Abstract
Background
In the phase 3, double-blind TOPAZ-1 study, durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) versus placebo plus GemCis in advanced biliary tract cancer (BTC). Updated data from TOPAZ-1, including outcomes in long-term survivors (LTS) are reported here.
Methods
In TOPAZ-1 (NCT03875235), participants aged ≥18 years with unresectable, locally advanced, or metastatic BTC were randomised 1:1 to durvalumab plus GemCis or placebo plus GemCis (administered intravenously) on a 21-day cycle for up to eight cycles. Durvalumab 1500 mg or placebo was administered on day 1 of each cycle, and GemCis (gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2) was administered on days 1 and 8 of each cycle. After completion of GemCis, durvalumab 1500 mg or placebo were administered once every four weeks until disease progression or other discontinuation criteria were met. Participants were randomly assigned to study treatment using a computer-generated randomisation scheme. Randomisation was stratified by disease status and primary tumour location. Investigators and participants were masked to study treatment. The primary objective was OS. Updated data from TOPAZ-1, with additional follow-up (data cut-off [DCO] February 25, 2022) and data maturity beyond the interim analysis, are reported here. Baseline characteristics, best objective response per RECIST v1.1 (DCO August 11, 2021), and safety were analysed in LTS (participants who survived for ≥18 months after randomisation).
Findings
In total, 685 participants were randomised (345 [50·4%] were male; 340 [49·6%] were female). For durvalumab plus GemCis (n=341) and placebo plus GemCis (n=344), median (95% CI) follow-up was 23·4 (20·6–25·2) months and 22·4 (21·4–23·8) months. OS hazard ratio (95% CI) for durvalumab plus GemCis versus placebo plus GemCis was 0·76 (0·64–0·91). Kaplan–Meier-estimated 24-month OS rates (95% CIs) were 23·6% (18·7–28·9) and 11·5% (7·6–16·2), respectively. Survival with durvalumab plus GemCis, including long-term survival, was improved in participants with disease control (complete or partial response or stable disease). In total, 39/88 (44·3%) of LTS on durvalumab plus GemCis had an objective response versus 22/65 (33·8%) of LTS in the placebo plus GemCis group. Adverse events with durvalumab plus GemCis were similar to the pre-planned interim analysis.
Interpretation
Durvalumab plus GemCis demonstrated robust and sustained OS benefit with no new safety signals. Findings continue to support the regimen as a standard of care for untreated advanced BTC.
In the phase 3, double-blind TOPAZ-1 study, durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) versus placebo plus GemCis in advanced biliary tract cancer (BTC). Updated data from TOPAZ-1, including outcomes in long-term survivors (LTS) are reported here.
Methods
In TOPAZ-1 (NCT03875235), participants aged ≥18 years with unresectable, locally advanced, or metastatic BTC were randomised 1:1 to durvalumab plus GemCis or placebo plus GemCis (administered intravenously) on a 21-day cycle for up to eight cycles. Durvalumab 1500 mg or placebo was administered on day 1 of each cycle, and GemCis (gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2) was administered on days 1 and 8 of each cycle. After completion of GemCis, durvalumab 1500 mg or placebo were administered once every four weeks until disease progression or other discontinuation criteria were met. Participants were randomly assigned to study treatment using a computer-generated randomisation scheme. Randomisation was stratified by disease status and primary tumour location. Investigators and participants were masked to study treatment. The primary objective was OS. Updated data from TOPAZ-1, with additional follow-up (data cut-off [DCO] February 25, 2022) and data maturity beyond the interim analysis, are reported here. Baseline characteristics, best objective response per RECIST v1.1 (DCO August 11, 2021), and safety were analysed in LTS (participants who survived for ≥18 months after randomisation).
Findings
In total, 685 participants were randomised (345 [50·4%] were male; 340 [49·6%] were female). For durvalumab plus GemCis (n=341) and placebo plus GemCis (n=344), median (95% CI) follow-up was 23·4 (20·6–25·2) months and 22·4 (21·4–23·8) months. OS hazard ratio (95% CI) for durvalumab plus GemCis versus placebo plus GemCis was 0·76 (0·64–0·91). Kaplan–Meier-estimated 24-month OS rates (95% CIs) were 23·6% (18·7–28·9) and 11·5% (7·6–16·2), respectively. Survival with durvalumab plus GemCis, including long-term survival, was improved in participants with disease control (complete or partial response or stable disease). In total, 39/88 (44·3%) of LTS on durvalumab plus GemCis had an objective response versus 22/65 (33·8%) of LTS in the placebo plus GemCis group. Adverse events with durvalumab plus GemCis were similar to the pre-planned interim analysis.
Interpretation
Durvalumab plus GemCis demonstrated robust and sustained OS benefit with no new safety signals. Findings continue to support the regimen as a standard of care for untreated advanced BTC.
| Original language | English |
|---|---|
| Journal | The Lancet Gastroenterology and Hepatology |
| Publication status | Accepted/In press - 22 Mar 2024 |
Embargoed Document
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Defining immunotherapy in combination with chemotherapy as first-line treatment of patients with advanced biliary tract cancer (durvalumab)
Valle, J. (Corresponding participant) & Mcnamara, M. (Participant)
Impact: Health and wellbeing