Hypertension as an Adverse Event Potentially Impacting the Therapeutic Efficacy of Atezolizumab Plus Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma

Abstract

Background and aim: Atezolizumab plus bevacizumab is used as a first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, the relationship between its adverse events (AEs) and treatment efficacy remains unclear. In this study, we aimed to clarify this association.

Methods: This study included 187 patients with uHCC treated with atezolizumab plus bevacizumab as first-line therapy at 19 affiliated hospitals in the Osaka Liver Forum. A landmark analysis was conducted to address biases in AE incidence.

Results: The objective response and disease control rates were 28.2% and 69.6%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 7.4 and 24.6 months, respectively. Among the 187 patients, 178 (95.2%) experienced at least one AE, with proteinuria being the most common (41.7%), followed by hypertension (34.8%) and fatigue (30.5%). All three major AEs had a median onset time of 6 weeks. We set the landmark point at Week 9 after treatment initiation, considering that the onset time for most AEs was within 9 weeks. In the landmark analysis, multivariable analysis identified the absence of bevacizumab interruption within 9 weeks and the occurrence of hypertension within 9 weeks as predictors of prolonged PFS. mALBI Grade 1/2a, the occurrence of hypertension, and the absence of fatigue and rash within 9 weeks were associated with prolonged OS. These results were consistent with those from the 6-week landmark analysis.

Conclusions: Patients with hypertension occurring as an AE within 9 weeks are expected to have better PFS and OS with atezolizumab plus bevacizumab therapy for uHCC.

Keywords: adverse event; irAE; landmark analysis.

FIGURE 1

Therapeutic responses according to RECIST v1.1 (A), progression‐free survival (B), and overall survival (C) in all patients. CR, complete response; PD, progressive disease; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease.

FIGURE 2

Comparisons of PFS in the landmark analysis according to bevacizumab interruption within 9 weeks (A) or the presence of hypertension as an AE occurring within 9 weeks (B). The total number of PFS events was 98. The median PFS (95% confidence interval) was 11.0 (9.9–12.0) months in patients without bevacizumab interruption and 7.4 (2.0–12.8) months in those with. For hypertension, the median PFS was 11.4 (10.1–12.7) months in patients with hypertension as an AE and 9.1 (7.7–10.4) months in those without. AE, adverse event; PFS, progression‐free survival.

FIGURE 3

Comparisons of OS in the landmark analysis according to mALBI grade (A), the presence of hypertension (B), fatigue (C), or rash (D) as AEs occurring within 9 weeks. The total number of OS events was 55. The median OS (95% confidence interval) was 33.2 (23.8–42.5) months in patients with mALBI Grade 1 or 2a and 13.1 (5.9–20.3) months in those with mALBI Grade 2b or 3. For hypertension, the median OS was not reached in patients with hypertension as an AE and 24.6 (14.9–34.3) months in those without. For fatigue, the median OS was 33.2 (25.2–41.1) months in patients without fatigue as an AE and 11.4 (7.7–15.0) months in those with. For rash, the median OS was 33.2 (25.2–41.1) months in patients without rash as an AE and 11.7 (0.3–23.0) months in those with. AE, adverse event; mALBI, modified albumin‐bilirubin; OS, overall survival.