPAZ-1 established **durvalumab + gemcitabine/cisplatin** as the new first-line standard for advanced biliary tract cancer. By adding PD-L1 inhibition to the longstanding ABC-02 Gem/Cis backbone, TOPAZ-1 demonstrated: - improved overall survival - improved progression-free survival - improved response rates - durable long-term survival benefit without meaningfully increasing serious toxicity. The trial marked the transition of BTC into the immunotherapy era and became the most important BTC systemic therapy study since ABC-02. --- ### Clinical Question Does the addition of durvalumab to gemcitabine/cisplatin improve survival compared with chemotherapy alone in advanced biliary tract cancer? --- ### Population Included: - Unresectable locally advanced BTC - Metastatic BTC - Recurrent BTC Tumor types: - Intrahepatic cholangiocarcinoma - Extrahepatic cholangiocarcinoma - Gallbladder carcinoma Excluded: - Ampullary carcinoma - Prior immunotherapy exposure Performance status: - ECOG 0-1 Importantly, this represented a modern global BTC population with predominantly metastatic disease. --- ### Study Design Randomized 1:1 double-blind placebo-controlled phase III trial. #### Arm 1 — Durvalumab + Gem/Cis - Durvalumab 1500 mg day 1 - Gemcitabine 1000 mg/m² - Cisplatin 25 mg/m² - Gem/Cis days 1 and 8 - 21-day cycles - Up to 8 cycles Followed by: - maintenance durvalumab every 4 weeks until progression or toxicity. --- #### Arm 2 — Placebo + Gem/Cis Identical chemotherapy backbone with placebo substitution. --- ### Endpoints #### Primary Endpoint Overall survival (OS) #### Secondary Endpoints - Progression-free survival (PFS) - Objective response rate (ORR) - Duration of response - Disease control - Safety --- ### Key Results ### Overall Survival - 12.8 vs 11.5 months - HR 0.80 - p = 0.021 Although the median OS improvement appeared numerically modest, the survival curves separated progressively over time, which became one of the most important findings of the study. --- ### Long-Term Survival #### 24-Month OS - 24.9% vs 10.4% This durable late survival signal strongly supported a true immunotherapy effect rather than simply incremental chemotherapy intensification. --- ### Progression-Free Survival - 7.2 vs 5.7 months - HR 0.75 - p = 0.001 --- ### Objective Response Rate - 26.7% vs 18.7% #### Complete Responses - 2.1% vs 0.6% --- ### Duration of Response Responses were more durable with durvalumab: #### Ongoing Response ≥12 Months - 26.1% vs 15.0% This durability became one of the strongest biologic arguments supporting immune checkpoint inhibition in BTC. --- ### Subgroup Findings Benefit was generally consistent across: - ICC - EHCC - gallbladder carcinoma - metastatic disease - recurrent disease - Asian and non-Asian populations Importantly: - PD-L1 status did not clearly predict benefit suggesting limited utility of PD-L1 as a BTC selection biomarker. --- ### Toxicity One of the most clinically important findings was the minimal increase in toxicity despite adding immunotherapy. #### [[CTCAE Grading|Grade 3-4 Adverse Events]] - 75.7% vs 77.8% #### Treatment Discontinuation Due to Toxicity - 13.0% vs 15.2% #### Immune-Mediated Toxicity - Mostly manageable - Grade 3-4 immune toxicity: 2.4% Overall, durvalumab did not substantially worsen the toxicity profile of Gem/Cis. --- ### Interpretation TOPAZ-1 fundamentally changed the first-line treatment paradigm for advanced BTC. For more than a decade after ABC-02, Gem/Cis remained the unchanged global standard despite numerous failed targeted and biologic strategies. TOPAZ-1 finally demonstrated a statistically significant survival improvement over the ABC-02 backbone and established immunotherapy as part of standard BTC management. Importantly, the trial’s significance extended beyond the modest median OS improvement. The key biologic signal was: - delayed separation of survival curves - improved long-term survival tail - durable responses which are classic immunotherapy response characteristics. The trial also reinforced BTC as an immunologically active disease despite relatively low MSI-high prevalence. --- ### Important Limitations #### Modest Median OS Gain Median OS improvement was: - 12.8 vs 11.5 months which led some criticism regarding the absolute magnitude of benefit. However, long-term survival differences were more compelling than median values alone. --- ### Molecularly Unselected Population The trial was not biomarker-driven and predated widespread incorporation of: - FGFR2 inhibitors - IDH1 inhibitors - HER2-directed therapy into earlier-line treatment algorithms. --- ### Predominantly Metastatic Population Approximately 86% of patients had metastatic disease, limiting extrapolation to more localized unresectable disease. --- ### Limited Biomarker Guidance PD-L1 expression did not clearly enrich for benefit, and MSI-high tumors were rare. Reliable predictive biomarkers remain poorly defined in BTC immunotherapy. --- ### Relationship to ABC-02 ABC-02 established: - Gem/Cis chemotherapy backbone TOPAZ-1 modernized that backbone by adding: - PD-L1 inhibition with durvalumab Thus: - ABC-02 created the standard - TOPAZ-1 evolved the standard Current first-line BTC systemic therapy is fundamentally built upon the sequence of these two landmark trials. --- ### Current Practice Relevance TOPAZ-1 directly established the current standard first-line regimen for advanced BTC: - Gemcitabine - Cisplatin - Durvalumab The study also accelerated broader interest in: - immunotherapy combinations - biomarker discovery - triplet systemic strategies - chemo-immunotherapy platforms in BTC --- ### Practice Impact TOPAZ-1 established: - chemoimmunotherapy as first-line BTC standard - durable immunotherapy benefit in BTC - the modern post-ABC-02 treatment era