Durvalumab + chemo: A new SoC for advanced BTC?

Patients with advanced biliary tract cancer (BTC) who receive durvalumab in addition to standard of care (SoC) gemcitabine plus cisplatin chemotherapy in the first-line setting have a reduced risk of death compared with those receiving SoC alone, according to results of the TOPAZ-1 study presented at ASCO GI 2022.

“TOPAZ-1 is the first phase III trial to show that adding immunotherapy to standard chemotherapy can increase survival in BTC, and importantly, does so without inducing any new serious side effects,” said principal investigator Professor Do-Youn Oh from the Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea.

“We are hopeful that durvalumab plus gemcitabine and cisplatin will become a new SoC for advanced BTC,” Oh said.

The multinational, double-blind study population comprised 685 patients (median age 64 years) with BTC (treatment-naïve if unresectable or metastatic at initial diagnosis) who experienced disease recurrence >6 months after curative surgery or adjuvant therapy and had an ECOG performance status of 0–1. They were randomized 1:1 to receive either durvalumab (1,500 mg) or placebo Q3W plus ≤8 cycles of gemcitabine (1,000 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8 Q3W. Patients then continued their assigned durvalumab or placebo therapy Q4W until disease progression. The most common primary tumour was intrahepatic cholangiocarcinoma (>55 percent).

After a median follow-up of 16.8 months in the durvalumab-chemo group and 15.9 months in the placebo-chemo group, overall survival (OS) was significantly improved in the durvalumab-chemo compared with the placebo-chemo group (median 12.8 vs 11.5 months; hazard ratio [HR], 0.80, 95 percent confidence interval [CI], 0.66–0.97; p=0.021). [ASCO GI 2022, abstract 378]

OS rates at 12, 18, and 24 months in the durvalumab-chemo vs placebo-chemo groups were 54.1 percent vs 48.0 percent, 35.1 percent vs 25.6 percent, and 24.9 percent vs 10.4 percent, respectively.

There was also a significant improvement in progression-free survival (PFS) with durvalumab-chemo vs placebo-chemo (median 7.2 vs 5.7 months; HR, 0.75, 95 percent CI, 0.63–0.89; p=0.001) after a median follow-up of 9.2 and 6.9 months in those respective groups.

PFS rates at 6, 9, and 12 months with durvalumab-chemo vs placebo-chemo were 58.3 percent vs 47.2 percent, 34.8 percent vs 24.6 percent, and 16.0 percent vs 6.6 percent.

Objective response rate was significantly improved with durvalumab-chemo vs placebo-chemo (26.7 percent vs 18.7 percent; odds ratio, 1.60, 95 percent CI, 1.11–2.31; p=0.011). Seven and two patients, respectively, achieved complete response, and 84 and 62, respectively, partial response. Duration of response was a median 6.4 and 6.2 months, respectively, with a median time to response of 1.6 vs 2.7 months. At ≥12 months, 26.1 and 15.0 percent of patients in the durvalumab-chemo and placebo-chemo groups, respectively, remained in response.

Acceptable safety profile

Grade 3–4 treatment-related adverse events (TRAEs) occurred in 62.7 and 64.9 percent of durvalumab-chemo and placebo-chemo recipients, respectively, and serious TRAEs in 15.7 and 17.3 percent, respectively. Immune-mediated AEs of any grade occurred in 12.7 and 4.7 percent, respectively. TRAEs led to treatment discontinuation in 8.9 and 11.4 percent, respectively, and to death in two and one patients, respectively.

The most common (≥2 percent) grade 3–4 TRAEs in the durvalumab-chemo vs placebo-chemo group were decreased neutrophil count (20.7 percent vs 25.4 percent), neutropenia (19.2 percent vs 20.2 percent), and anaemia (18.9 percent vs 18.7 percent). The most common grade ≥3 immune-mediated AEs in the durvalumab-chemo group were dermatitis/rash (n=3) and hepatic events (n=2).

“Durvalumab did not add additional toxicity to that observed with gemcitabine-cisplatin, and no new safety signals were identified from the known safety profiles of each individual treatment,” said Oh.

At data cut-off, 18.6 and 5.8 percent of durvalumab-chemo and placebo-chemo recipients, respectively, were still on treatment, with radiological disease progression the main reason for discontinuation (56.2 and 69.6 percent, respectively). Among those who discontinued, 42.5 and 49.4 percent, respectively, received subsequent anticancer treatment.

A new SoC?

“Advanced, unresectable BTC is an area of high unmet need due to its aggressive nature, limited treatment options, and poor prognosis,” remarked Oh.

“The current SoC for inoperable BTC is combined chemotherapy. That standard has not changed in over a decade,” commented Professor Cathy Eng, ASCO Expert in gastrointestinal cancers, who was not affiliated with the study.

“TOPAZ-1 is the first global phase III study to report positive results testing immunotherapy plus chemotherapy as first-line treatment for advanced BTC,” said Oh.

“Patients have a greater reason for hope given the positive results seen with the use of immunotherapy in BTC,” noted Eng.