The global, double-blind, placebo-controlled, phase 3 TOPAZ-1 clinical trial evaluated the first-line chemoimmunotherapy regimen of the PD-L1 inhibitor durvalumab plus gemcitabine/cisplatin (GemCis) in patients with advanced biliary tract cancer (BTC). The results of the planned interim analysis for this study were presented at the 2022 ASCO GI Cancers Symposium.
The study included patients with treatment-naïve, locally advanced unresectable or metastatic BTC if unresectable or metastatic at diagnosis, recurrent disease of >6 months after curative surgery or adjuvant therapy, and ECOG performance status 0 or 1. Patients were randomized 1:1 to durvalumab (1500 mg every 3 weeks) or to placebo plus GemCis (gemcitabine 1000 mg/m2; cisplatin 25 mg/m2 on days 1 and 8 every 3 weeks) for up to 8 cycles, followed by durvalumab (1500 mg every 4 weeks) or placebo until disease progression or unacceptable toxicity.
Patients were stratified by disease status and primary tumor site, including intrahepatic cholangiocarcinoma (CCA), extrahepatic CCA, and gallbladder cancer. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Statistical testing of PFS was to be conducted only if the OS was statistically significant. The data cutoff date was August 11, 2021.
Of 685 patients who were enrolled, 341 received durvalumab plus GemCis and 344 received placebo plus GemCis. Compared with the placebo cohort, the durvalumab cohort was associated with significant improvement in OS (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66-0.97; P = .021) and PFS (HR, 0.75; 95% CI, 0.64-0.89; P = .001). The ORR was higher in the durvalumab cohort versus placebo (26.7% vs 18.7%; P = .011). The median duration of response was similar (6.4 months vs 6.2 months).
Because the OS results were statistically significant at the planned interim analysis, and the study met its primary end point, these results are considered the final statistical OS analysis.
The incidence of grade 3 or 4 treatment-related adverse events (TRAEs) was 62.7% with durvalumab and 64.9% with placebo, and serious TRAEs were also similar between the 2 groups. TRAEs led to treatment discontinuation in 8.9% and 11.4% of patients, respectively. Immune-mediated adverse events were 12.7% in the durvalumab cohort versus 4.7% in the placebo cohort and included hypothyroid events (5.9%), dermatitis or rash (3.6%), pneumonitis (0.9%), hepatic events (1.2%), and adrenal insufficiency (1.2%).
These data indicate that chemoimmunotherapy with durvalumab plus GemCis offers a significant survival advantage—OS and PFS—versus placebo plus GemCis, with a manageable safety profile.
This is the first study to demonstrate the efficacy of chemoimmunotherapy in patients with BTC and may potentially represent a new first-line standard-of-care regimen in patients with advanced disease.
Source: Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2022. Abstract 378.