In a randomized expansion phase of a phase I/II study reported in the Journal of Clinical Oncology, Robin Kate Kelley, MD, and colleagues found that a novel regimen consisting of a single priming dose of tremelimumab in combination with durvalumab was associated with good outcomes in patients with unresectable hepatocellular carcinoma whose disease progressed on, who were intolerant of, or who refused sorafenib treatment.

Robin Kate Kelley, MD

Study Details

In the open-label trial, 332 patients enrolled from sites in 9 countries as of February 2020 were randomly assigned to receive:

• Tremelimumab at 300 mg plus durvalumab 1,500 mg at one dose each during the first cycle followed by durvalumab at 1,500 mg once every 4 weeks (T300+D group, n = 75)
• Durvalumab alone at 1,500 mg once every 4 weeks (n = 104)
• Tremelimumab alone at 750 mg once every 4 weeks for seven doses and then once every 12 weeks (n = 69)
• Tremelimumab at 75 mg once every 4 weeks plus durvalumab at 1,500 mg once every 4 weeks for four doses followed by durvalumab at 1,500 mg once every 4 weeks (T75+D group, n = 84).

Efficacy Outcomes

On blinded independent central review, objective response rates were 24.0% in the T300+D group, 10.6% in the durvalumab group, 7.2% in the tremelimumab group, and 9.5% in the T75+D group. Median durations of response were not reached, 11.12 months, 24.0 months, and 13.2 months, respectively. Early expansion of CD8+ lymphocytes was associated with response in all groups, with the highest proliferating CD8+ lymphocyte levels observed in the T300+D group.

Median progression-free survival in the four groups was 2.2, 2.1, 2.7, and 1.9 months, respectively. Median overall survival was 18.7 months (95% CI = 10.8–27.3 months), 13.6 months (95% CI = 8.7–17.6 months), 15.1 months (95% CI = 11.3–20.5 months), and 11.3 months (95% CI = 8.4–15.0 months) in the four groups, respectively.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 37.8% of the T300+D group, 20.8% of the durvalumab group, 43.5% of the tremelimumab group, and 24.4% of the T75+D group.

Serious treatment-related adverse events occurred in 17.6%, 10.9%, 24.6%, and 14.6% of patients. Treatment-related adverse events of any grade requiring systemic steroid treatment occurred in 24.3%, 9.9%, 26.1%, and 24.4%, respectively. Immune-mediated adverse events of any grade occurred in 31.1%, 15.8%, 24.6%, and 26.8%, respectively. Discontinuation of therapy due to treatment-related adverse events occurred in 10.8%, 7.9%, 13.0%, and 6.1% of patients. Death considered possibly related to treatment occurred in one, three, none, and one patient(s), respectively.

The investigators concluded: “All regimens were found to be tolerable and clinically active; however, the T300+D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with objective response rate of the T300+D regimen further support its continued evaluation in hepatocellular carcinoma.”

Dr. Kelley, of the Department of Medicine (Hematology/Oncology), University of California, San Francisco, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.