TOPAZ-1 Data Support New Frontline Option in Patients With BTC


During a Targeted Oncology case-based roundtable event, Nilofer S. Azad, MD, discussed the data supporting the previous standard of care and the new frontline regimen of gemcitabine, cisplatin, and durvalumab for patients with biliary tract cancers.

Azad image

Nilofer S. Azad, MD

Codirector of Cancer Genetics and Epigenetics

Professor of Oncology

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, MD

Targeted OncologyTM: What regimens are available for patients with newly diagnosed advanced biliary tract cancer (BTC)?

There are no biomarker-based regimens that are appropriate in the first line yet for patients with BTC. [To] give a sense of the options in all of the different lines of therapies, for over a decade, gemcitabine/cisplatin has been the first-line regimen for patients based on the ABC-02 study [NCT00262769]. But now, with the TOPAZ-1 trial [NCT03875235], we have a first-line regimen that incorporates IO [immunotherapy] with durvalumab [Imfinzi].

In the second line, we have chemotherapy options as well as targeted therapy options for patients who have the [FGFR or IDH1] biomarkers. And then in the third line, similarly, there are options that include potential biomarker-based options; BRAF and NTRK. NTRK is very rare everywhere, but in cholangiocarcinoma [it is present in fewer] than 1%. Pembrolizumab [Keytruda] can be used for patients with MSI [microsatellite instability]-high disease, and then other chemotherapy regimens [can be used] as well.

What did the ABC-02 study show about the combination of gemcitabine and cisplatin?

The publication date of this [study] was 2010.1 So, for the last 12 years until just a couple of months ago, this was the standard-of-care regimen. [There was an] overall survival [OS] benefit of the doublet over single-agent gemcitabine [HR, 0.64, 95% CI, 0.52-0.80; P < .001]. The PFS [progression-free survival] benefit also statistically significant [HR, 0.63, 95% CI, 0.51-0.77; P < .001]. There was a median OS of [11.7 months with gemcitabine/cisplatin].

In the subgroup analysis, even if it’s not statistically significant, everything is to the left on the forest plot showing the benefit of gemcitabine/cisplatin broadly.

What efforts have there been to improve upon the efficacy of the combination chemotherapy regimen?

There has been interest in the idea of intensifying this chemotherapy regimen, and, in particular, data from Rachna T. Shroff, MD, looking at the triplet therapy of gemcitabine, cisplatin, and nab-paclitaxel [Abraxane] has been quite compelling. This was reported 3 years ago in JAMA Oncology, with a median PFS of 11.8 months and then OS of 19.2 months.2 But this was a single-arm, nonrandomized trial [NCT02392637]. For an advanced gastrointestinal adenocarcinoma; [this study had] a nice waterfall plot [showing best response to the triplet therapy].

Gemcitabine, cisplatin, and nab-paclitaxel at the high dose had [a median OS] of 19.5 months, [and] the median OS at the reduced dose was 15.7 months, [whereas] the ABC-02 overall survival was 11.7 months.1,2 By tumor type, it looked like patients with intrahepatic cholangiocarcinoma might do a bit better, and that was seen broadly when you look at these different tumor types.2 The PFS data showed a very similar pattern.

Initially, the study was designed with higher doses, so basically more standard doses of gemcitabine, cisplatin, and nab-paclitaxel. The patients couldn’t tolerate it…so it was given at a lower dose. The gemcitabine was [reduced from 1000 mg/m2 to] 800 mg/m2, cisplatin dosing was 25 mg/m2 [but was not reduced], and nab-paclitaxel’s dosing came down [from 125 mg/m2 to 100 mg/m2]. That’s lower dose was more tolerable. That is the dose that is being tested in the phase 3 [SWOG 1815; NCT03768414] study.

What was the design and results of the TOPAZ-1 study?

TOPAZ-1 was reported in January 2022 and has resulted in an approval of durvalumab in the first line.3,4 This was a study that randomly assigned patients 1:1 to gemcitabine/cisplatin plus durvalumab versus gemcitabine/cisplatin plus placebo.3 There are many important caveats to this trial. First, patients received 6 months of therapy with the triplet or the doublet and then if you were on the placebo arm, you then received only placebo. Chemotherapy was discontinued, and the patients continued in the experimental arm on durvalumab alone.

The patient demographics are similar to what one would expect for a global trial that’s enrolled, but I want to draw your attention to the fact that 54% of the patients in the triplet arm were Asian and enrolled in Asia and that’s going to be important.5

The updated OS benefit is a median of 12.9 months [for triplet] versus 11.3 months [for the doublet arm].6 There is a tail to this [Kaplan-Meier] curve, so at the 24-month mark, we’re at 23.6% overall survival in the triplet arm versus just 11.5% in the doublet arm. But remember that at the 6-month mark, those patients were not getting any more chemotherapy and they likely were exposed to chemotherapy again in the second or third line. But patients were not being treated with an active regimen at the time of the 6-month mark, and that’s where the OS curve separates. So there were superimposed curves until 6 months, and then at the 6-month mark when patients started moving to placebo versus durvalumab alone, that’s where the curves start to separate.

The forest plots show that there is a trend towards benefit [for the triplet] in every subgroup.6 The statistically significant benefit was in all the patients and then in patients who were enrolled in Asia.

Similarly, the curves separate and patients have a statistically significant improvement in PFS, 7.2 months [with triplet] versus 5.7 months [with doublet], so 1.5 months median PFS benefit.3

Safety-wise, this was a very well tolerated regimen in terms of adding the durvalumab.5 There was a slight increase in some autoimmune adverse events is expected, but, overall, the grade 3 or 4 adverse events were similar in both arms.

What are your conclusions on these data and what does the future hold for this regimen?

Based on these data, it’s hard to know whether the benefit is being fully driven by patients that are in Asia or if the OS benefit is equal in [non-Asian] populations as well. Merck has fully enrolled and hopefully in the next year is going to release a study that is more heavily enrolled in the West. There’s a lot of interest in how those results are going to inform how we can look at gemcitabine/cisplatin/durvalumab. But right now, the TOPAZ-1 regimen is an option for patients, and it is FDA approved.4


1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721

2. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5(6):824-830. doi:10.1001/jamaoncol.2019.0270

3. Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J Clin Oncol. 2022;40(4_suppl):378. doi:10.1200/JCO.2022.40.4_suppl.378

4. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. FDA. September 2, 2022. Accessed January 30, 2023.

5. 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

6. Oh DY, He AR, Qin S, et al. Updated overall survival (OS) from the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in patients (pts) with advanced biliary tract cancer (BTC). Ann Oncol. 2022;33(suppl_7):S19-S26. doi: 10.1016/annonc/annonc1036

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