Durvalumab Plus Chemotherapy for Advanced Biliary Tract Cancer

This post hoc analysis of a phase 3 randomized clinical trial evaluates 4-year overall survival and safety of durvalumab plus gemcitabine and cisplatin in participants with advanced biliary tract cancer.

Key Points

Question

After more than 4 years of follow-up, what are the efficacy and safety outcomes for participants with advanced biliary tract cancer treated with immunotherapy plus chemotherapy?

Findings

In this post hoc analysis of the phase 3 TOPAZ-1 randomized clinical trial including 685 participants with advanced biliary tract cancer, when compared with placebo plus gemcitabine and cisplatin, durvalumab plus gemcitabine and cisplatin continued to demonstrate long-term survival benefit and a consistent safety profile after 4 years of follow-up.

Meaning

These findings continue to support durvalumab plus gemcitabine and cisplatin as a first-line treatment option for participants with advanced biliary tract cancer.

Abstract

Importance

In the TOPAZ-1 trial’s primary analysis, durvalumab plus gemcitabine and cisplatin (GemCis) showed statistically significant improved overall survival (OS) vs placebo plus GemCis with comparable safety between treatment groups in participants with advanced biliary tract cancer (aBTC). Durvalumab plus GemCis was recently established as the first-line standard of care among patients with aBTC.

Objective

To evaluate 4-year OS and safety of durvalumab plus GemCis in participants with aBTC.

Design, Setting, and Participants

This post hoc analysis of the global, double-blind, placebo-controlled, phase 3 TOPAZ-1 randomized clinical trial included participants 18 years and older with histologically confirmed unresectable, locally advanced, or metastatic biliary tract adenocarcinoma. In the TOPAZ-1 trial, patients were enrolled from April 2019 to December 2020 at 105 sites in 17 countries. Data cutoff was February 28, 2025.

Intervention

Participants received intravenous durvalumab, 1500 mg, or placebo plus gemcitabine, 1000 mg/m², and cisplatin, 25 mg/m², on days 1 and 8 every 3 weeks for up to 8 cycles, followed by durvalumab or placebo monotherapy every 4 weeks.

Main Outcomes and Measures

OS, duration of treatment exposure, serious adverse events, and adverse events resulting in discontinuation were assessed approximately 48 months after the last participant was randomized.

Results

Overall, 685 participants were randomized, with 341 receiving durvalumab plus GemCis (median [range] age, 64 [20-84] years; 172 [50.4%] female) and 344 receiving placebo plus GemCis (median [range] age, 64 [31-85] years; 168 [48.8%] female). Median (range) follow-up in censored participants was 56.9 (1.7-67.2) months for participants who received durvalumab plus GemCis and 50.7 (0.9-62.6) months for participants who received placebo plus GemCis. Median OS was 13.0 (95% CI, 11.6-14.1) months for durvalumab plus GemCis and 11.4 (95% CI, 10.1-12.5) months for placebo plus GemCis (hazard ratio, 0.75; 95% CI, 0.64-0.88); 48-month OS rate was 11.8% vs 4.3%, respectively. The rate of serious adverse events possibly related to treatment was similar between arms (52 of 338 participants [15.4%] in the durvalumab plus GemCis arm vs 59 of 342 participants [17.3%] in the placebo plus GemCis arm). In the durvalumab plus GemCis and placebo plus GemCis arms, 21 of 338 participants (6.2%) and 18 of 342 participants (5.3%), respectively, experienced adverse events leading to study drug discontinuation.

Conclusions and Relevance

In this post hoc analysis of the phase 3 TOPAZ-1 randomized clinical trial, durvalumab plus GemCis demonstrated long-term survival benefit and a clinically manageable safety profile, supporting its use as a first-line treatment for aBTC.

