Immune-Related Adverse Events in the TOPAZ-1 Study of Durvalumab or Placebo plus GemCis in Advanced BTC

Web Exclusives — November 15, 2022

The TOPAZ-1 trial compared durvalumab (D) with placebo (PBO) in patients with biliary tract cancer who were also taking gemcitabine/cisplatin (GemCis). It has been previously reported that D plus GemCis significantly improved overall survival (OS) compared with PBO plus GemCis, and that D, which is an immune checkpoint inhibitor, may cause immune-related adverse events (irAEs).1

This presentation examined characteristics of D-related irAEs, including incidence, timing, and association with efficacy outcomes. Patients included in this safety analysis received ≥1 dose of D (1500 mg every 3 weeks; n = 338) or PBO (n = 342), as well as GemCis (1000 mg/m2 and 25 mg/m2, respectively) on days 1 and 8 every 3 weeks for a maximum of 8 cycles, followed by D (1500 mg every 4 weeks) or PBO monotherapy until disease progression or unacceptable toxicity. irAEs were defined as adverse events of special or possible interest that probably have an immune-mediated mechanism and no clear alternate etiology and are related to drug exposure.

Incidence of irAEs was higher for those receiving D plus GemCis versus those receiving PBO plus GemCis (12.7% vs 4.7%), and the incidence of grade 3 or 4 irAEs was 2.4% in the D plus GemCis arm versus 1.5% in the PBO plus GemCis arm. However, the incidence of irAEs leading to treatment discontinuation was similar between the 2 arms (0.9% for D plus GemCis vs 1.2% for PBO plus GemCis). Wide variability was seen in time to onset, with a mean of 108.0 days (range, 1-511 days) with D plus GemCis and 86.5 days (range, 4-533 days) with PBO plus GemCis. The most common irAEs were hypothyroid events (5.9% with D plus GemCis vs 1.5% with PBO plus GemCis), dermatitis/rash (3.6% with D plus GemCis vs 0.3% with PBO plus GemCis), hepatic events (1.2% with D plus GemCis vs 0.6% with PBO plus GemCis), and adrenal insufficiency (1.2% with D plus GemCis vs 0.3% with PBO plus GemCis). When >1 patient experienced the irAE, the median time to onset for each of these was variable. Concomitant treatment for irAEs, such as systemic corticosteroids, high-dose steroids, or endocrine therapy, was required more frequently in the D plus GemCis arm versus the PBO plus GemCis arm.

In the D plus GemCis arm, median OS was numerically greater in patients who experienced an irAE of any grade compared with those who did not experience an irAE: 17.3 months (95% confidence interval [CI], 12.4-noncalculable) versus 12.6 months (95% CI, 10.5-13.6; OS hazard ratio, 0.62; 95% CI, 0.38-0.97). irAEs were generally manageable and consistent with the previously characterized safety profile. Further investigation to characterize the relationship between irAEs and OS benefit is warranted.


  1. 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 with advanced biliary tract cancer (BTC). TOPAZ-1. J Clin Oncol. 2022;40(suppl 4):378-378.

Source: Antonuzzo L, Takahashi H, Park JO, et al. Immune-mediated adverse event (imAE) incidence, timing and association with efficacy in the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in advanced biliary tract cancer (BTC). Ann Oncol. 2022;33(suppl 7):S566-S567.

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