Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha‐fetoprotein after sorafenib in REACH and REACH‐2

Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH‐2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha‐fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post‐hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years).


| INTRODUC TI ON
Hepatocellular carcinoma (HCC) is a relatively common cancer associated with significant morbidity and mortality. [1][2][3] In eastern Asia and Africa, HCC usually presents in younger patients, whereas in Japan and Western countries, HCC generally presents at an older age. This is partly because of differences in aetiology across regions. The risk of HCC increases with advancing age. [1][2][3] Different definitions exist to define "elderly"; however, 65 years is most commonly used; in recent HCC clinical trials, patients ≥75 years of age were considered. 4 In developed countries, increasing life expectancy is leading to a progressively aging population, resulting in higher numbers of elderly patients with HCC. 4,5 Elderly patients are often fragile, have comorbidities, altered drug pharmacokinetics and a poor prognosis. Treatment of elderly patients with HCC remains an unresolved clinical challenge, with increasing unmet need, especially for those ≥70 years of age. [4][5][6] Despite recently available data supporting the efficacy of multitargeted tyrosine kinase inhibitors (mTKIs), [4][5][6][7][8][9] single-agent immune checkpoint inhibitors (CPI) 10,11 or CPI in combination with an anti-angiogenic agent, 12 data for elderly patients are scarce. Of note, where data are available, the use of mTKIs is associated with significant adverse effects 4,6,13 or unknown toxicity profiles 8,9 in this population. Most global trials enrol younger or fit older adults, which limits the application of their results to older adults in clinical practice. Additionally, most HCC treatment guidelines offer no specific guidance for the treatment of elderly patients owing to limited evidence-based data. 4,5 Ramucirumab, a human immunoglobulin G1 monoclonal antibody that inhibits ligand activation of vascular endothelial growth factor receptor 2 (VEGFR2), was assessed for efficacy and safety vs placebo in patients with HCC after prior sorafenib in two global, randomized, double-blind, placebo-controlled phase III clinical trials (REACH and REACH-2). 14 Index (FHSI)-8. 14 Ramucirumab had an acceptable safety profile in these trials and therefore may be considered for HCC treatment in elderly patients. This post-hoc analysis evaluated the efficacy, safety and patient-reported outcomes (PROs) for ramucirumab in three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years of age) using the pooled data of patients with baseline AFP ≥400 ng/mL from the REACH and REACH-2 trials.

| Study design and population
The REACH and REACH-2 study designs have been published elsewhere. 14

| Treatment and procedures
Patients were randomly assigned (1:1 ratio in REACH; 2:1 ratio in REACH-2) to receive ramucirumab or placebo. In REACH, randomization was stratified by geographical region and aetiology of liver disease (hepatitis B vs hepatitis C vs other aetiologies). 15 In REACH-2, randomization was stratified by macrovascular invasion, geographical region and ECOG performance status. 14 Patients received ramucirumab (8 mg/kg) or placebo intravenously on Day 1 of each 14-day cycle plus best supportive care until disease progression, unacceptable toxicity or withdrawal of consent. Tumour response was assessed every 6 weeks during the first 6 months and every 9 weeks thereafter, according to Response Evaluation Criteria in Solid Tumors v1.1. The FHSI-8 was used to assess PROs. 16 Estimates of exposure (minimum concentration after administration of first dose [C min ,1]) were calculated using population pharmacokinetic analysis. 17

| Statistical analyses
This post-hoc analysis of pooled individual patient data (stratified by study) from REACH (patients with baseline AFP ≥ 400 ng/mL) and REACH-2 assessed the efficacy, safety and health-related quality of life outcomes for ramucirumab vs placebo in three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years of age). Efficacy was assessed in all randomized patients with baseline AFP ≥ 400 ng/mL.

| Demographic and baseline clinical characteristics
This subgroup analysis included 542 patients with AFP ≥400 ng/ mL (REACH: 250; REACH-2:292). All randomized patients received study treatment and were included in the efficacy and safety analyses. Baseline characteristics were generally similar between treatment arms and across the age subgroups (Table 1).
However, patients <65 years of age had higher incidences of hepatitis B and extrahepatic spread and higher median baseline AFP, whereas steatohepatitis was higher in the older subgroups (Table 1).

| Treatment exposure
The median relative dose intensity (RDI) of ramucirumab was consistently high (≥97.8%) in the three age subgroups (Table 2). Similarly, TA B L E 1 Baseline demographic and disease characteristics of the pooled REACH (AFP ≥400 ng/mL) and REACH-2 age subgroups the estimated mean minimum ramucirumab concentration (C min ,1) was comparable across the age subgroups (≥24.1 ng/mL) ( Table S1).
The proportion of patients requiring a ramucirumab dose adjustment was similar in the subgroups (<65 years: 31% vs ≥65 to <75 years: 36.6% vs ≥75 years: 38.5%) ( Table 2). Most dose adjustments were as a result of TEAEs. The median number of treatment cycles was 5, 5 and 7 in the <65, ≥65 to <75 and ≥75 years subgroups respectively.
Common TEAEs leading to dose adjustments in the ramucirumab arm were proteinuria in patients <65 years of age (4.1%) and hypertension in the two older subgroups (7.5% and 5.8%). Adverse events of special interest in the ramucirumab arm, based on its known safety profile, were comparable between the age subgroups (Table S3).

