A post-hoc analysis of the phase III TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin (GemCis) in advanced biliary tract cancer (aBTC) has found that while durvalumab demonstrated an overall survival (OS) benefit vs placebo irrespective of immune-mediated adverse events (imAEs), the improvement in OS was numerically greater among patients who experienced imAEs.
After a median follow-up of 41.3 months, at 89.3 percent of data maturity, the randomized, double-blind, global, phase III TOPAZ-1 study (n=685) demonstrated significant improvements in OS with durvalumab plus GemCis vs placebo plus GemCis (hazard ratio [HR], 0.74; 95 percent confidence interval [CI], 0.63–0.87; ptwo-sided=0.021 in patients with aBTC, with similar safety reported for both regimens. [J Hepatol 2025:S0168-8278(25)02201-9]
While survival benefit with immunotherapy has been observed irrespective of imAE occurrence, some studies have shown associations between imAEs and increased OS. [Front Immunol 2022;13:1026964; Cancer Manag Res 2020;12:4585-4593; BMC Cancer 2020;20:656] “[In the present analysis,] we assessed imAE incidence and timing, and association between imAE occurrence and OS in TOPAZ-1,” wrote the investigators. [Oncologist 2025;30:oyaf148]
Overall, 13.9 vs 4.7 percent of TOPAZ-1 participants in the durvalumab vs placebo arm experienced any-grade imAEs. These resolved in 7.1 and 2.3 percent of patients, respectively. The most commonly reported imAE for durvalumab was hypothyroidism (5.9 percent). Hypothyroidism was also the most common unresolved imAE for durvalumab, although the investigators noted that it is typically well managed with endocrine therapy. [Front Endocrinol (Lausanne) 2022;13:886930] Grade 3 or 4 imAEs were reported in 2.4 vs 1.5 percent of patients and serious imAEs in 1.8 vs 1.5 percent, respectively. imAEs leading to treatment discontinuation were reported in 0.9 percent of patients in the durvalumab arm and 1.2 percent of patients in the placebo arm.
Median time to onset of imAEs was 127.0 (range, 1–511 days) and 86.5 days (range, 4–533 days) in the respective arms. Maculopapular rash was among the first imAEs to occur with durvalumab, while hypothyroidism generally emerged after 8 weeks.
OS HR for durvalumab vs placebo was 0.59 (95 percent CI, 0.30–1.23) in study participants with and 0.83 (95 percent CI, 0.70–1.00) in participants without recorded imAEs. “In this post-hoc analysis, the limited number of participants experiencing imAEs impacted precise estimation of the treatment effect, as demonstrated by wide CIs,” wrote the investigators. Of note, the median OS (mOS) was longer in those treated with durvalumab vs placebo regardless of imAEs (mOS with imAEs, 20.0 vs 14.9 months; mOS without imAEs, 12.5 vs 11.3 months).
“People with aBTC benefit from durvalumab despite the occurrence of imAEs. Therefore, careful monitoring and management of imAEs is important to enable them to continue treatment and receive therapeutic benefit,” concluded the investigators.