TOPAZ-1: Overall Survival Prolonged With First-Line Immunotherapy Plus Chemotherapy in Biliary Tract Cancer

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For the first time, a phase III study has shown an overall survival benefit for upfront treatment using immunotherapy plus chemotherapy in advanced biliary tract cancer. In the TOPAZ-1 trial, the addition of the anti–PD-L1 agent durvalumab to gemcitabine plus cisplatin significantly improved survival without additional toxicity, according to Do-Youn Oh, MD, PhD, Professor at Seoul National University Hospital and Seoul National University College of Medicine in Korea, who presented the findings at the 2022 ASCO Gastrointestinal Cancers Symposium.1

“TOPAZ-1 is the first global phase III study to report positive results testing immunotherapy plus chemotherapy as first-line treatment for advanced biliary tract cancer,” Dr. Oh said. “Durvalumab plus gemcitabine/cisplatin is an effective first-line therapy and could become a new standard of care.”

The new regimen could answer an unmet clinical need for a cancer whose incidence is rising worldwide, she said. “Advanced, unresectable biliary tract cancer has an aggressive nature, limited treatment options, and a poor prognosis. The first-line standard of care for advanced disease—gemcitabine/chemotherapy—has remained unchanged for over a decade.”

Do-Youn Oh, MD, PhD

Do-Youn Oh, MD, PhD

TOPAZ-1 met its primary endpoint at the prespecified interim analysis. Median overall survival was 12.8 months with durvalumab and chemotherapy vs 11.6 months with gemcitabine/cisplatin alone (hazard ratio [HR] = 0.80; P = .021). The curves began to separate at around 6 months, widening over time: the hazard ratio was 0.91 for up to 6 months, improving to 0.74 thereafter. For the experimental vs control arms, overall survival rates were 54.1% vs 48.0% at 12 months, 35.1% vs 25.6% at 18 months, and 24.9% vs 10.4% at 24 months, Dr. Oh reported.

The global double-blind study had a multiple-testing design. Because the result for overall survival was statistically significant at the planned interim analysis, the results she presented are considered the final formal statistical analysis for overall survival.

About TOPAZ-1

Biliary tract cancer has immunogenic features that indicate it is a good candidate for immunotherapy; however, only limited activity has been observed for single-agent immune checkpoint inhibitors in the second-line setting. Durvalumab plus gemcitabine/cisplatin showed some antitumor activity in a previous phase II study.2

TOPAZ-1 enrolled 685 patients from around the world who had received no prior treatment for unresectable, locally advanced, recurrent, or metastatic biliary tract cancer. Within the population (more than half of whom were Asian), 56% had intrahepatic cholangiocarcinoma, 19% had extrahepatic cholangiocarcinoma, and 25% had gallbladder cancer. For 89% of patients, the disease was metastatic. PD-L1 tumor area positivity [TAP] ≥ 1% was found in approximately 58% of patients, and 30% had TAP < 1%. TAP reflects the proportion of tumor area occupied by tumor cells with membrane and immune cells with cytoplasmic/membrane PD-L1 staining at any intensity.

Subgroup analysis showed some benefit across the board. By PD-L1 expression, benefits were observed regardless of the level of PD-L1 expression. For the durvalumab/chemotherapy arm, hazard ratios were as follows: 0.79 for TAP ≥ 1% and 0.86 for TAP < 1%; 0.70 for TAP ≥ 5% and 0.88 for TAP < 5%; 0.75 for TAP ≥ 10% and 0.83 for TAP < 10%.

The combination also greatly improved progression-free survival compared with chemotherapy alone. Median progression-free survival was 7.2 months with durvalumab plus gemcitabine/cisplatin vs 5.7 months with chemotherapy alone (HR = 0.75; P =.001). The percentages of patients who were progression-free were, respectively, 34.8% and 24.6% at 9 months and 16.0% and 6.6%, respectively, at 12 months.

Overall response rates, by investigator assessment, were 26.7% with durvalumab/chemotherapy compared with 18.7% with chemotherapy alone, yielding an odds ratio for response of 1.60 (P = .011). From 9 months on, 32.6% of the combination arm was still in response, compared with 25.3% of the chemotherapy arm; responses continued for 12 months and beyond in 26.1% and 15.0%, respectively, she reported.

Grade 3 or 4 treatment-related adverse events occurred at a similar rate between the arms:  62.7% for the durvalumab arm and 64.9% for chemotherapy alone, suggesting that toxicity was largely driven by chemotherapy, the investigators said. 

DISCLOSURE: Dr. Oh has served as a consultant or advisor for ASLAN Pharma­ceuticals, AstraZeneca, Basilea, Bayer, BeiGene, Celgene, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, and Zymeworks; and has received research support from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok.


1. Oh DY, et al: A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin in patients with advanced biliary tract cancer: TOPAZ-1. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 378. Presented January 21, 2022.

2. Oh DY, et al: Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab ± tremelimumab and gemcitabine/cisplatin in chemo-naive advanced biliary tract cancer. J Clin Oncol 38(suppl 15): 4520, 2020.


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