TOPAZ-1: First-line durvalumab plus GemCis improves survival in advanced BTC

In the phase III TOPAZ-1 trial, adding the immune checkpoint inhibitor (ICI), durvalumab, to standard-of-care (SoC) chemotherapy with gemcitabine plus cisplatin (GemCis) resulted in improved survival and response rates in patients with advanced biliary tract cancer (BTC). In an interview with MIMS Oncology, Dr Thomas Yau, Specialist in Medical Oncology in Hong Kong, who is one of the investigators of TOPAZ-1, discussed the trial’s key findings and how adding first-line immunotherapy may improve the limited survival gained from upfront chemotherapy alone in patients with advanced BTC.

Unmet needs in advanced BTC management
“BTC is a heterogeneous group of malignancies with various initial presen­tations, including right upper quadrant pain, signs of biliary obstruction or unex­plained weight loss,” said Yau. “With the aggressive nature of BTC, patients often have advanced disease at diagnosis.” [Lancet 2021;397:428-444; J Gastrointest Oncol 2017;8:293- 301; Int J Mol Sci 2022;23:13961]

“First-line chemotherapy consisting of GemCis has remained SoC for patients with advanced BTC in the last decade despite its limited benefits in terms of long-term survival,” he noted. [NEJM Evid 2022;doi:10.1056/EVIDoa2200015; N Engl J Med 2010;362:1273-1281]

With SoC chemotherapy, progno­sis remains poor for many patients with unresectable and advanced BTC, repre­senting an unmet need in this population. [J Gastrointest Oncol 2017;8:293-301; NEJM Evid 2022;doi:10.1056/EVIDoa2200015]

Meanwhile, immunogenic features associated with BTC, such as expres­sion of immune checkpoint molecules (eg, PD-L1 and CTLA-4), have led to the development of novel treatment. [Nat Genet 2015;47:1003-1010; Clin Can­cer Res 2016;22:470-478; J Hepatol 2019;71:753-762] In particular, a phase II study previously demonstrated antitumour activity of a PD-L1 inhibitor, durvalumab, when used in combination with GemCis in patients with advanced BTC. [J Clin Oncol 2020;38(Suppl S15):4520]

TOPAZ-1: Adding durvalumab to GemCis improves OS and PFS
TOPAZ-1 was a double-blind, placebo-controlled, phase III trial that eval­uated the efficacy and safety of durvalum­ab plus GemCis vs placebo plus GemCis in patients with previously untreated, unre­sectable, locally advanced, or metastatic BTC, or in those who developed recurrent BTC after curative intent surgery or adju­vant therapy. Patients were randomized to receive durvalumab (n=341) or placebo (n=344) in combination with GemCis for up to eight cycles, followed by durvalum­ab or placebo monotherapy until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. [Oh DY, et al, ESMO 2022, poster 56P; NEJM Evid 2022;doi:10.1056/EVIDoa2200015]

After a median follow-up of 23.4 months in the durvalumab group and 22.4 months in the placebo group, the updated OS at 6.5 months of additional follow-up after primary analysis was longer in pa­tients who received durvalumab vs place­bo (median, 12.9 months vs 11.3 months; hazard ratio [HR], 0.76; 95 percent confi­dence interval [CI], 0.64–0.91). (Figure) [Oh DY, et al, ESMO 2022, poster 56P]

“The OS curves started separating at 6 months of treatment, and we saw this separation sustained in favour of durvalumab through 24 months,” said Yau. “At 6 months, the OS HR was 0.91 [95 percent CI, 0.66–1.25], which further improved to 0.71 [95 percent CI, 0.58– 0.88] after 6 months.” (Figure) [NEJM Evid 2022;doi:10.1056/EVIDoa2200015; Oh DY, et al, ESMO 2022, poster 56P]

The difference in OS rates between the two groups also gradually increased over the long term, from 7.2 percent at 12 months to 12.1 percent at 24 months. Meanwhile, the Kaplan-Meier survival curve for durvalumab started plateauing after 24 months, as demonstrated by the extended tail in this treatment group. (Figure)

Durvalumab was also associated with significantly improved PFS vs place­bo (HR, 0.75; 95 percent CI, 0.63–0.89; p=0.001). ORR was in favour of the durvalumab arm at 26.7 percent vs 18.7 percent in the placebo arm (odds ratio, 1.60; 95 percent CI, 1.11–2.31). [NEJM Evid 2022;doi:10.1056/EVIDoa2200015]

The OS and PFS benefits attained with durvalumab plus GemCis were gen­erally consistent across clinically relevant and prespecified subgroups. [NEJM Evid 2022;doi:10.1056/EVIDoa2200015; Oh DY, et al, ESMO 2022, poster 56P]

In terms of safety, the incidence of adverse events (AEs) and treatment-related AEs in the updated analysis was consistent with that in the primary analysis. Similar rates of discontinua­tion due to AEs were observed in the durvalumab and placebo groups (12.7 percent vs 15.2 percent). Toxicities re­ported with durvalumab plus GemCis were similar to those commonly seen with either durvalumab or GemCis alone. Rates of grade 3/4 AEs were similar be­tween treatment groups. [NEJM Evid 2022;doi:10.1056/EVIDoa2200015; Oh DY, et al, ESMO 2022, poster 56P]

“These results show that adding durvalumab to SoC GemCis provides du­rable survival benefits without additional toxicity in patients with advanced BTC,” Yau noted. “The long-tail effect in the OS curve suggests that patients with favour­able response to durvalumab will likely continue to obtain survival benefits from this regimen. For instance, at our centre, a female patient with advanced cholangio­carcinoma enrolled in TOPAZ-1 continued to respond well to durvalumab plus Gem­Cis after 2 years of treatment.”

“These exciting and practice-changing results have become the basis of the first major treatment guideline up­date in BTC after more than a decade, with durvalumab plus GemCis now con­sidered as a preferred first-line treatment option for patients with advanced BTC [in clinical practice],” concluded Yau. [NCCN Clinical Practice Guidelines in Oncology, Hepatobiliary Cancers, version 1.2023]

How to assess efficacy of immunotherapy?
“In clinical trials, we traditionally as­sess treatment efficacy based mainly on early OS benefits,” Yau commented. “In TOPAZ-1, however, a gradual diver­gence of survival curves between the durvalumab and placebo groups was observed after 6 months of treatment, with a plateauing of the durvalumab curve beyond 24 months. This highlights the importance of longer follow-up with im­munotherapy plus chemotherapy combi­nations in solid tumours.” [J Immunother Cancer 2020;8:e000648; NEJM Evid 2022;doi:10.1056/EVIDoa2200015; Oh DY, et al, ESMO 2022, poster 56P]

“Unlike chemotherapies which are designed to directly attack tumour cells, immunotherapies prime the immune sys­tem to attack the tumour, which partly explains why the OS data may still be im­mature during the initial treatment phase [ie, <6 months],” he explained. “Since OS efficacy may be delayed with emerging treatments such as immunotherapies, exploratory endpoints may be needed. For example, landmark survival rates and the modified Response Evaluation Criteria in Solid Tumours are useful for measuring clinical benefits while await­ing OS data to mature.” [J Immunother Cancer 2020;8:e000648; J Thorac Dis 2018;10(Suppl 13):S1564-S1580]

Conclusion
TOPAZ-1 is the first global phase III study to report positive OS results and no additional toxicity when combining immunotherapy (ie, durvalumab) with SoC chemotherapy in patients with advanced BTC. These findings support the use of durvalumab plus GemCis as first-line treatment for advanced BTC.