Trial Registration

ClinicalTrials.gov Identifier: NCT03875235

Introduction

Treatment options for people with advanced biliary tract cancers (aBTCs) are limited, and until 2022, a double chemotherapy regimen was the standard of care.¹ The primary analysis of the phase 3 TOPAZ-1 study showed that treatment with durvalumab plus gemcitabine and cisplatin (GemCis) resulted in statistically significant improved overall survival (OS) in participants with aBTCs vs placebo plus GemCis (hazard ratio [HR], 0.80; 95% CI, 0.66-0.97; P = .02; 24-month OS rate, 24.9% vs 10.4%), with a comparable safety profile between treatment groups.² Results from the 2-year analysis demonstrated sustained benefit with durvalumab plus GemCis vs placebo plus GemCis, with participants reporting no detrimental effects on quality-of-life outcomes.^3,4 Based on the TOPAZ-1 primary and longer follow-up analyses, durvalumab plus GemCis has been established as a recommended first-line treatment for people with unresectable, metastatic, or recurrent BTCs.^2,3,4,5,6

In this post hoc analysis, we evaluate survival, subsequent anticancer therapy use, and safety outcomes in the TOPAZ-1 study at the final data cutoff approximately 4 years after the last participant was randomized (estimated to be the last data cutoff with sufficient participants for analysis), representing, to our knowledge, the longest follow-up of an immunotherapy plus chemotherapy regimen in first-line aBTC to date.

Methods

The study design of TOPAZ-1 has been previously described,² and the trial protocol is available in Supplement 1. In the TOPAZ-1 trial, patients were enrolled from April 2019 to December 2020 at 105 sites in 17 countries. Participants were randomized 1:1 to receive durvalumab, 1500 mg, or placebo plus gemcitabine, 1000 mg/m², and cisplatin, 25 mg/m². Participants received treatment on days 1 and 8 of a 21-day cycle for up to 8 cycles, followed by durvalumab or placebo monotherapy every 4 weeks until any discontinuation criteria were met. Randomization was stratified by disease status (initially unresectable or recurrent) and primary tumor site (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer). This final analysis occurred approximately 48 months after the last participant was randomized (data cutoff, February 28, 2025). Efficacy assessments included median OS, OS HR, 48-month OS rates, and OS exposure. OS rate ratios at 24, 36, and 48 months are also presented, demonstrating the ratio between the 2 treatment groups at each given time point (an OS rate ratio >1 favors the durvalumab group). No progression-free survival data were included in this 4-year analysis, as progression-free survival was mature at the primary data cutoff and, therefore, tumor response data were no longer collected. Subsequent anticancer therapy use, including rechallenge with durvalumab plus GemCis, is also described. Safety assessments included duration of treatment exposure, adverse events (AEs) resulting in discontinuation, and serious AEs (SAEs; these were the only types of AEs reported by physicians after the 90-day safety follow-up of February 24, 2022). Deaths were also reported, including those related to aBTC and AEs with outcome of death.

Efficacy analyses and deaths were reported in the full analysis set. OS analysis was performed using a log-rank analysis test and Cox proportional hazards model, stratified by disease status and primary tumor location, as previously described² and in the statistical analysis plan (Supplement 2). Median follow-up time and associated 95% CIs were calculated using the reverse Kaplan-Meier method. Median OS and OS rates were calculated using the Kaplan-Meier method. Safety assessments were reported descriptively in the safety analysis set.

The TOPAZ-1 study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation guidelines for Good Clinical Practice. The study protocol was approved by local institutional review boards, and written informed consent was obtained from participants or their legal representatives before participation. The TOPAZ-1 study is reported per the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

Results

In total, 685 participants were randomized, with 341 receiving durvalumab plus GemCis and 344 receiving placebo plus GemCis in the TOPAZ-1 study. Baseline demographics and disease characteristics were comparable between treatment arms and have been reported previously.² Across the durvalumab plus GemCis and placebo plus GemGis arms, the median (range) age was 64 (20-84) years and 64 (31-85) years, and 172 participants (50.4%) and 168 participants (48.8%) were female, respectively.²

Median (range) duration of follow-up in censored participants was 56.9 (1.7-67.2) months for participants receiving durvalumab plus GemCis and 50.7 (0.9-62.6) months for participants receiving placebo plus GemCis. At data cutoff, 33 participants (9.7%) remained in survival follow-up in the durvalumab plus GemCis arm and 17 (4.9%) remained in the placebo plus GemCis arm; 7 (2.1%) and 0 participants, respectively, were still receiving any study treatment (eFigure 1 in Supplement 3).

