Why This Study Matters
Advanced biliary tract cancers (aBTCs) — a group that includes intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer — have long carried a poor prognosis. Until 2022, a gemcitabine-cisplatin (GemCis) chemotherapy doublet was the only standard of care. The phase 3 TOPAZ-1 trial changed that landscape, establishing durvalumab plus GemCis as a first-line standard based on its primary analysis and subsequent 2-year follow-up.
What has been missing until now is long-term, multi-year survival and safety data for an immunotherapy-chemotherapy combination in this setting. This post hoc analysis reports TOPAZ-1’s final data cutoff — approximately 4 years after the last participant was randomized — which the authors describe as the longest follow-up reported to date for an immunotherapy-plus-chemotherapy regimen in first-line aBTC.
Study Design
TOPAZ-1 is a global, double-blind, placebo-controlled, phase 3 randomized clinical trial. Participants were randomized 1:1, stratified by disease status (initially unresectable or recurrent) and primary tumor site (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer). This report reflects the trial’s final analysis, occurring approximately 48 months after the last participant was randomized (data cutoff: February 28, 2025). No progression-free survival data are included in this update, as PFS was already mature at the primary data cutoff and tumor response data were no longer being collected.
In the experimental arm, participants received durvalumab 1500 mg IV plus gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on days 1 and 8 of a 21-day cycle for up to 8 cycles, followed by durvalumab monotherapy every 4 weeks. The control arm received placebo plus the same GemCis regimen, followed by placebo monotherapy every 4 weeks.
Patient Population
Eligible participants were adults 18 years or older with histologically confirmed unresectable, locally advanced, or metastatic biliary tract adenocarcinoma, enrolled between April 2019 and December 2020. Across the durvalumab + GemCis and placebo + GemCis arms, median (range) age was 64 (20-84) years and 64 (31-85) years, respectively, with 172 participants (50.4%) and 168 participants (48.8%) female. Baseline demographics and disease characteristics were comparable between the two arms.
Primary Endpoint Results
At the final ~48-month data cutoff, median overall survival was 13.0 months (95% CI, 11.6-14.1) with durvalumab plus GemCis compared with 11.4 months (95% CI, 10.1-12.5) with placebo plus GemCis (hazard ratio, 0.75; 95% CI, 0.64-0.88). The 48-month OS rate was 11.8% in the durvalumab arm versus 4.3% in the placebo arm — an OS rate ratio of 2.74. Earlier landmarks told a consistent story: at 24 months, OS was 23.2% versus 13.7% (rate ratio, 1.69); at 36 months, 15.0% versus 7.6% (rate ratio, 1.97).
Median (range) follow-up in censored participants was 56.9 (1.7-67.2) months for the durvalumab + GemCis arm and 50.7 (0.9-62.6) months for the placebo + GemCis arm. At data cutoff, 33 participants (9.7%) remained in survival follow-up in the durvalumab arm versus 17 (4.9%) in the placebo arm, and 7 (2.1%) versus 0 participants were still receiving study treatment.
Subsequent anticancer therapy use was broadly similar between arms. Notably, 13 participants (3.8%) who received durvalumab plus GemCis went on to receive subsequent immunotherapy, compared with 28 participants (8.1%) who had received placebo plus GemCis. Four participants (1.2%) in the durvalumab arm and 1 (0.3%) in the placebo arm were rechallenged with durvalumab plus GemCis.
Subgroup Analyses
The published text states that OS benefits with durvalumab plus GemCis "across clinically relevant subgroups were generally consistent with what was previously reported." However, exact subgroup-level hazard ratios, confidence intervals, or p-values are not provided in the accessible article text — those figures are referenced as appearing only in eFigure 2 of Supplement 3, a supplementary file not included in the retrieved full text.
| Subgroup | Reported Result |
|---|---|
| Clinically relevant subgroups (composite) | Described qualitatively as "generally consistent" with prior reporting; exact statistics not specified in the accessible source (see Supplement 3, eFigure 2) |
Note: Specific subgroup statistics are not reproduced here in the absence of source data, consistent with this outlet’s accuracy standards.
