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 at the 2022 ESMO congress 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) and 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.
The incidence of irAEs was higher in 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 an 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.
Reference
- 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.
Sources: 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.
Oh D, 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). European Society for Medical Oncology Congress 2022. Abstract 56P.