Abstract CT185: Assessment of the impact of anti-drug antibodies on PK and clinical outcomes with atezolizumab + bevacizumab in HCC
Authors: Galle Peter R. , Finn Richard S. , Cheng Ann-Lii , Bernaards Coen , Shemesh Colby S. , Vilimovskij Alexandr , Verret Wendy J. , Stanzel Sven F. , Ma Ning , Ducreux Michel , Zhu Andrew X. 
Published: July 2021

Abstract
Background: Atezo + bev is the standard of care for pts with unresectable HCC and no prior systemic therapy. We report on post hoc exploratory analyses of the immune response to atezo and the impact assessment of ADAs on PK and clinical outcomes in the Ph 3 study IMbrave150. Methods: ADAs were assessed using an industry-standard validated test and sampling frequencies. We report tx-emergent ADA incidence and adjusted efficacy by ADA status at landmark Wk 6, adjusted for imbalances in BL health and disease characteristics using IPW. PK and safety by ADA status were also evaluated. Results: An assessment of BL characteristics in ADA+ (n=94) vs ADA− (n=224) pts showed a higher rate of negative HCC prognostic factors, including CPS A6, BCLC Stage C and MVI in ADA+ pts. ADA− pts had a higher rate of EHS. There was considerable overlap in exposure distributions across ADA+ and ADA− pts. Despite the trend for a 38.4% lower Cycle 1 Cmin in ADA+ vs ADA− pts, at any time during tx, 93% of ADA+ and 99% of ADA− pts had Cmin ≥6 μg/mL (target exposure). Per OS adjustment modeling analyses: HR=0.96 (95% CI 0.62-1.48) for ADA+ (n=61.7) and HR=0.55 (95% CI 0.41-0.74) for ADA− pts (n=242.3) with atezo + bev vs sor. Adjusted PFS and ORR results were similar between ADA subgroups (table). Among ADA+ (n=88) and ADA− pts (n=227), G3-4 AEs occurred in 64% and 53% of pts, G5 AEs in 8% and 3% of pts and SAEs in 52% and 32% of pts, respectively. Conclusions: Most pts achieved atezo target exposure regardless of ADAs. ADA+ pts had a similar OS while ADA− pts had improved OS with atezo + bev vs sor. PFS and ORR benefits vs sor were clinically meaningful and similar between ADA subgroups. While there were some numerical differences in AE rates between ADA+ and ADA− pts, ADAs did not have a clinically significant effect on the incidence or severity of AEs. In ITT pts, a statistically significant OS benefit and overall favorable benefit-risk balance with atezo + bev have been established in HCC, and the combination has been approved in over 60 countries.
PFS- and ORR-adjusted analyses at landmark Wk 6ADA+ADA−IRF PFS per RECIST 1.1n51223HR (95% CI) for atezo + bev vs sor0.59 (0.39-0.91)0.60 (0.47-0.77)IRF ORR per RECIST 1.1n61.7232.3ORR difference for atezo + bev vs sor (95% CI), %19 (6-32)19 (10-28)318 pts were evaluable post BL and therefore were included in these analyses. Efficacy data cutoff: Aug 31, 2020. Safety data cutoff: Aug 29, 2019. Methods and results from IMbrave150 (Ph 3; NCT03434379) have been published (Finn et al NEJM 2020). ADA, anti-drug antibody; AE, adverse event; atezo, atezolizumab; BCLC, Barcelona Clinic Liver Cancer; bev, bevacizumab; BL, baseline; Cmin, minimum blood plasma concentration; CPS, Child-Pugh score; EHS, extrahepatic spread; G, grade; HCC, hepatocellular carcinoma; IPW, inverse probability weighting; IRF, independent review facility; ITT, intent to treat; MVI, macrovascular invasion; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Ph, Phase; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; sor, sorafenib; tx, treatment.
Citation Format: Peter R. Galle, Richard S. Finn, Ann-Lii Cheng, Coen Bernaards, Colby S. Shemesh, Alexandr Vilimovskij, Wendy J. Verret, Sven F. Stanzel, Ning Ma, Michel Ducreux, Andrew X. Zhu. Assessment of the impact of anti-drug antibodies on PK and clinical outcomes with atezolizumab + bevacizumab in HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT185.