Tremelimumab–Durvalumab Receives FDA Approval for Unresectable Liver Cancer

For unresectable hepatocellular carcinoma (liver cancer), the FDA (US Food and Drug Administration) has approved a dual immunotherapy combination for first-line treatment for the first time.

On 21 October 2022, the FDA approved tremelimumab (Imjudo, AstraZeneca) immunotherapy with durvalumab (Imfinzi, AstraZeneca) for adults with unresectable liver cancer.

Türkiye Cancer Statistics 2020 show that this is the 14th most common cancer in Türkiye, with 5649 new cases annually, and the 7th leading cause of cancer death, with 5461 deaths.

Hepatocellular carcinoma (HepatoCellular Carcinoma =  HCC) is the most common liver cancer subtype, accounting for  75%  of all liver cancers.

The new combination involves a single dose of tremelimumab followed by durvalumab maintenance. It is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab).

This marks the first worldwide approval for tremelumumab, a CTLA-4 antibody.

The other medicine in the combination, durvalumab, is an anti-PD-L1 antibody already FDA-approved for several tumour types, including lung, bladder and biliary tract cancers.

The STRIDE regimen consists of a single 300 mg tremelimumab dose followed by durvalumab 1500 mg every 4 weeks.

This regimen was used in the study published in June 2022 in NEJM Evidence: the phase-3 HIMALAYA trial.

The clinical trial showed that, compared with 20% of patients treated with the standard sorafenib regimen, 30% of patients receiving the combination were still alive at 3 years.

FDA Approval Based on the HIMALAYA Study

Efficacy was assessed in HIMALAYA, a randomised (1:1:1), open-label, multicentre study in patients with confirmed unresectable hepatocellular carcinoma (liver cancer) who had received no previous systemic treatment.

Patients were randomised to one of three arms:

• Tremelimumab 300 mg as a single intravenous (IV) infusion plus durvalumab 1500 mg IV on the same day, followed by durvalumab 1500 mg IV every 4 weeks;
• Durvalumab 1500 mg IV alone every 4 weeks;
• Sorafenib 400 mg twice daily until disease progression or unacceptable adverse effects.

Approval was based on comparison of 782 patients randomised to tremelimumab plus durvalumab or sorafenib.

The primary efficacy outcome was overall survival.

• Tremelimumab plus durvalumab significantly improved overall survival, statistically and clinically, compared with sorafenib: a 22% reduction in the risk of death
• Median overall survival was 16.4 months in the combination arm versus 13.8 months in the sorafenib arm.
• Median progression-free survival was 3.8 months with tremelimumab plus durvalumab versus 4.1 months with sorafenib.
• Overall response rates were 20.1% in the combination arm versus 5.1% with sorafenib.

The most common adverse effects (≥20%) were rash, diarrhoea, fatigue, itching, musculoskeletal pain and abdominal pain.

The STRIDE regimen showed a lower bleeding risk than combinations containing VEGF inhibitors such as bevacizumab. However, this clinical trial excluded patients with main portal vein thrombosis at high bleeding risk.

For patients weighing 30 kg or more, recommended dosing is a single 300 mg tremelimumab dose on the first treatment day, with durvalumab 1500 mg that day, followed by durvalumab 1500 mg every 4 weeks.

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