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Addition of durvalumab to gemcitabine-cisplatin significantly improves outcomes in first-line advanced biliary tract cancer

For patients with inoperable biliary tract cancer, the current standard of care combined chemotherapy has not changed in over a decade. However, results from the global phase III TOPAZ-1 study now demonstrate that pairing durvalumab with gemcitabine and cisplatin improved overall survival in patients with advanced biliary tract cancer, compared with the current standard of giving the chemotherapy combination alone.

First-line, standard of care for advanced biliary tract cancer (BTC) consists of gemcitabine and cisplatin (GemCis) chemotherapy and has remained unchanged for over a decade. Reports on immunogenic features of BTC indicate it is a good candidate for immunotherapy, although only limited clinical activity has been reported for immune checkpoint inhibitor monotherapies in the second-line setting. Durvalumab, a PD-L1 inhibitor, plus GemCis demonstrated promising antitumour activity as first-line treatment for patients with advanced BTC in a phase II study. TOPAZ-1 is the first global phase III study evaluating immunotherapy plus chemotherapy as first-line treatment for advanced BTC to report results.

Study Design

TOPAZ-1 is a randomised, double-blind, placebo controlled, multicentre, global phase III trial of durvalumab in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a first-line treatment in 685 patients with unresectable advanced or metastatic BTC including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer (ampullary carcinoma was excluded). Patients should be previously untreated if they have unresectable or metastatic disease at initial diagnosis or their disease recurrence should occur more than six months after curative surgery or adjuvant therapy. Patients were randomised (1:1) to receive durvalumab (1,500 mg Q3W) or placebo + GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to eight cycles, followed by durvalumab (1,500 mg Q4W) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by disease status (initially unresectable versus recurrent) and primary tumour location.


In total, 685 patients were randomised to durvalumab + GemCis (N= 341) or placebo + GemCis (N= 344). Patient demographics and baseline characteristics were well balanced between both arms. Median age of study participants was 64 years, approximately half were female and 54% were recruited from Asian countries. At the time of the data cut-off, more patients in the durvalumab arm were still receiving treatment (18.6% vs. 5.8%). Main reason for drug discontinuation was disease progression in both arms. After a median follow-up of 16.8 months with durvalumab + GemCis and 15.9 months with placebo + GemCis, OS was significantly longer in the durvalumab arm (median OS 12.8 vs. 11.5 months, HR[95%CI]: 0.80[0.66-0.97], p= 0.021). The 24-month OS rates were 24.9% and 10.4% for durvalumab + GemCis and placebo + GemCis, respectively. Because these OS results were thus statistically significant at the planned interim analysis, these results are to be considered the final, formal statistical analysis for OS.

Furthermore, also PFS was significantly improved with durvalumab versus placebo (median PFS 7.2 vs. 5.7 months, HR[95%CI]: 0.75[0.63-0.89], p= 0.001). At 12 months, PFS rate was 16.0% for patients in the durvalumab arm, as compared to only 6.6% in the placebo arm. The objective response rate (ORR) in the durvalumab arm was 26.7%, including seven patients (2.1%) who obtained a complete response (CR). For patients treated in the placebo arm, the ORR was 18.7%, of which only two CR (0.6%). Median duration of response was 6.4 months for durvalumab + GemCis and 6.2 months for placebo + GemCis. Median time to response was 1.6 and 2.7 months, respectively.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 62.7% of patients receiving durvalumab and 64.9% of patients receiving placebo. TRAEs led to discontinuation of any study medication in 8.9% and 11.4% of patients receiving durvalumab or placebo, respectively. Immune-mediated AEs were reported in 12.7% of patients in the durvalumab arm, versus 4.7% in the placebo arm. However, grade ≥3 immune-mediated AEs were rarely observed, even in the durvalumab arm (2.4%).


TOPAZ-1 is the first global phase III study to report positive results testing immunotherapy plus chemotherapy as first-line treatment for advanced BTC. Durvalumab plus GemCis demonstrated statistically significant and clinically meaningful prolonged overall survival compared with placebo plus GemCis. In addition, durvalumab did not add additional toxicity to that observed with GemCis, and no new safety signals were identified from the known safety profile of each individual treatment. In conclusion, durvalumab plus GemCis is an effective first-line therapy and could become the new standard of care for patients with advanced BTC.


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. Presented at ASCO GI 2022; Abstract 378.

Speaker Do-Youn Oh

Do-Youn Oh

Do-Youn Oh, MD, PhD, Seoul National University Hospital, Seoul, South Korea


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