The addition of durvalumab to gemcitabine and cisplatin demonstrated an improvement in overall survival vs gemcitabine and cisplatin plus placebo as frontline therapy in patients with advanced biliary tract cancer, regardless of primary tumor location.
The addition of durvalumab (Imfinzi) to gemcitabine and cisplatin demonstrated an improvement in overall survival (OS) vs gemcitabine and cisplatin plus placebo as frontline therapy in patients with advanced biliary tract cancer, regardless of primary tumor location, according to findings from a subgroup analysis of the phase 3 TOPAZ-1 trial (NCT03875235) presented by Aiwu Ruth He, MD, PhD, during the 2022 ESMO World Congress on Gastrointestinal Cancer.
Findings previously presented from the primary analysis demonstrated a 20% reduction in the risk of death with durvalumab plus chemotherapy vs placebo plus chemotherapy in this patient population (HR, 0.80; 95% CI, 0.66-0.97; P = .021).1
At a median follow-up of 13.7 months in the durvalumab/chemotherapy arm and 12.6 months in the placebo/chemotherapy arm, the median OS was 12.8 months (95% CI, 11.1-14) vs 11.5 months (95% CI, 10.1-12.5), respectively. The 18-month OS rates were 35.1% (95% CI, 29.1%-41.2%) and 25.6% (95% CI, 19.9%-31.7%), respectively. The 24-month OS rates were 24.9% (95% CI, 17.9%-32.5%) and 10.4% (95% CI, 4.7%-18.8%), respectively.
On May 4, 2022, the FDA accepted a supplemental biologics license application and granted priority review to the combination for the treatment of patients with locally advanced or metastatic biliary tract cancer based on findings from the trial.2
“Based on the subgroup analysis and the primary report, I feel comfortable recommending the combination of durvalumab plus gemcitabine and cisplatin as frontline systemic therapy for patients with biliary tract cancer, if those patients do not have any contraindications for immunotherapy,” said He.
In an interview with OncLive®, He, the scientific lead in liver and biliary cancers at MedStar Georgetown University Hospital, discussed the benefit seen with the combination in patients with advanced biliary tract cancer and the importance of additional correlative research evaluating potential biomarkers of response.
He: The combination of cisplatin and gemcitabine had been the standard first-line therapy based on the phase 3 ABC-02 study [NCT00262769] for over a decade. [TOPAZ-1] is the first positive randomized, phase 3 study that has shown benefit of adding another drug to this standard chemotherapy combination.
The preplanned interim analysis of TOPAZ-1 showed the study met the primary end point. There was a statistically significant improvement in OS in patients treated with the combination of durvalumab plus gemcitabine and cisplatin vs gemcitabine and cisplatin plus placebo.
[At the 2022 ESMO World Congress on Gastrointestinal Cancer,] I presented a subgroup analysis of the efficacy and safety data from the trial based on primary tumor location. Biliary cancer is a very heterogeneous disease that includes intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. Each anatomic location can have different risk factors, etiology, and presentation or prognosis.
In this subgroup analysis of TOPAZ-1, the addition of durvalumab to gemcitabine and cisplatin was associated with improved OS in patients with advanced biliary tract cancer, irrespective of primary tumor location.
I am very excited about additional biomarker analysis. Blood samples have been collected from patients enrolled in this study. In this cancer, there are a lot of potentially targetable mutations [because it’s] genetically very heterogeneous. There will be a lot of information we can learn [from these analyses]. Are we able to find patients with a certain genetic background or molecular profile that would benefit most from the combination therapy? That information also may teach us how to overcome resistance.
I always talk about targeted therapy, because 40%-50% of patients with biliary tract cancer may have targetable mutations. We keep identifying targetable mutations and [ways] to use targeted therapy to treat those patients with certain genetic alterations. We have FDA-approved agents for FGFR2 fusions and IDH1/2 mutations. Now there are data coming out in BRAF-mutated cholangiocarcinoma [and] HER2-amplified biliary cancer. Those are always very exciting areas for us who treat patients with cholangiocarcinoma. We expect better targeted therapies to come out, and better selective biomarkers will define the patient population that responds to this therapy.
Second, durvalumab has shown, for the first time in the phase 3 TOPAZ-1 study, improved outcomes in combination with chemotherapy. I expect more work will be done with immune checkpoint inhibitors in cholangiocarcinoma evaluating dual immunotherapy and immunotherapy plus another targeted therapy in combination with chemotherapy. Also, the combination of durvalumab plus gemcitabine and cisplatin was quite well tolerated. Durvalumab did not increase toxicity much [in the trial]. This could be a good regimen to build on with additional immunotherapy in combination with the goal of improving patient outcome.
The other thing that’s always exciting is circulating [tumor DNA (ctDNA)] biomarkers, because in cholangiocarcinoma it’s very difficult to get a lot of tissue to do profiling. Circulating biomarkers will help us identify mutations and track patients’ response to therapy and development of early resistance. There’s a lot of ongoing research [aiming] to make ctDNA markers work better for cholangiocarcinoma. Those are the 3 areas we’ll have a lot more information on in the next couple of years.