| Patient-reported outcomes
A trend for a delay in the deterioration of symptoms as measured by FHSI-8 was observed in the ramucirumab arm across all age subgroups but was not statistically significant. Median TtD was numerically longer in the ramucirumab vs the placebo arms in all three age subgroups ( Figure 4). Overall, ramucirumab had an acceptable safety profile across all three age subgroups, which is consistent with the previously reported safety profile of ramucirumab. 20 The higher incidence of grade ≥3 TEAEs (ie hypertension and fatigue) with ramucirumab in the ≥75 years subgroup may be owing to slightly longer treatment duration in this subgroup, allowing more time for recording TEAEs.

| D ISCUSS I ON
Use of mTKIs in elderly patients is associated with significant adverse effects 4,6,18 or unknown toxicity profiles. 8,9 Ramucirumab may offer a favourable safety profile for elderly patients with HCC, particularly for hand-foot syndrome, diarrhoea and fatigue, which are common side effects of mTKIs in elderly patients. 13 Additionally, the median RDI (≥97.8%) and treatment duration for ramucirumab in the current analyses were maintained irrespective of age, suggesting good treatment administration compliance, and the proportion of patients requiring a dose adjustment in the ramucirumab arm was similar between the age subgroups, indicating favourable treatment tolerance.
The aetiology of HCC may affect treatment response. 4,6 In this analysis, patients <65 years of age were more likely to have hepatitis B-related HCC vs older patients, who were more likely to have hepatitis C-related HCC. This is consistent with previously described characteristics of HCC in young and elderly patients. [4][5][6]21 Longer treatment duration for ramucirumab in the ≥75 years of age subgroup than in the younger subgroups may be attributed to lower AFP levels in the ≥75 years subgroup, which are associated with less aggressive tumour types and a better prognosis (Tables 1 and 2).
Finally, different geographical regions may be associated with different patient characteristics for age, HCC aetiology and AFP levels and, therefore, different treatment outcomes.
Comprehensive PRO data are lacking from randomized controlled trials of targeted therapy in HCC. 22 Some recent phase III trials in HCC have reported on quality of life; however, the use of different methodologies in these studies makes their interpretation difficult. 8,9,22 In this analysis, the effect of ramucirumab on PROs did not appear to be influenced by age, with a trend towards a delay in deterioration of symptoms (as assessed by FHSI-8) in all three age subgroups.
One of the strengths of this study is the use of pooled individual patient data from two similarly designed phase III trials, which substantially increased the sample size. Additionally, the age subgroups were prespecified. However, several aspects of this analy- trials for cancer treatments should be performed using appropriate geriatric assessments. 23 Therefore, these results must be interpreted with caution in clinical practice. Furthermore, the implications of these results in elderly non-Japanese Asian patients remain to be defined because of their underrepresentation in this study.
In conclusion, this post-hoc subgroup analysis in patients with HCC and elevated AFP, who had progressed on or were intolerant to sorafenib, showed that ramucirumab had a survival benefit with a trend for a delay in deterioration of PROs, irrespective of age, including patients ≥75 years of age. The overall safety profile of ramucirumab was comparable across the three age subgroups, with a high median RDI and similarly maintained treatment duration irrespective of age. Therefore, ramucirumab may offer an active and well-tolerated treatment option for elderly patients with HCC and elevated AFP levels. This post-hoc analysis provides valuable information for the treatment algorithm of elderly patients with HCC, especially those ≥75 years of age.

ACK N OWLED G EM ENTS
Medical writing assistance was provided by Sandra Kurian, MPharm, Note: The data for any dose adjustment were obtained from exposure analysis and the data for dose adjustments owing to TEAEs were obtained from safety analysis, and the difference between both sets of data is owing to different definitions used in the respective analyses. Abbreviations: AFP, alpha-fetoprotein; max, maximum; min, minimum; TEAE, treatment-emergent adverse event.
F I G U R E 1 Kaplan-Meier plots of OS for patients receiving ramucirumab or placebo in the pooled REACH (patients with AFP ≥400 ng/mL) and REACH-2 age subgroups:

E TH I C S A PPROVA L A N D PATI E NT CO N S E NT S TAT E M E N T
The ethical review board of each participating site in both REACH and REACH-2 trials approved the respective study protocol and all patients provided informed consent before treatment.