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Impact of relative dose intensity of bevacizumab in first-line treatment of hepatocellular cancer
Background
Atezolizumab-Bevacizumab (AB) is the current standard of care for treatment of unresectable hepatocellular cancer (HCC), with the recommended dosage of bevacizumab at 15mg/kg. Notable adverse events with an incidence of >20% in the AB group include hypertension and proteinuria, consistent with bevacizumab’s distinctive toxicity profile. In the real-world, many physicians choose to use a lower dose of bevacizumab upfront based on patients' comorbidities, anticipated toxicities, and cost considerations. Early phase II data comparing 5mg/kg versus 10mg/kg of bevacizumab in advanced HCC suggested no difference in outcomes, though they were not powered to examine this. In other tumour types like colon cancer, the standard dose of bevacizumab is lower, though there is some data describing higher dose intensity of bevacizumab and improved survival on progression. A relative dose intensity (RDI) of ≥70% is correlated with better overall survival (OS) and radiological responses for other first-line therapies for HCC like Lenvatinib. We sought to examine the dose effect of bevacizumab in the use of AB for HCC treatment.
Methods
We retrospectively analysed data on patients treated at a single-centre in Singapore who received at least one dose of AB for unresectable HCC between September 2020 and December 2021. RDI over the 1st two doses was calculated as the cumulative dose for those two cycles divided by the weight-based standard dose of bevacizumab. We evaluated the association of RDI ≥70% compared to RDI < 70%, with OS, progression free survival (PFS), and response rate (by RECIST v1.1).
Results
57 patients were included, with a mean age of 65 years. All were ECOG 0 and majority were male (96.49%), Chinese (85.69%), had underlying viral hepatitis (56.14%) and were Child’s-Pugh A (98%) on treatment initiation. 65.91% had BCLC C disease, while the rest had BCLC B disease. Majority used AB as 1st line of systemic therapy (82.46%), and 42.11% achieved a relative dose intensity ≥70%. Patients who had RDI ≥70% were not significantly different from those with RDI < 70% in terms of baseline characteristics such as age, gender, race, cirrhosis etiology, BCLC status, or line of usage of AB (1st or later). Response rates (25.0% vs 18.2%, p = 0.742) and disease control rates (43.8% vs 54.6%, p = 0.435) did not differ between those with RDI ≥70% or < 70%. Median OS was 10.99 months (95% CI, 5.83-NR) in the RDI ≥70% group and did not differ significantly from 10.76 months (95% CI, 8.45-NR) in the RDI < 70% group (HR 0.94; 95% CI, 0.404-2.215). Median PFS was likewise similar in both groups, at 4.04 months (95% CI, 1.01-7.76) in RDI ≥70% and 3.09 months (95% CI, 1.55-NR) in RDI < 70% (HR 0.83; 95% CI, 0.45-1.70). Both OS and PFS remained not significantly different on adjustment for age, gender, BCLC status, viral/non-viral etiologies, and line of usage of AB. Frequency of common adverse events were similar between both groups.
Conclusions
We demonstrated that a lower dose of bevacizumab at < 70% RDI achieved similar radiological and survival outcomes as ≥70% when given in combination with atezolizumab for advanced HCC. Use of reduced dose bevacizumab can be considered to reduce cost and toxicity without significantly affecting treatment outcomes. This should be explored further in a prospective setting.
Legal entity responsible for the study
The author.
Funding
Has not received any funding.
Disclosures
D. Tai: Advisory / Consultancy: Bms, Ipsen, Norvartis. J. Jie Xin Lee: Advisory / Consultancy: Eisai, Ipsen, Bayer; Research grant / Funding (institution): Bayer. The author has declared no conflicts of interest.
