A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Durvalumab in Combination with Gemcitabine/Cisplatin in Advanced BTC (TOPAZ-1)

Immune checkpoint inhibitor therapy in advanced biliary tract cancer (BTC) is associated with limited clinical activity. However, a phase 2 study showed that the addition of cytotoxic chemotherapy to the PD-L1 inhibitor durvalumab was associated with promising antitumor activity as first-line treatment for patients with advanced BTC.¹

Based on these results, the phase 3 TOPAZ-1 study evaluated the first-line chemoimmunotherapy regimen of the PD-L1 inhibitor durvalumab plus gemcitabine/cisplatin in patients with advanced BTC. Dr Do-Youn Oh from the Cancer Research Institute at the Seoul National University College of Medicine presented the planned interim analysis data of the study at the Cholangiocarcinoma Foundation meeting.

In this global, double-blind, placebo-controlled study, 685 patients were randomized 1:1 to receive durvalumab (n = 341) or placebo (n = 344) plus gemcitabine/cisplatin for up to 8 cycles, followed by durvalumab or placebo alone until disease progression or unacceptable toxicity.²

Patients treated with the durvalumab plus gemcitabine/cisplatin regimen demonstrated a statistically significant and clinically meaningful improvement in the primary end point of overall survival (OS) (median OS, 12.8 vs 11.5; hazard ratio [HR], 0.80; P = .021) compared with those administered with placebo/chemotherapy.²

The secondary end point, progression-free survival (PFS), was also significantly improved (median PFS, 7.2 vs 5.7; HR, 0.75; P = .001) and a higher objective response rate was achieved by the durvalumab plus gemcitabine/cisplatin cohort (26.7% vs 18.7%; P = .011) compared with those treated with placebo plus gemcitabine/cisplatin.²

Because the OS analysis results were statistically significant at the planned interim analysis and the study met its primary end point, these results are considered the final statistical OS analysis.

The addition of durvalumab to gemcitabine/cisplatin chemotherapy did not exacerbate toxicities associated with gemcitabine/cisplatin. The incidence of grade 3/4 treatment-related adverse events (TRAEs) and serious TRAEs were similar between the 2 groups. Immune-mediated adverse events occurred in 12.7% of durvalumab-treated patients compared with 4.7% in the placebo cohort; however, no new safety signals emerged from that previously described for durvalumab.²

Based on these data, Dr Oh concluded that “TOPAZ-1 is the first global phase 3 study to report positive results testing immunotherapy plus chemotherapy as first-line treatment for advanced BTC. Durvalumab plus gemcitabine/cisplatin is an effective first-line therapy and could become a new standard of care for patients with advanced BTC.”

References

1. Oh D-Y, Lee K-H, Lee D-W, et al. Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). J Clin Oncol. 2020;38:4520.
2. Oh D-Y, He A, 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. Presented at ASCO Gastrointestinal Cancers Symposium 2022; January 20-22, 2022. Abstract 378.