On October 21, 2022, the FDA approved tremelimumab (Imjudo; AstraZeneca), a CTLA-4 monoclonal antibody, in combination with durvalumab (Imfinzi; AstraZeneca), a PD-L1 inhibitor, for the treatment of adults with unresectable hepatocellular carcinoma (HCC). The FDA granted tremelimumab an orphan drug designation for this indication.
The efficacy of this new dual immunotherapy combination was evaluated in the HIMALAYA study, a randomized, open-label, multicenter clinical trial of patients with unresectable HCC who had not received systemic treatment for HCC. Patients were randomized to 1 of 4 arms: (1) tremelimumab 300 mg as a single intravenous (IV) infusion in combination with durvalumab 1500 mg IV, followed by durvalumab 1500 mg IV every 4 weeks; (2) durvalumab 1500 mg IV every 4 weeks; (3) sorafenib (Nexavar) 400 mg, orally, twice daily; or (4) tremelimumab 75 mg every 4 weeks plus durvalumab every 4 weeks. Treatment continued until disease progression or unacceptable adverse events.
The FDA approval of this combination was based on a comparison of 782 patients who were randomized to the tremelimumab plus durvalumab arm versus those in the sorafenib arm.
The main efficacy outcome was overall survival (OS). Tremelimumab plus durvalumab in arm 1 showed significant and meaningful improvements in OS compared with sorafenib (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.66-0.92; 2-sided P = .0035). The median OS was 16.4 months (95% CI, 14.2-19.6) versus 13.8 months (95% CI, 12.3-16.1), respectively.
Additional efficacy outcomes included progression-free survival (PFS) and overall response rate (ORR). The median PFS was 3.8 months (95% CI, 3.7-5.3) with the combination versus 4.1 months (95% CI, 3.7-5.5) with sorafenib (HR, 0.90). The ORR was 20.1% (95% CI, 16.3-24.4) with the combination versus 5.1% (95% CI, 3.2-7.8) with sorafenib.
The most common (≥20%) adverse events with the immunotherapy combination were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.