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. 2024 Apr 8;6(6):101065.
doi: 10.1016/j.jhepr.2024.101065. eCollection 2024 Jun.

Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multicenter real-world study with focus on bleeding and thromboembolic events

Najib Ben Khaled  1 , Marie Möller  2 , Leonie S Jochheim  3 , Catherine Leyh  3 , Ursula Ehmer  4 , Katrin Böttcher  4 , Matthias Pinter  5 , Lorenz Balcar  5 , Bernhard Scheiner  5 , Alexander Weich  6 , Hans Benno Leicht  2 , Valentina Zarka  2 , Liangtao Ye  1   7 , Julia Schneider  1 , Ignazio Piseddu  1 , Osman Öcal  8 , Monika Rau  2 , Friedrich Sinner  9 , Marino Venerito  9 , Simon Johannes Gairing  10 , Friedrich Förster  10 , Julia Mayerle  1 , Enrico N De Toni  1 , Andreas Geier  2 , Florian P Reiter  2
Affiliations

Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multicenter real-world study with focus on bleeding and thromboembolic events

Najib Ben Khaled et al. JHEP Rep. .

Abstract

Background & aims: Atezolizumab/bevacizumab (atezo/bev) and lenvatinib have demonstrated efficacy as first-line therapies for hepatocellular carcinoma (HCC). However, vascular endothelial growth factor (VEGF) inhibition with these therapies may be associated with the risk of bleeding and thromboembolic events. In this study, we evaluated the efficacy and safety with focus on the bleeding and thromboembolic events of atezo/bev vs. lenvatinib in a large, multicenter real-world population.

Methods: This study is based on HCC cohorts from seven centers in Germany and Austria. Incidences of bleeding or thromboembolic events and efficacy outcomes were assessed and compared.

Results: In total, 464 patients treated with atezo/bev (n = 325) or lenvatinib (n = 139) were analyzed. Both groups were balanced with respect to demographics, presence of liver cirrhosis, and variceal status. Duration of therapy did not differ between groups. Within 3 months of therapy, bleeding episodes were described in 57 (18%) patients receiving atezo/bev compared with 15 (11%) patients receiving lenvatinib (p = 0.07). Variceal hemorrhage occurred in 11 (3%) patients treated with atezo/bev compared with 4 (3%) patients treated with lenvatinib (p = 0.99). Thromboembolic events were reported in 19 (6%) of patients in the atezo/bev cohort compared with 5 (4%) patients in the lenvatinib cohort (p = 0.37). In addition, incidence of overall bleeding, variceal hemorrhage, and thromboembolic events did not differ significantly in patients who received either atezo/bev or lenvantinib for 6 months.

Conclusions: Safety considerations related to bleeding and thromboembolic events may not be helpful in guiding clinical decision-making when choosing between atezo/bev and lenvatinib.

Impact and implications: The inhibition of VEGF by current first-line therapies for HCC, such as atezolizumab/bevacizumab or lenvatinib, may be associated with the risk of bleeding and thromboembolic events. Studies comparing the incidence of these side effects between atezolizumab/bevacizumab and lenvatinib, which are preferred treatments over sorafenib for HCC, are needed. Differences in this side effect profile may influence the choice of first-line therapy by treating physicians. Because no significant differences were observed regarding bleeding or thromboembolic events between both therapies in the present study, we conclude that safety considerations related to these events may not be helpful in guiding clinical decision-making when choosing between atezolizumab/bevacizumab and lenvatinib.

Keywords: Hepatocellular carcinoma; Immunotherapy; Tyrosine kinase inhibition.

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Conflict of interest statement

NBK has received reimbursement of meeting attendance fees and travel expenses from EISAI and lecture honoraria from the Falk Foundation and AstraZeneca. UE has received honoraria for lectures from AstraZeneca, the Falk Foundation, Ipsen, and Novartis and travel support from AstraZeneca and Biotest. She has served as an advisory board or steering committee member to AstraZeneca, Bayer, EISAI, and MSD. KB has received honoraria for lectures from Ipsen. MP served as a speaker and/or consultant and/or advisory board member for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche and received travel support from Bayer, Bristol-Myers Squibb, Ipsen, and Roche. BS received grant support from AstraZeneca and Eisai; speaker honoraria from Eisai; and travel support from AbbVie, AstraZeneca, Ipsen and Gilead. OÖ received honorarium from Bayer. MV has received honoraria for her speaker, consultancy, and advisory roles from Amgen, AstraZeneca, Bayer, BMS, EISAI, Ipsen, Lilly, Merck Serono, MSD, Nordic Pharma, Roche, Servier, and Sirtex. SJG has received travel expenses from Gilead and Ipsen. FF has received honoraria for lectures from AstraZeneca, MSD, Pfizer, and Roche and reimbursement of meeting attendance fees and travel expenses from Merck KGaA and Servier. He has served as an advisory board or steering committee member to AstraZeneca, BMS, Eisai, and Roche. ENDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, Ipsen, and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, AstraZeneca, BMS, Bayer, Celsion, and Roche and lecture honoraria from BMS and Falk Foundation. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche. AG is an advisory board or steering committee member to AbbVie, Alexion, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, and Sequana and a speaker for Advanz. FPR has received honoraria for lectures, consulting activities, and travel support from the Falk Foundation, AbbVie, Gilead, Ipsen, AstraZeneca, Roche and Novartis. All other authors report no conflicts of interest. MM, LSJ, CL, LB, AW, HBL, VZ, LY, JS, IP, MR, FS, and JM have nothing to declare. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Study flowchart. HCC, hepatocellular carcinoma; mOS, median overall survival.
Fig. 2
Fig. 2
Baseline characteristics. (A) Platelets and (B) spleen size as surrogates of portal hypertension were not different between the groups (platelets: p = 0.82; spleen size: p = 0.51). (C) Time on therapy was reported as 214.6 ± 193.9 days in the atezo/bev group and 195.9 ± 248.4 days in the lenvatinib group, which was not significantly different (p = 0.13). For comparison of both groups, the normal distribution of variables was assessed using the Shapiro–Wilk test and through inspection of qq-plots. Continuous variables were compared using either the t test or the Mann–Whitney U test, depending on their distribution. atezo/bev, atezolizumab/bevacizumab.
Fig. 3
Fig. 3
Efficacy analysis of atezo/bevvs.lenvatinib in first-line therapy. (A) mOS, (B) mPFS, and (C) best response according to local investigator evaluation were assessed in patients receiving either atezo/bev or lenvatinib in the first-line situation. Kaplan–Meier analysis was performed to calculate the median survival. Survival was compared using the log-rank test. Fisher’s exact test was used to compare response rates. atezo/bev, atezolizumab/bevacizumab; CR, complete response; DCR, disease control rate; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
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