Durvalumab Triplet Improves OS Across Biliary Tract Cancer Locations

Aiwu Ruth He, MD, PhD

The addition of durvalumab (Imfinzi) to gemcitabine and cisplatin chemotherapy led to overall survival (OS) benefit compared with treatment with chemotherapy alone in patients with advanced biliary tract cancer across various primary tumor sites, according to an exploratory subgroup analysis of the phase 3 TOPAZ-1 trial (NCT03875235).

In findings presented at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2022, patients with intrahepatic and extrahepatic cholangiocarcinoma who were treated with the durvalumab triplet regimen demonstrated improved OS compared with the chemotherapy doublet. Comparatively, OS was similar between arms for patients with gallbladder cancer.¹

Analysis by primary tumor location showed a median OS of 13.5 months (95% CI, 11.9-15.1) with durvalumab plus gemcitabine and cisplatin compared with 11.5 months (95% CI, 9.8-12.8) with gemcitabine and cisplatin alone in patients with intrahepatic cholangiocarcinoma (HR, 0.76; 95% CI, 0.58-0.98). In patients with extrahepatic cholangiocarcinoma, the median OS with the triplet regimen was 12.7 months (95% CI, 9.8-16.6) compared with 12.1 months (95% CI, 7.8-14.4) with the doublet regimen (HR, 0.76; 95% CI, 0.49-1.19). With the addition of durvalumab, the median OS was 10.7 months (95% CI, 8.9-13.2) in those with gallbladder cancer compared with 11.0 months (95% CI, 8.7-12.8) without durvalumab (HR, 0.94; 95% CI, 0.65-1.37) (TABLE¹).

"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,”csaid presenter Aiwu Ruth He, MD, PhD, scientific lead in liver and biliary cancers at MedStar Georgetown University Hospital, in an interview. “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.”

TOPAZ-1 is a randomized, double-blind, placebocontrolled, global study of durvalumab plus chemotherapy compared with chemotherapy and placebo in patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease. Patients were randomly assigned 1:1 to receive either 1500 mg durvalumab (n = 341) or placebo (n = 344) on day 1 of each 21-day cycle plus 1000 mg/m² gemcitabine and 25 mg/m² cisplatin on days 1 and 8 of each for 8 cycles. Then durvalumab monotherapy was administered once every 4 weeks until disease progression or unacceptable toxicity.

The primary end point was OS and secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety.

In the primary analysis, whose findings were recently published in NEJM Evidence, the median OS was 12.8 months (95% CI, 11.1-14.0) with durvalumab plus gemcitabine and cisplatin compared with 11.5 months (95% CI, 10.1-12.5) in patients who received placebo plus gemcitabine and cisplatin (HR, 0.80; 95% CI, 0.66-0.97; P = .021). At 12 months, the OS rate with the durvalumab triplet was 54.1% (95% CI, 48.4%-59.4%) compared with 48.0% (95% CI, 42.4%-53.4%) with the chemotherapy doublet, and at 24 months, OS rates were 24.9% (95% CI, 17.9%-32.5%) and 10.4% (95% CI, 4.7%-18.8%), respectively.²

The median PFS was 7.2 months (95% CI, 6.7-7.4) with the addition of durvalumab compared with 5.7 months (95% CI, 5.6-6.7) without durvalumab (HR, 0.75; 95% CI, 0.63- 0.89; P =.001).

In the durvalumab arm, the ORR was 26.7%, with complete responses in 2.1%, compared with an ORR of 18.7% in the placebo arm and a complete response rate of 0.6%. The DCRs were 85.3% and 82.6% in the durvalumab and placebo arms, respectively.

The median DOR was 6.4 months (IQR, 4.6-17.2) with durvalumab plus gemcitabine and cisplatin vs 6.2 months (IQR, 3.8-9.0) with gemcitabine and cisplatin. The DOR was ongoing for at least 12 months in 26.1% of patients in the durvalumab arm and in 15.0% of patients in the placebo arm.

In terms of safety, adverse events (AEs) of any grade were reported in 99.4% of patients in the durvalumab arm and 98.8% of the placebo arm. Grade 3 or 4 AEs were observed in 75.7% of patients treated with the durvalumab triplet compared with 77.8% of those treated with the chemotherapy doublet, and serious AEs were reported in 47.3% and 43.6% of patients, respectively. AEs led to treatment discontinuation in 13.0% and 15.2% of patients in the durvalumab and placebo arms, respectively, and AEs led to death in 3.6% and 4.1% of patients. Treatment-related AEs leading to death in the durvalumab arm included ischemic stroke and hepatic failure in the durvalumab arm and polymyositis in the placebo arm.

On May 4, 2022, the FDA granted a priority review to the durvalumab and chemotherapy combination for the treatment of patients with locally advanced or metastatic biliary tract cancer.³

_REFERENCES:

_{1. He AR, Valle JW, Lee CK, et al. Outcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study. Presented at: ESMO World Congress on Gastrointestinal Cancer 2022; June 29-July 2, 2022; Barcelona, Spain.}

_{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. Imfinzi plus chemotherapy granted priority review in the US for patients with locally advanced or metastatic biliary tract cancer based on TOPAZ-1 phase III trial. News release. AstraZeneca. May 4, 2022. Accessed July 13, 2022. https://bit.ly/3MOUKLA}