Durvalumab Plus Standard-of-Care Chemotherapy Shakes Up First-line Care in Advanced Biliary Tract Cancers

Frontline therapy for patients with advanced biliary tract cancers has remained unchallenged for decades, until investigators demonstrated that the addition of the immunotherapeutic agent durvalumab (Imfinzi) could prolong survival for this patient population. On September 2, 2022, the FDA approved durvalumab in combination with gemcitabine and cisplatin for patients with advanced biliary tract cancer.¹

The approval was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235), which randomly assigned patients to durvalumab (n = 341) or placebo (n = 344) in combination with standard-of-care gemcitabine plus cisplatin chemotherapy. The median overall survival (OS) was 12.8 months (95% CI, 11.1-14.0) vs 11.5 months (95% CI, 10.1-12.5) in the experimental and placebo arms, respectively (HR, 0.80; 95% CI, 0.66-0.97; P = .021). The estimated 24-month OS rates were 24.9% (95% CI, 17.9%-32.5%) and 10.4% (95% CI, 4.7%-18.8%), respectively.^1,2

The median progression-free survival was 7.2 months (95% CI, 6.7-7.4) in the durvalumab arm compared with 5.7 months (95% CI, 5.6-6.7) in the placebo arm (HR, 0.75; 95% CI, 0.63-0.89; P = .001). The incidence of grade 3/4 adverse events (AEs) was 75.7% and 77.8%, respectively.^1,2

“TOPAZ-1 is the first success of immunotherapy in biliary tract cancers. It opened the door of the study using immunotherapy agents in this field, which is quite an important message,” said principal investigator Do-Youn Oh, MD, PhD, of Seoul National University Hospital and Seoul National University College of Medicine in South Korea, in an interview with OncologyLive^®. “It is the first global phase 3 study to [show] improvement in the OS of patients compared with the current long-lasting, decades-lasting standard of care. At this time, we can say that we have a new standard of care first line [in] advanced biliary tract cancer, with the durvalumab plus gemcitabine and cisplatin combination.”

In our discussion, Oh highlighted the nuances of the TOPAZ-1 trial data that signal new pathways forward for investigative efforts in advanced biliary tract cancers.

What is the significance of the approval of durvalumab in combination with chemotherapy for patients with biliary tract cancer?

In advanced biliary tract cancer, there have been very limited treatment options, especially in the first line where we [have] only adopted gemcitabine and cisplatin globally for over a decade. Median OS [has been] less than 1 year.

With this approval of durvalumab, immunotherapy in combination with gemcitabine/cisplatin cytotoxic chemotherapy, the median OS has been improved. The beauty of immunotherapy is that [among the] responding patients their response [is] quite durable. In the TOPAZ-1 study [data], we observed [that] the 2-year survival rate of the patients is nearly 24%—a huge improvement of the OS in this field.

With this success, we can say, “Yes, biliary tract cancer is an immunotherapy-responsive tumor type.” This approval encourages the further study and further drug development using the very interesting, good immunotherapeutic agents in biliary tract cancer. I think TOPAZ-1 is just the start of the immunotherapy [for] biliary tract cancer.

Based on the success of the TOPAZ-1 trial, the NCCN [National Comprehensive Cancer Network] guidelines have already adopted the durvalumab, gemcitabine, and cisplatin regimen as a preferred regimen category 1 in first-line advanced biliary tract cancer.

What data from TOPAZ-1 stood out?

In TOPAZ-1, the total sample size was 684, so a relatively smaller clinical trial compared with tumor types in other phase 3 trials targeting first-line [therapy]. We observed a durvalumab benefit regardless of clinical characteristics such as region, even though the Asian population get more benefit—the HR is better compared with [that of] non-Asian patients. The primary tumor location did not matter, and disease extent did not matter. And so far, PD-L1 expression [has] not mattered.

The benefit of durvalumab plus gemcitabine and cisplatin was observed regardless of the primary origin, including [patients with] intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer....There is some difference; for example, the HR for gallbladder cancer was higher compared with the other 2 tumor types in TOPAZ-1.

But now with [these data] we can say that the PD-L1 is not the biomarker for patient selection. Patients showed a benefit with durvalumab regardless of PD-L1 level at this time. We definitely need more studies on the biomarker selection and exploration of the role of PD-L1 for patient selection in larger clinical trials.

In the updated efficacy analysis, which has [6.5 months’] longer follow-up duration compared with the primary analysis, the median follow-up duration is...nearly 2 years, at 23 months. The HR for OS is 0.76 and in the original analysis, the HR was 0.80. With these data, we can say that the durvalumab benefit is shown consistently and is clinically meaningful in patients with biliary tract cancer compared with just [gemcitabine and cisplatin alone].

What should the toxicity findings signal for providers?

A very important finding from the TOPAZ-1 study is that adding durvalumab on top of [gemcitabine and cisplatin] had a safety profile that is quite good. In the placebo arm and the durvalumab arm, the frequency of all AEs, including serious AEs [and] those leading to study discontinuation, is all quite similar.

In the durvalumab arm the [incidence of] immune-related AEs was a bit high compared with the placebo arm, but grade 3/4 immune-related AEs were quite rare. And with longer follow-up data there were no new safety issues compared with the primary analysis safety data. [This regimen] can be easily and comfortably implemented in daily practice globally.

What is next for immunotherapy in biliary tract cancers?

At [Seoul National University Hospital and Seoul National University College of Medicine] we have many clinical trials targeting biliary tract cancer and new compounds in phase 1 studies, which includes a biliary tract cancer cohort. I am exploring the role of immunotherapy not only in the first-line setting, but also second-line or later-line setting, [as well as] in combination with other targeted agents, for example, antiangiogenics and other DNA damage response agents.

References

1. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. FDA. September 2, 2022. Accessed September 23, 2022. bit.ly/3LDKkyJ
2. Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2200015