TOPAZ-1 3-year data reflect long-term survival benefit with durvalumab-chemo in BTC

In the 3-year updated analysis of the phase III TOPAZ-1 study, the combination of durvalumab and gemcitabine-cisplatin (GC) chemotherapy continues to deliver an overall survival (OS) benefit in individuals with biliary tract cancer (BTC).

“After a median follow-up duration of ~41 months – the longest reported in this setting – durvalumab-GC continued to demonstrate clinically meaningful long-term survival benefit,” said Dr Do-Youn Oh from Seoul National University College of Medicine, Seoul, Republic of Korea, at ESMO GI 2024.

From a hazard ratio (HR) of 0.80 in the primary analysis (data cutoff [DCO] August 11, 2021), the updated analysis (DCO October 23, 2023) showed sustained OS benefit with the experimental vs placebo regimen, as reflected by the current HR of 0.74.

Discussant Professor Zev Wainberg from the University of California Los Angeles School of Medicine, Los Angeles, California, US, noted that the HR improvement between the two timepoints is “often driven by the tail of the curve wherein we are starting to see long-term survivors.”

At 36 months, the survival rate was twofold higher in the durvalumab vs placebo arm (14.6 percent vs 6.9 percent), translating to an OS rate ratio of 2.12. This effect was similarly seen in the subgroup of patients who have achieved disease control (17 percent vs 7.6 percent).

Median OS was longer with durvalumab-GC than with placebo-GC, both in the full analysis set (FAS; 12.9 vs 11.3 months) and in the analysis by disease control (14.6 vs 12.8 months). [ESMO GI 2024, abstract 279MO]

Extended long-term survival

There were more durvalumab-GC vs placebo-GC recipients categorized as extended long-term survivors (eLTS; 17 percent vs 8.7 percent). These patients are those who were still alive ≥30 months after randomization (n=88).

In the analysis of eLTS, there were more durvalumab-GC recipients who had an objective response as opposed to those on the placebo-GC regimen (55.2 percent vs 40 percent).

Conversely, there were fewer patients in the durvalumab arm who required subsequent anticancer therapy compared with those on placebo-GC. This goes for chemotherapy (51.7 percent vs 80 percent), immunotherapy (6.9 percent vs 23.3 percent), and targeted therapy (19 percent vs 26.7 percent). This pattern was similarly observed in the FAS.

“All clinically relevant subgroups were represented in the eLTS analysis. The long-term survival benefit was not driven by any particular subgroup of participants,” Oh noted.

What drives extended long-term survivorship?

“There was no obvious impact on location* [nor were there any] correlations with region and PD-L1 score,” Wainberg said. “It seems to be driven by patients who have achieved better disease control, implying that response rate matters.”

He called for data on any surgical or procedural intervention to check if these influenced the extended long-term survivorship. “Patients with locally advanced disease represent a larger percentage of eLTS than those with metastatic disease. [We’d like to know if] any of the patients who had this incredible response [underwent] conversion surgery, ablation, or something along those lines that led to [this outcome].”

Wainberg also pointed to depth of response and molecular subtypes as other potential drivers of the extended long-term survival. “We have not seen extensive details on MSI. Although it represents a very small percentage of cholangiocarcinoma, we do not know. [Also,] as some molecular subtypes are prognostic (eg, FGFR), we’d like to see if that represented a group of [eLTS].”

Safety update

Thirteen participants on the durvalumab-GC regimen remained on study treatment at the updated OS analysis; in the placebo arm, there were none.

Median duration of durvalumab exposure was longer in the eLTS subgroup compared with the FAS (17.8 vs 7.3 months). Nonetheless, the rates of serious adverse events (SAEs) in the eLTS subgroup were comparable between the durvalumab and placebo arms (32.8 percent vs 36.7 percent), and these were less frequent than in the FAS (48.8 percent vs 44.4 percent).

Current data support durvalumab-GC as SoC

In TOPAZ-1, 685 participants were randomized 1:1 to receive durvalumab 1,500 mg or placebo Q3W on top of GC (up to eight cycles), followed by durvalumab 1,500 mg or placebo Q4W until disease progression.

After 3 years of follow-up, the durvalumab-GC regimen continued to show clinically meaningful long-term survival benefit, more so among patients who have achieved disease control.

“These updated survival and safety data further support the use of durvalumab-GC as standard-of-care treatment in diverse patients with locally advanced or metastatic cholangiocarcinoma,” Oh concluded.