In the phase 3 TOPAZ-1 trial, the addition of durvalumab to standard-of-care chemotherapy achieved a statistically significant improvement in overall survival compared chemotherapy alone, meeting the study's primary end point.
Treatment with durvalumab (Imfinzi) plus standard-of-care chemotherapy demonstrated statistically significant improvement in overall survival (OS) compared with chemotherapy alone across all biliary tract primary tumor locations, including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer.1
Results are from 685 patients treated with the combination of durvalumab and chemotherapy or placebo and chemotherapy in the phase 3 TOPAZ-1 clinical trial (NCT03875235). The primary end point of the study has been met, and promising findings have been reported for the secondary end points of progression-free survival (PFS) and objective response rate (ORR). Interim analysis results from the study were presented during the European Society of Medical Oncology World Congress on Gastrointestinal Cancer and published in the NEJM Evidence.
At a median follow up of 16.8 months (95% CI, 14.8-17.7) in the durvalumab group and 15.9 months (95% CI, 14.9-16.9) in the placebo group, the median OS was 12.8 months (95% CI, 11.1-14.0) vs 11.5 months (95% CI, 10.1-12.5), resulting in a 0.70 hazard ratio (HR) for the decrease in the risk of death with added durvalumab.2
Survival rates were estimated for the 12-month, 18-months, and 24-month timepoints. In the durvalumab/chemotherapy arm, the estimated 12-month OS was 54.1% (95% CI, 48.4-59.4) vs 48.0% (95% CI, 42.4-53.4) with placebo/chemotherapy. At 18 months, the estimated OS rate was 35.1% (95% CI, 29.1-41.2) in the durvalumab/chemotherapy arm compared with 25.6% (95% CI, 19.9-31.7) in the placebo/chemotherapy arm. Finally, the 24-month OS rate was estimated to be 24.9% (95% CI, 17.9-32.5) with durvalumab plus chemotherapy compared with 10.4% (95% CI, 4.7-18.8) with placebo and chemotherapy.
The HR for the decrease in the risk of death in patients with intrahepatic cholangiocarcinoma who received durvalumab/chemotherapy vs those who received placebo/chemotherapy was 0.76 (95% CI, 0.58-0.98). Among patients with extrahepatic cholangiocarcinoma, the HR for the decrease in the risk of death with the addition of durvalumab compared to chemotherapy alone was 0.76 (95% CI, 0.49-1.19). In the gallbladder cancer cohort, the OS benefit of durvalumab was even higher compared with chemotherapy alone (HR, 0.94; 95% CI, 0.65-1.37).
The median PFS observed with the combination of durvalumab, and placebo was 7.2 months (95% CI, 6.7-7.4) compared with 5.7 months (95% CI, 5.6-6.7). The HR for the decrease in the risk of disease progression or death observed with durvalumab vs placebo was 0.75 (95% CI, 0.63-0.89; P =.001).
Treatment with durvalumab in the study led to an ORR of 36.7% compared with 18.7% in the placebo arm (Odds ratio, 1.60; 95% CI, 1.11-2.31). Durvalumab added to chemotherapy also achieved a complete response rate of 2.1% vs 0.6% with placebo/chemotherapy, and a partial response rate of 24.6% compared with 18.1%, respectively. Moreover, 32.6% of patients treated with durvalumab/chemotherapy had a continued response compared with 25.3% of the placebo/chemotherapy arm. Response continued for 12 months in 26.1% of the durvalumab arm vs 15.0% of the placebo arm.
A total of 680 patients were included in the safety analysis, including 338 patients from the durvalumab arm and 342 from the placebo arm. The median duration of treatment was 7.3 months (range 0.1-24.5) with durvalumab and chemotherapy vs 5.8 months (range, 0.2-21.5) with placebo and chemotherapy.
Adverse events of any grade were observed in 99.4% of patients in the experimental arm vs 98.8% of the control arm. The AEs were grade 30 or 4 in 75.7% of the durvalumab arm compared with 77.8% of the placebo arm. The most common AEs observed among patients who received durvalumab were anemia (48.2%), nausea (40.2%), constipation (32.0%), and neutropenia (31.7%). In comparison, the most common AEs in the placebo group were anemia (44.7%), nausea (34.2%), and decreased neutrophil count (31.0%). There was 12.7% rate of immune-mediated AEs in the durvalumab arm compared with 4.7% in the placebo arm, and immune-mediated AEs were grade 3 or 4 in 2.4% vs 1.5%, respectively.
Treatment discontinuations occurred in both groups, including in 13.0% of the durvalumab arm vs 15.2% of the placebo arm. There were also treatment-related deaths in 3.6% of the durvalumab arm compared with 4.1% of the placebo arm.
TOPAZ-1 is an ongoing clinical trial that aims to enroll 810 patients with advanced biliary tract cancers. In the randomized, double-blind, placebo-controlled study, patients are assigned 1:1 to receive with durvalumab with chemotherapy (n = 341) or placebo with chemotherapy (n = 344). All patients included in the study have histologically confirmed, unresectable advanced or metastatic biliary tract cancer. The patients were all previously untreated with recurrent disease more than 6 months after curative surgery or more than 6 months after the completion of adjuvant treatment. All patients also have a WHO or ECOG performance score of 0 or 1. Patients with a history of another primary malignancy, brain metastases, spinal cord compression, and uncontrolled intercurrent illness are excluded from the study. The study also excludes patients who had a major surgical procedure within 28 prior to the first dose of TOPAZ-1 treatment, and those who had prior locoregional therapy such as radioembolization.3
“TOPAZ-1 data show that Imfinzi plus chemotherapy improved outcomes for biliary tract cancer patients regardless of where their tumor was located or where they lived. These important subgroup analyses add to the body of evidence demonstrating the potential for Imfinzi combinations to meaningfully improve outcomes for these patients who are in need of effective and generally well tolerated treatments,” said Cristian Massacesi, chief medical officer and Oncology chief development officer, AstraZeneca, in a press release.
1. AstraZeneca shares data at EASL and ESMO World GI for Imfinzi combinations in patients with liver and biliary tract cancers. News release. AstraZeneca. July 1, 2022. Accessed July 6, 2022. https://bit.ly/3NLPAA6
2. Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evidence. Published online June 1, 2022. doi: 10.1056/EVIDoa2200015
3. Durvalumab or placebo in combination with gemcitabine/cisplatin in patients with 1st line advanced biliary tract cancer (TOPAZ-1) (TOPAZ-1). Clinicaltrials.gov. Updated April 20, 2022. Accessed July 6, 2022. https://bit.ly/3ajWxKV