FDA Approves Durvalumab Plus Tremelimumab for Unresectable HCC

Findings from the phase 3 HIMALAYA trial have led the FDA to grant approval to the combination of tremelimumab and durvalumab for the treatment of patients with unresectable hepatocellular carcinoma.

The FDA has approved tremelimumab (Imjudo) in combination with durvalumab (Imfinzi) for the treatment of patients with unresectable hepatocellular carcinoma (HCC), according to an announcement by AstraZeneca.1

The approval is based on the final results of the HIMALAYA phase 3 trial (NCT03298451) which showed treatment with durvalumab plus tremelimumab to demonstrate a significant improvement in overall survival (OS) compared with sorafenib (Nexavar) as frontline therapy. These findings were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium

“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival. In addition to this regimen demonstrating a favourable three-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” said Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, in a press release.

Previously, the FDA granted priority review to a biologics license application (BLA) for tremelimumab in this patient population in April 2022. Also at this time, a supplemental BLA was submitted for durvalumab in this indication with the novel dose and schedule of the combination called the STRIDE regimen (Single T Regular Interval D).2

The randomized, open-label, multicenter, global HIMALAYA trial looked to evaluate the efficacy and safety of the combination of durvalumab plus tremelimumab and durvalumab monotherapy versus sorafenib (Nexavar) in the treatment of patients with no prior systemic therapy for unresectable HCC.

Those with HCC based on histopathological confirmation who had no prior systemic therapy, a Barcelona Clinic Liver Cancer stage B that is not eligible for locoregional therapy or stage C, a Child-Pugh Score of class A, and an ECOG performance status of 0 or 1 were eligible for enrollment in the trial.

A total of 1171 patients were randomized to receive either the combination of durvalumab plus tremelimumab (n = 393), durvalumab alone (n = 389), or sorafenib alone (n = 389). Those enrolled within the trial were randomized to the STRIDE regimen, 1500 mg of durvalumab every 4 weeks, 400 mg of sorafenib twice daily, or 75 mg of tremelimumab plus 1500 mg of durvalumab every 4 weeks.3

Based on the investigators opinion, patients throughout all arms with confirmed progressive disease (PD) who benefited from their assigned treatment and met criteria for treatment in the setting of PD were able to continue to receive their assigned treatment. Those who discontinued due to disease progression entered survival follow-up while those who discontinued treatment due to toxicity, symptomatic deterioration, or who have commenced subsequent anticancer therapy, had tumor assessments until confirmed PD. Those patients were followed for survival.

OS for durvalumab/tremelimumab vs sorafenib was the primary end point of the trial with secondary end points consisting of progression-free survival (PFS), objective response rate (ORR) per RECIST v.1.1 criteria, disease control rate, duration of response (DOR), and safety.

Findings from the data cutoff met the primary end point of the study as durvalumab in addition to tremelimumab showed a significant improvement in OS vs sorafenib (HR, 0.78; 96% CI, 0.65-0.92; P =.0035). Additionally, durvalumab demonstrated noninferior OS vs sorafenib (HR, 0.86; 96% CI, 0.73-1.03).2

The median OS was reported as being 16.4 months (95% CI, 14.2-19.6) with durvalumab/tremelimumab, 16.6 months (95% CI, 14.1-19.1) with durvalumab, and 13.8 months (95% CI, 12.3-16.1) with sorafenib. The median follow-up in the durvalumab/tremelimumab arm was 16.1 months, 16.5 months in the durvalumab arm, and 13.3 months in the sorafenib arm. Additionally, 66.7%, 72%, and 75.3% of patients had died, respectively, at the time of the data cutoff.

The 24-month OS rate was 40.5% for patients given the combination of durvalumab and tremelimumab, 39.6% with durvalumab, and 32.6% with sorafenib, with 36-month OS rates being 30.7%, 24.7%, and 20.2%, respectively.

In the durvalumab/tremelimumab arm, the median PFS was 3.8 months (95% CI, 3.7-5.3) vs 3.7 months (95% CI, 3.2-3.8) in durvalumab alone arm, and 4.1 months (95% CI, 3.8-5.5) in the sorafenib alone arm.

ORR reported in those given the combination was higher at 20.1% than in those given with durvalumab (17.0%) or sorafenib (5.1%). The median DOR was 22.3 months, 16.8 months, and 18.4 months, respectively. Patients treated with the STRIDE regimen also showed a 22% reduction in the risk of death vs sorafenib (HR 0.78, 96.02% CI, 0.65 - 0.93; P =0.0035). Approximately 31% of these patients were still alive at 3 years vs 20% of those treated with sorafenib.

Further, there were no new signals identified. Grade 3 or 4 treatment-related adverse effects (TRAEs) occurred in a total of 25.8% of patients on durvalumab/tremelimumab, 12.9% of patients on durvalumab, and 36.9% of patients on sorafenib. Grade 3 or 4 hepatic TRAEs occurred in 5.9%, 5.2%, and 4.5% of patients, respectively.

In regard to serious TRAEs, 17.5% of patients on durvalumab/tremelimumab reported having such effects compared to 8.2% of patients on durvalumab, and 9.4% of patients on sorafenib. Grade 5 TRAEs were seen in 2.3%, 0%, and 0.8% of patients, and no TRAE of esophageal varices hemorrhage occurred. However, TRAEs led to discontinuation in the trial in 8.2% of patients on durvalumab/tremelimumab, 4.1% of patients on durvalumab, and 11.0% of patients on sorafenib.

“With this first regulatory approval for Imjudo, patients with unresectable liver cancer in the US now have an approved dual immunotherapy treatment regimen that harnesses the potential of CTLA-4 inhibition in a unique combination with a PD-L1 inhibitor to enhance the immune response against their cancer,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, in the press release.


1. Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer. News release. AstraZeneca. October 24, 2022. Accessed October 24, 2022. https://bit.ly/3VUsQTw

2. Tremelimumab accepted under priority review in the US for patients with unresectable liver cancer in combination with imfinzi. News Release. Astrazeneca. April 25, 2022. Accessed April 25, 2022. https://bit.ly/3rRpzqN

3. Study of durvalumab and tremelimumab as first-line treatment in patients with advanced hepatocellular carcinoma (HIMALAYA). Clinicaltrials.gov. Accessed April 25, 2022. https://clinicaltrials.gov/ct2/show/NCT03298451