Tremelimumab-actl (Imjudo, AstraZeneca Pharmaceuticals) in combination with durvalumab was approved on Oct. 21, 2022, for the treatment of unresectable hepatocellular carcinoma (HCC) in adult patients. Tremelimumab-actl is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody. Durvalumab is a human monoclonal antibody that binds to the PD-L1 protein.

The recommended regimen begins with a single IV infusion of tremelimumab, followed by durvalumab infusion later that same day. This initial administration is then followed by durvalumab every four weeks. Dosing of both agents is weight based.

Serious adverse reactions occurring in >1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2%), pneumonia (2%), rash (1.5%), vomiting (1%), acute kidney injury (1%), and anemia (1%). Fatal adverse reactions occurred in 8% of patients who received combination treatment. No increased severe liver toxicity or bleeding risk was seen with combined tremelimumab plus durvalumab. No new safety concerns were identified with the combined regimen, compared with the known safety profiles of each medicine alone. The most common adverse reactions, occurring in ≥20%, were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

The approval was based on the results of the HIMALAYA trial, a multicenter, open-label clinical trial involving patients with unresectable, advanced HCC who had not been treated with prior systemic therapy. For the approval analysis, the results for the 782 patients randomized to tremelimumab plus durvalumab or oral sorafenib 400 mg twice a day were compared.

Patients treated with tremelimumab plus durvalumab had a 22% reduced risk of death, as shown by a significantly improved OS compared with those treated with sorafenib (stratified HR, 0.78 [95% CI, 0.66-0.92], P = 0.0035). The median OS was 16.4 months versus 13.8 months with sorafenib. PFS was not significantly different between the groups (median 3.8 months with tremelimumab plus durvalumab vs 4.1 months with sorafenib). The overall response rates (ORR) were 20% in the tremelimumab plus durvalumab treatment arm and 5% in the sorafenib arm.

References
Imjudo (tremelimumab-actl) injection [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 10/2022.

FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma