A single, high priming dose of tremelimumab plus durvalumab resulted in a statistically significant and clinically meaningful improvement in overall survival vs sorafenib when used in the frontline treatment of patients with unresectable hepatocellular carcinoma who had not previously received systemic therapy and were not eligible for localized treatment.
A single, high priming dose of tremelimumab plus durvalumab (Imfinzi) resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) vs sorafenib (Nexavar) when used in the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC) who had not previously received systemic therapy and were not eligible for localized treatment, meeting the primary end point of the phase 3 HIMALAYA trial (NCT03298451).1
The approach, referred to as the STRIDE regimen, also showcased an encouraging toxicity profile in this patient population. Notably, the addition of tremelimumab to durvalumab was not found to result in increased severe hepatic toxicity.
Moreover, durvalumab monotherapy was also found to be noninferior to sorafenib, with a numerical trend in favor of the former. Single-agent durvalumab also had better tolerability than sorafenib.
“HIMALAYA is the first phase 3 trial to add a novel single priming dose of an anti–CTLA-4 antibody to another checkpoint inhibitor, durvalumab,” Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center and principal investigator of the HIMALYA trial, stated in a press release. “This serves to boost the patient’s own immune system against their liver cancer, aiming to maximize long-term survival with minimal [adverse] effects. This is very exciting news for our patients.”
The open-label, multicenter HIMALAYA trial enrolled patients with unresectable HCC who were at least 18 years of age. To be eligible for enrollment, patients need to have Barcelona Clinic Liver Cancer stage B or C disease, a Child-Pugh Score of class A, and an ECOG performance status of 0 or 1 at the time of enrollment.2
Patients could not have received prior systemic therapy for their disease. Moreover, patients who had hepatic encephalopathy within the past 12 months or who required medication to prevent or control this condition were excluded. Other exclusion criteria comprised ascites that required ongoing paracentesis to control symptoms, history of allogeneic organ transplantation, main portal vein tumor thrombosis, active or prior documented gastrointestinal bleeding within 12 months, or hepatitis B and C co-infection.
Study participants were randomized to 1 of 4 treatment arms: single-agent durvalumab, durvalumab plus tremelimumab (regimen 1), durvalumab plus tremelimumab (regimen 2), or sorafenib monotherapy. The STRIDE regimen was comprised of a single priming dose of tremelimumab at 300 mg plus durvalumab at 1500 mg followed by durvalumab every 4 weeks. Sorafenib was delivered at the standard dose and schedule. A total of 1324 patients were included.
The primary end point of the trial was OS for the STRIDE regimen vs sorafenib. Important secondary end points included OS for durvalumab monotherapy vs sorafenib, objective response rate (ORR), and progression-free survival (PFS) for STRIDE and for durvalumab monotherapy.
Investigators will also evaluate all immunotherapy arms vs sorafenib, as well as durvalumab plus tremelimumab vs durvalumab monotherapy, with respect to 18- and 24-month OS, time to progression, PFS, ORR, disease control rate, and duration of response.
They will also examine efficacy according to PD-L1 expression in the durvalumab/tremelimumab arms vs single-agent durvalumab and in all immunotherapy arms vs sorafenib. Disease-related symptoms will be examined, as well as health-related quality of life in all immunotherapy arms vs sorafenib utilizing the EORTC QLQ-C30 and QLQ-HCC18 instruments.
Other exploratory objectives will focus on efficacy of all immunotherapy arms vs sorafenib utilizing irRECIST and mRECIST criteria, changes in alpha-fetoprotein level and efficacy measures, the association of interferon gamma and immune-related gene expression with efficacy measures, the association of candidate biomarkers with efficacy measures, patient-reported outcomes, and healthcare research utilization.
“Inhibition of CTLA-4 has shown the ability to drive benefit particularly in the tail of the survival curve in several settings,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, added in the press release. “This is the first time a dual immunotherapy regimen has improved OS as a first-line treatment for patients with unresectable liver cancer for whom treatment options are limited and long-term outcomes are poor.”
The findings from HIMALAYA will be shared at an upcoming medical conference.
Previously, in 2020, durvalumab and tremelimumab were granted orphan drug designations by the FDA for the treatment of patients with HCC. In 2020, tremelimumab was also granted an orphan drug designation in the European Union in this disease.