Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials.

Abstract

PURPOSE:

Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials.

PATIENTS AND METHODS:

Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated.

RESULTS:

Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49-0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40-0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit.

CONCLUSIONS:

Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.

• Authors: Josep M Llovet, Amit G Singal, Augusto Villanueva, Richard S Finn, Masatoshi Kudo, Peter R Galle, Masafumi Ikeda, Sophie Callies, Louise M McGrath, Chunxiao Wang, Paolo Abada, Ryan C Widau, Elena Gonzalez-Gugel, Andrew X Zhu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 11 Pg. 2297-2305 (06 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35247922 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• alpha-Fetoproteins

Topics

• Antibodies, Monoclonal, Humanized
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Clinical Trials, Phase III as Topic
• Humans
• Hypertension
• Liver Neoplasms (drug therapy, pathology)
• Prognosis
• Randomized Controlled Trials as Topic
• alpha-Fetoproteins
• Ramucirumab