FDA Grants Durvalumab Plus Tremelimumab Orphan Drug Status in HCC

The FDA has granted an orphan drug designation to durvalumab and tremelimumab for the treatment of patients with hepatocellular carcinoma.

José Baselga, MD, PhD

The FDA has granted an orphan drug designation to durvalumab (Imfinzi) and tremelimumab for the treatment of patients with hepatocellular carcinoma (HCC).1

The combination is being investigated in the phase III HIMALAYA trial (NCT03298451) of patients with unresectable, advanced HCC who have not previously received systemic treatment and are ineligible for locoregional therapy. The study is also evaluating single-agent durvalumab in this patient population.

“Many patients with liver cancer are diagnosed and treated only after the disease is advanced, and there is an urgent need for new effective and tolerable treatments,” José Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZeneca, the developer of the PD-1 and CTLA-4 inhibitors, stated in a press release. “We are eager to bring new potential options to these patients and look forward to the results of our ongoing phase III HIMALAYA trial later this year.”

The FDA grants orphan drug designation to drugs that are intended for the treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States.

In the open-label, multicenter, international, phase III HIMALAYA trial, investigators are evaluating durvalumab alone and in combination with tremelimumab compared with standard sorafenib (Nexavar) in approximately 1310 patients with unresectable, advanced HCC who have not received prior systemic treatment and are ineligible for locoregional therapy. The combination arm is split into 2 cohorts of different dosing regimens.

The study is being conducted at 189 centers across 16 countries, including the United States, Canada, Europe, South America, and Asia. To be eligible for enrollment, patients must have Barcelona Clinic Liver Cancer stage B or stage C HCC, could not have received prior systemic treatment for HCC, had Child-Pugh Score of class A, and ECOG performance status of 0 or 1. Those who had hepatic encephalopathy within the past 12 months or were required to take medication to prevent or control encephalopathy, had clinically meaningful ascites, main portal vein tumor thrombosis, had active or prior documented gastrointestinal bleeding within 12 months, or had hepatitis B virus and hepatitis C virus co-infection, or hepatitis B virus and hepatitis D co-infection were excluded from enrollment.

The primary endpoint is overall survival; secondary endpoints include time to progression, objective response rate (ORR), disease control rate, duration of response, and progression-free survival. Safety is also being explored.

In an earlier phase I/II study, 40 patients with HCC were evaluable to assess the safety and tolerability of the durvalumab/tremelimumab combination. The confirmed ORR was 17.5%, with 7 patients having a partial response.2 The ORR on the basis of confirmed and unconfirmed response was 25.0%. Additionally, the median time to response was 8 weeks (range, 7.6-24.0).

The combination was also generally well tolerated and showed no unexpected safety signals in patients with unresectable HCC. The most common all-grade treatment-related adverse events (TRAEs) included fatigue (27.5%), increased alanine aminotransferase (ALT; 20.0%), pruritus (22.5%), and increased aspartate aminotransferase (AST; 17.5%).

Twenty-five percent of patients experienced grade 3/4 TRAEs or serious AEs. The most common grade ≥3/4 TRAE or serious AE was elevated AST (10.0%) and elevated lipase (10.0%); the most common TRAEs of special interest were pruritus (22.5%), elevated ALT (20.0%), and increased AST (17.5%). No treatment-related deaths occurred.


  1. Imfinzi and tremelimumab granted orphan drug designation in the US for liver cancer [news release]. AstraZeneca. Published January 21, 2020. https://bit.ly/37g8XwG. Accessed January 21, 2020.
  2. Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35(suppl; abstr 4073). https://meetinglibrary.asco.org/record/147423/abstract.