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.

Trial registration: ClinicalTrials.gov NCT01140347 NCT02435433.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.

Kaplan–Meier plots of OS by baseline AFP for ramucirumab versus placebo. Patients with AFP ≥4,081.5 ng/mL (A) and AFP <4,081.5 ng/mL (B). Kaplan–Meier analysis for OS shown by elevated AFP status (≥4,081.5 vs.<4,081.5 ng/mL) by treatment arm. *Median AFP used to define a very aggressive phenotype in patients with very high AFP. Pinteraction = 0.5106, not significant. AFP, alpha-fetoprotein; CI, confidence interval; HR, hazard ratio; mos, months; N, total number of patients; PL, placebo; RAM, ramucirumab.

Figure 2.

Kaplan–Meier plots of OS by etiology for ramucirumab versus placebo. Patients with viral etiology (A) and nonviral etiology (B). Kaplan–Meier analysis for OS shown by etiology status (HBV and HBC vs. nonviral) by treatment arm. Pinteraction = 0.2899, not significant. CI, confidence interval; HR, hazard ratio; mos, months; N, total number of patients; PL, placebo; RAM, ramucirumab; PL, placebo.

Figure 3.

Kaplan–Meier plots of OS (A and B) and PFS (C and D) by TE-hypertension for ramucirumab versus placebo. Kaplan–Meier analysis for OS and PFS shown by TE-hypertension status by treatment arm: ramucirumab (Red) versus placebo (Gray). Patients with (A and C) and without (B and D) TE-hypertension. OS Pinteraction = 0.0392, significant. CI, confidence interval; HR, hazard ratio; mos, months; N, total number of patients; PL, placebo; RAM, ramucirumab; TE, treatment-emergent.

Figure 4.

Conditional landmark analysis for OS according to TE-hypertension (Pinteraction: 0.0942): survival time from 2 months until death. Kaplan–Meier plots of OS shown by TE-hypertension status (survival time from 2 months until death): ramucirumab (red) versus placebo (gray). Patients with (A) and without (B) TE-hypertension OS Pinteraction = 0.0001, significant. CI, confidence interval; HR, hazard ratio; mos, months; N, total number of patients; PL, placebo; RAM, ramucirumab; TE, treatment-emergent.

Figure 5.

Kaplan–Meier survival curves for the pooled efficacy population by RAM Cmin,1 quartiles versus PL. Unadjusted data are shown for OS. All included patients had a baseline AFP of ≥400 ng/mL. Patients with missing baseline covariate factors were omitted from the analysis. HRs were adjusted for macrovascular invasion (CRF), ECOG PS at baseline, baseline AFP (ng/mL) (log-transformed). Quartiles: Q1 = <25%; Q2 = 25%–<50%; Q3 = 50%–<75%; Q4 = ≥75%. AFP, alpha-fetoprotein; CI, confidence interval; CRF, case report form; ECOG PS, Eastern Cooperative Oncology Group performance score; HR, hazard ratio; N, total number of patients; Q1–Q4, quartiles 1 through 4; RAM, ramucirumab.