Findings from the phase 3 HIMALAYA trial indicate that durvalumab with or without tremelimumab remained efficacious regardless of the presence of anti-drug antibodies in unresectable hepatocellular carcinoma.
Among patients with unresectable hepatocellular carcinoma (HCC), the presence of anti-drug antibodies (ADAs) did not appear to impact the efficacy of durvalumab (Imfinzi) on its own or in combination with tremelimumab (Imjudo), according to findings from the phase 3 HIMALAYA trial (NCT03298451) presented during the 2023 Gastrointestinal Cancers Symposium.1
Investigators concluded that, among those assigned to the STRIDE regimen (durvalumab plus tremelimumab), 11.0% of patients developed ADAs to tremelimumab following treatment and 3.1% developed ADAs to durvalumab. In the monotherapy group, 2.8% of patients developed treatment-emergent (TE) ADAs. However, the ADAs “did not seem to affect how well STRIDE or durvalumab [alone] worked and had no impact on side effects.”
At 2 years or longer of follow-up, 33.3% (n = 9/27) of patients in the STRIDE arm who were positive for TE-ADAs were alive at the data cutoff date. In the monotherapy arm, 37.5% (3/8) of patients with TE-ADAs were alive.
The incidence of adverse events was nearly identical between all ADA-positive and ADA-negative groups.
The immune system develops ADAs following treatment with immunotherapy, and these molecules can cause side effects and reduce treatment efficacy. Investigators have detected ADA incidence as low as 1.5% with pembrolizumab (Keytruda) and up to 54.1% with atezolizumab (Tecentriq).2 Previous results have shown an incidence range of 1.8% to 16.7% for tremelimumab and 0% to 10.1% for durvalumab, the investigators noted.
This analysis includes findings from 393 patients randomly assigned to STRIDE and 389 who were assigned to durvalumab in the HIMALAYA trial, in which investigators sought to determine what effect these ADAs might have on patients receiving treatment for unresectable HCC. Investigators collected samples for ADA analysis at baseline, once during treatment, and once after discontinuation. Participants were considered ADA positive if they had a positive test at any point.
Investigators evaluated both incidence, specifically the proportion of patients who were positive for TE-ADAs, and prevalence, looking at the proportion of ADA-evaluable patients who were ADA positive at any point. They also evaluated patients for overall survival (OS), overall response rate (ORR), and safety by ADA status.
In October 2022, the FDA approved STRIDE for adults with unresectable HCC based on results from HIMALAYA.3 Treatment with a single dose of tremelimumab at 300 mg plus durvalumab at 1500 mg followed by durvalumab every 4 weeks induced a 22% reduction in the risk for death vs sorafenib (Nexavar; HR, 0.78; 95% CI, 0.66-0.92; P = .0035).4
According to data published in the New England Journal of Medicine Evidence, approximately 31% of patients treated with the combination were still alive after 3 years vs 20% of patients on sorafenib.5
Among patients assigned to STRIDE in this analysis, 182 patients were evaluable for TE-ADAs related to tremelimumab and 294 were evaluable for durvalumab. A total of 282 patients in the durvalumab monotherapy group were evaluable for TE-ADAs.
The prevalence of TE-ADAs was 15.9% for tremelimumab in the STRIDE arm, 8.2% for durvalumab in the STRIDE arm, 7.1% in the monotherapy arm.
In the STRIDE arm, 25.9% (n = 7/27) had an objective response and 66.7% (n = 18/27) experienced a reduction in target lesion size. In the durvalumab-monotherapy arm, the ORR was 25.0% (n = 2/8) and 62.5% (n = 5/8) saw a reduction in lesion size.