Median OS was 13.0 (95% CI, 11.6-14.1) months for durvalumab plus GemCis vs 11.4 (95% CI, 10.1-12.5) months for placebo plus GemCis (HR, 0.75; 95% CI, 0.64-0.88). The 48-month OS rate was 11.8% for durvalumab vs 4.3% for placebo, with an OS rate ratio of 2.74 (Figure 1). The observed OS benefits with durvalumab plus GemCis across clinically relevant subgroups were generally consistent with what was previously reported (eFigure 2 in Supplement 3).²

Figure 1. Kaplan-Meier Curve of Overall Survival (OS).

Median OS was 13.0 months (95% CI, 11.6-14.1 months) in the durvalumab plus gemcitabine and cisplatin (GemCis) arm and 11.4 months (95% CI, 10.1-12.5 months) in the placebo plus GemCis arm (hazard ratio, 0.75; 95% CI, 0.64–0.88). OS data maturity across the durvalumab plus GemCis arm was 90.3%.

^aAt 24 months, OS was 23.2% in the durvalumab plus GemCis arm and 13.7% in the placebo plus GemCis arm (OS rate ratio, 1.69).

^bAt 36 months, OS was 15.0% in the durvalumab plus GemCis arm and 7.6% in the placebo plus GemCis arm (OS rate ratio, 1.97).

^cAt 48 months, OS was 11.8% in the durvalumab plus GemCis arm and 4.3% in the placebo plus GemCis arm (OS rate ratio, 2.74).

Any subsequent anticancer therapy use was similar across the durvalumab plus GemCis and placebo plus GemCis treatment arms, with cytotoxic chemotherapy being most common (if requested, participants could be unblinded to guide decisions regarding subsequent therapy). Notably, 13 participants (3.8%) who received durvalumab plus GemCis received subsequent immunotherapy, compared to 28 participants (8.1%) who had received placebo plus GemCis (Figure 2). The number of participants rechallenged with durvalumab plus GemCis was 4 (1.2%) in the durvalumab plus GemCis arm and 1 (0.3%) in the placebo plus GemCis arm.

Figure 2. Bar Graph Showing Any Subsequent Anticancer Therapy Use.

GemCis indicates gemcitabine and cisplatin.

In the safety analysis set, for 338 participants who received durvalumab plus GemCis and 342 participants who received placebo plus GemCis, the median (range) duration of durvalumab or placebo treatment was 7.3 (0.1-65.2) months and 5.8 (0.2-28.4) months, respectively. Rates of SAEs, SAEs possibly related to study treatment, and AEs leading to study drug discontinuation were similar in the durvalumab plus GemCis and placebo plus GemCis arms (Table). The most common SAEs in the durvalumab plus GemCis arm were cholangitis in 25 participants (7.4%), pyrexia in 15 (4.4%), anemia in 12 (3.6%), and sepsis in 12 (3.6%); in the placebo plus GemCis arm, the most common SAEs were cholangitis in 17 participants (5.0%), sepsis in 9 (2.6%), pyrexia in 8 (2.3%), and abdominal pain in 8 (2.3%).

Table. Safety Outcomes.

