From the Journals

Priming tremelimumab dose regimen shows promising benefit-risk profile in HCC


 

FROM THE JOURNAL OF CLINICAL ONCOLOGY

In patients with unresectable hepatocellular carcinoma (HCC), a single, priming dose of tremelimumab followed by durvalumab showed reduced toxicity, compared with other regimens containing tremelimumab, and the greatest efficacy, compared with durvalumab and tremelimumab as monotherapy or in combination.

The novel regimen featuring a single, priming dose of tremelimumab “displayed the most encouraging benefit-risk profile,” wrote Robin Kate Kelley, MD, of the University of California, San Francisco, and colleagues in the Journal of Clinical Oncology. “These findings suggest that a single dose of tremelimumab may be sufficient to activate the tumor-fighting potential of the immune system.”

The incidence of HCC has been increasing worldwide over the last 20 years. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth-leading cause of cancer deaths in the United States. The 1-year survival rates in patients with HCC are less than 50%.

Atezolizumab plus bevacizumab gained regulatory approval in 2020 for the treatment of unresectable HCC. Several other immunotherapy-containing regimens are being evaluated, including immune checkpoint inhibitors combined with antiangiogenic agents. Immune checkpoint inhibitors – programmed death–ligand 1 and cytotoxic T-lymphocyte–associated antigen-4 – have shown promise in unresectable HCC, but they are insufficient as single agents and anti–CTLA-4 can be accompanied by challenging toxicities.

In this phase 1/2 study, researchers evaluated tremelimumab (anti–CTLA-4) and durvalumab (anti–PD-L1) as monotherapies and in combination, including a regimen featuring a single, priming dose of tremelimumab and durvalumab followed by durvalumab every 4 weeks. A total of 332 patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive one of the four regimens. The primary endpoint was safety.

While the priming doses regimen showed the best benefit-risk profile, all regimens were found to be tolerable and clinically active.

Specifically, in patients on the priming dose, durvalumab, tremelimumab and combination regimes, grade 3 or higher treatment-related adverse events occurred in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. For secondary endpoints, objective response rates were 24.0%, 10.6%, 7.2%, and 9.5%, respectively. The median overall survival was 18.7, 13.6, 15.1, and 11.3 months, respectively.

The priming dose regimen stimulated CD8+ T-cell production, which the authors suggested enhanced response and efficacy.

This novel regimen “may offer distinct differentiating features beyond demonstration of durable objective responses and promising overall survival, including a favorable safety profile with a relatively low steroid requirement, rare [antidrug antibody] formation, and a single, priming dose of tremelimumab followed by monthly durvalumab administration schedule,” the authors wrote. “Moreover, the absence of an antiangiogenic partner allows for treatment of patients who are contraindicated for antiangiogenics because of bleeding risks or comorbidities like cardiovascular disease.”

Another study, recently published in the Journal of Clinical Oncology, showed that donafenib was superior to sorafenib in improving overall survival, along with improved safety and tolerability, rendering it a potential first-line monotherapy for patients with advanced HCC.

The tremelimumab/durvalumab study was funded by AstraZeneca.

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