Biliary tract cancers (BTCs) are heterogeneous and rare cancers. These cancers are historically categorized based on the site of origin which includes the gallbladder, the intrahepatic and the extrahepatic ducts, and the ampulla of Vater. Although these cancers are rare, they are associated with poor prognoses. Apart from the biology of cancer and advanced stage at presentation, one of the main reasons is the lack of improvement in the chemotherapy regimen. BTCs are more prevalent in Southeast Asia; however, the incidence of these cancers in the U.S. has increased over the years. Gemcitabine-based chemotherapy regimen has been a mainstay of treatment for advanced disease and gemcitabine/cisplatin has remained the standard of care for more than a decade. With the advent of next-generation sequencing, multiple actionable mutations have been discovered, and agents are being developed as targeted therapy toward these alterations. Some of the approved agents include Pembrolizumab for MSI-H/dMMR and or tumor mutation burden of greater than 10 mut/Mb; Pemigatinib or infigratinib for FGFR2 fusion; Ivosidenib for IDH1 mutation; Dabrafenib/trametinib for BRAF V600E, Pertuzumab/trastuzumab for HER2, Pralsetinib for RET; PARP inhibitor for BRCA1/2, DDR; Larotrectinib for NTRK fusion; and Crizotinib for ROS1. However, most of the patients do not possess these alterations, so improving the first line regimen is an unmet need to enhance survival in these cancers.
In a phase 2 study, PD-L1 inhibitor (Durvalumab) combined with chemotherapy showed promising antitumor activity. At the annual ASCO GI meeting, Dr. Oh from Seoul National University Hospital presented the data from the TOPAZ-1 (NCT03875235, the first international phase 3 randomized study to evaluate the Chemo + immunotherapy combination in the first-line setting in advanced BTC. In this double-blind study, previously untreated for unresectable locally advanced, recurrent, or metastatic BTC patients were randomized 1:1 to receive durvalumab (1500 mg every 3 weeks [Q3W]) or placebo + GemCis (Gemcitabine 1000 mg/m2 and Cisplatin 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by durvalumab (1500 mg Q4W) or placebo monotherapy until disease progression or unacceptable toxicity. The patients were stratified based on primary tumor location and initial resectability. The primary endpoint was to assess overall survival (OS). Secondary objectives included progression-free survival (PFS), objective response rate (ORR), and safety. The PD-L1 expression was measured by Tumor Area Positivity (TAP) score using Ventana PD-L1 (SP263). TAP score is defined as a combination of tumor cell area with PD-L1 expression and immune cell area with PD-L1 expression.
Out of the total 685 patients, 341 were randomized to durvalumab + GemCis arm and 344 to placebo + GemCis arm. At the point of data cut-off, more patients received treatment in the durvalumab arm (18.6%) than placebo (5.4%). Discontinuation of the treatment was similar in both arms, 5.9% in Durva and 5.3% in control arm. The majority of the population were Asian, 54.3% in Durva and 58.4 % in control arm. At the interim analysis in August 2021, the treatment arm showed significant improvement in OS as compared to the control arm (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p=0.021) and are considered as the final and formal analysis for OS. The survival curves have shown gradual separation after the initial six months of therapy, and the absolute difference in survival rate after 12, 18, and 24 months is 6%, 10%, and 15%, respectively. The benefit of immunotherapy was observed across all subgroups and PDL-1 expression. PFS was also significantly improved with durvalumab versus placebo (HR, 0.75; 95% CI, 0.64–0.89; p=0.001). The absolute difference of PFS at 6, 9, and 12 months was 1%, 10%, and 10%, respectively. ORR was 26.7% with durvalumab and 18.7% with placebo, with 2.1% patients with complete response in the durva arm. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 62.7% of patients receiving durvalumab and 64.9% of patients receiving placebo. The majority of the Grade 3/4 events were hematological toxicity, and the frequency was quite similar in both arms. Immune-mediated AEs were 12.7% and 4.7% in the durva and placebo arm, respectively; however, grade 3/4 events were rarely observed in the durva arm.
This trial has shown that a combination of Durvalumab and GemCis significantly approved survival in patients irrespective of the PD-L1 expression status and may be a new standard of care in advanced biliary tract cancers.
Dr. Rahman has no conflicts of interest to report.
Illustration by Jennifer Bogartz