Safety Profile
In the safety analysis set (338 participants receiving durvalumab + GemCis; 342 receiving placebo + GemCis), median (range) duration of durvalumab or placebo treatment was 7.3 (0.1-65.2) months versus 5.8 (0.2-28.4) months, respectively. The authors report that rates of serious adverse events (SAEs), SAEs possibly related to treatment, and AEs leading to discontinuation were similar between arms, with no new safety signals identified compared with prior analyses despite prolonged treatment exposure.
| Outcome | Durvalumab + GemCis (n=338) | Placebo + GemCis (n=342) |
|---|---|---|
| Total SAEs | 168 (49.7%) | 152 (44.4%) |
| Any SAE possibly related to treatment | 52 (15.4%) | 59 (17.3%) |
| Any AE leading to discontinuation of durvalumab/placebo | 21 (6.2%) | 18 (5.3%) |
| Any immune-mediated AE | 102 (30.2%) | 71 (20.8%) |
| Any infusion-reaction AE | 11 (3.3%) | 8 (2.3%) |
| Most Common SAE (Durvalumab + GemCis) | Rate | Most Common SAE (Placebo + GemCis) | Rate |
|---|---|---|---|
| Cholangitis | 7.4% (n=25) | Cholangitis | 5.0% (n=17) |
| Pyrexia | 4.4% (n=15) | Sepsis | 2.6% (n=9) |
| Anemia | 3.6% (n=12) | Pyrexia | 2.3% (n=8) |
| Sepsis | 3.6% (n=12) | Abdominal pain | 2.3% (n=8) |
Total deaths were reported in 308 participants (90.3%) in the durvalumab + GemCis arm and 326 (94.8%) in the placebo + GemCis arm; of these, 283 (83.0%) and 307 (89.2%), respectively, were attributed solely to the disease under investigation. Treatment-emergent adverse events with an outcome of death were reported in 4 participants (1.2%) in each arm.
Note: Per the study methods, AEs with onset after February 25, 2022, were reported only if they were serious adverse events — the full adverse event spectrum was not re-collected at this later cutoff.
Interpretation and Broader Context
At this final ~4-year analysis, durvalumab plus GemCis continued to show a sustained overall survival advantage over placebo plus GemCis, with the OS rate ratio remaining similar to the 3-year analysis. Subsequent anticancer therapy use and duration of durvalumab exposure were also consistent with prior reporting. The authors state that, on average, participants in the durvalumab arm had a 25% lower risk of death than those in the placebo arm over this follow-up period, consistent with the reported hazard ratio of 0.75.
Despite prolonged treatment exposure, the safety profile of durvalumab remained consistent with earlier analyses, with SAEs reported in 48.8% and 49.7% of the durvalumab arm at the 3-year and 4-year analyses, respectively, and 44.4% in the placebo arm at both time points — suggesting durvalumab can be added to chemotherapy without considerable additional toxicity, even with long-term therapy.
The authors also note that another regimen, pembrolizumab plus GemCis, has separately been recommended for first-line aBTC treatment, with a reported OS benefit versus GemCis alone (HR, 0.86; 95% CI, 0.75-0.98) at a median follow-up of 36.6 months — providing useful context for how the durvalumab combination’s long-term data compare within the evolving first-line treatment landscape.
The study authors describe this update’s limitations explicitly: all assessments were exploratory, without formal statistical hypothesis testing, and adverse event reporting after the 90-day safety follow-up window was restricted to serious adverse events and treatment discontinuations rather than the complete adverse event profile.
At its longest-ever follow-up of approximately 4 years, TOPAZ-1 confirms a durable first-line overall survival benefit for durvalumab plus gemcitabine-cisplatin in advanced biliary tract cancer — median OS 13.0 vs 11.4 months (HR, 0.75) and a 48-month OS rate of 11.8% vs 4.3% (rate ratio, 2.74) — achieved without new safety signals despite prolonged immunotherapy exposure. These final data reinforce durvalumab + GemCis as a first-line standard of care, while the authors caution that all analyses were exploratory and that late adverse-event capture was limited to serious events.