Safety analysis seta	Participants, No. (%)
	Durvalumab + GemCis (n = 338)	Placebo + GemCis (n = 342)
Total SAEs	168 (49.7)	152 (44.4)
Any SAE possibly related to study treatment	52 (15.4)	59 (17.3)
Any AE leading to discontinuation of durvalumab or 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)
Full analysis set	Durvalumab + GemCis (n = 341)	Placebo + GemCis (n = 344)
Total deaths	308 (90.3)	326 (94.8)
Death related to disease under investigation onlyb	283 (83.0)	307 (89.2)
TEAE with outcome of death onlyc	4 (1.2)	4 (1.2)
Death related to disease under investigation and with TEAE with outcome of deathb,c	10 (2.9)	10 (2.9)
Death related to disease under investigation and with AE with outcome of deathb,d	3 (0.9)	1 (0.3)
Participants with unknown reason for death	3 (0.9)	2 (0.6)
Other deathse	5 (1.5)	2 (0.6)

Abbreviations: AE, adverse event; GemCis, gemcitabine and cisplatin; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

^a AEs with onset after February 25, 2022, are reported only if they are SAEs.

^b Death related to disease under investigation is determined by the investigator.

^c Includes AEs with an onset date on or after the date of first dose or pretreatment AEs that increased in severity on or after the date of first dose up to and including 90 days following the date of the last dose of study medication, or up to but excluding the date of initiation of the first subsequent therapy (whichever occurred first).

^d AE start date more than 90 days after the last dose of the study drug or AE start date after the date of initiation of the subsequent therapy (whichever occurred first).

^e Participants who died and were not captured in the earlier categories.

The total number of deaths was 308 (90.3%) in the durvalumab plus GemCis arm and 326 (94.8%) in the placebo plus GemCis arm; of all deaths, 283 (83.0%) and 307 (89.2%), respectively, were related to the disease under investigation only. Treatment-emergent AEs with the outcome of death only were reported in 4 participants (1.2%) from each arm (Table).

Discussion

At the 4-year analysis, durvalumab plus GemCis continued to demonstrate survival benefit vs placebo plus GemCis. Participants in the experimental arm had, on average, a 25% lower risk of death than those in the placebo arm. Furthermore, the OS rate ratio was sustained in the 4-year analysis at a similar ratio to the 3-year analysis.⁵ Subsequent anticancer therapies used and the duration of durvalumab exposure were also consistent with previous analyses.^2,4,5

Despite prolonged exposure at 48 months, the safety profile of durvalumab remained consistent, with no new safety signals identified compared with the prior analyses.^2,4,5 Overall safety results were comparable between the 3-year and 4-year OS analyses, with any SAEs reported in 48.8% and 49.7% of participants in the durvalumab treatment arm, respectively, and 44.4% reported in the placebo arm for both analyses.⁵ Since the 3-year analysis, no additional participants had AEs leading to discontinuation, and no new SAEs possibly related to treatment were reported, suggesting that durvalumab can be added to chemotherapy without considerable toxic effects, even with long-term therapy. Death due to disease was the most common reason for death.

Based on the results of TOPAZ-1, durvalumab plus GemCis has been established as a first-line treatment and standard of care for patients with aBTCs.^2,4,5,6 Another regimen recommended for first-line treatment of aBTC is pembrolizumab plus GemCis, with benefit observed vs GemCis (OS HR, 0.86; 95% CI, 0.75-0.98) at a median follow-up of 36.6 months.^6,7

Limitations

Limitations of the TOPAZ-1 study have been described previously.² Limitations of this updated analysis include that all assessments were exploratory with no formal statistical calculations. Furthermore, AEs resulting in discontinuation and SAEs were the only safety assessments reported after the 90-day safety follow-up.

Conclusions

To our knowledge, the phase 3 TOPAZ-1 randomized clinical trial is the first to report 4-year OS among participants with aBTC treated with immunotherapy plus chemotherapy. The final post hoc findings of this trial demonstrate the long-term sustained benefit and clinically manageable safety profile of durvalumab plus GemCis for participants with aBTC, supporting the regimen as a standard-of-care treatment in these participants.

Supplement 1.

Trial Protocol

Supplement 2.

Statistical Analysis Plan

Supplement 3.

eFigure 1. Study Profile

eFigure 2. Forest Plot of OS

Supplement 4.

Data Sharing Statement