Baseline patient characteristics
Baseline characteristics of these patients are presented in Table 1. The median ALBI score was −2.01 (range, −2.99 to −1.60) and baseline modified ALBI grades were 1, 2a, and 2b in 1 (6.2%), 2 (12.5%), and 13 patients (81.3%), respectively. HCC progression at the beginning of ramucirumab therapy was classified as BCLC stage B and C in 8 (50.0%) and 8 patients (50.0%), respectively. The major portal invasion was present in 4 patients (25.0%). Extrahepatic metastasis was present in 6 patients (37.5%). The median AFP level was 2296.5 ng/mL (range, 447.2–34327.7 ng/mL). Second-line, third-line, and fourth-line treatments were administered in 4 (25.0%), 2 (12.5%), and 10 patients (62.5%), respectively. Among 4 patients who received ramucirumab as second-line, 3 patients were treated with lenvatinib as first-line and 1 patient participated in the double-blind clinical trial of lenvatinib or lenvatinib + pembrolizumab (NCT03713593). Among 2 patients who received ramucirumab as third-line, 1 patient was treated with sorafenib-lenvatinib and 1 patient received lenvatinib-sorafenib. Among 10 patients who received ramucirumab as fourth-line, 5 patients were treated with sorafenib-regorafenib-lenvatinib, 3 patients were treated with lenvatinib-sorafenib-regorafenib, 1 patient received sorafenib-lenvatinib-regorafenib, and 1 patient received axitinib + avelumab (NCT03289533), cabozantinib (NCT03586973), and lenvatinib.
Table 1. Baseline characteristics
|
n = 16
|
Age (years), median (range)
|
70 (53–88)
|
Sex, male/female (%)
|
11(68.8)/5 (31.2)
|
Body weight (kg), median (range)
|
60.6 (49.6–91.8)
|
Etiology HBV/HCV/alcohol/others (%)
|
3(18.8)/11(68.8)/1(6.2)/1(6.2)
|
Pretreatment ALBI score, median (range)
Pretreatment modified ALBI grade 1/2a/2b (%)
|
−2.01 (−2.99 to −1.60)
1 (6.2)/2 (12.5)/13 (81.3)
|
ECOG-PS, 0/1/2 (%)
|
7 (43.8)/9 (56.2)/0 (0)
|
BCLC stage, A/B/C (%)
|
0(0)/8(50.0)/8(50.0)
|
Major portal invasion, yes/no (%)
|
4 (25.0)/12 (75.0)
|
Extrahepatic spread, yes/no (%)
|
6 (37.5)/10 (62.5)
|
Baseline AFP concentration (ng/mL),
median (range)
|
2296.5 (447.2–34327.7)
|
Clinical course,
second-line/third line/fourth-line (%)
|
4 (25.0)/2 (12.5)/10 (62.5)
|
Therapeutic efficacy
At the end of the data cutoff (April 30, 2020), the median duration of follow-up was 3.7 months (range, 1.9–9.4 months). The median course of ramucirumab was 5 (range, 2–18). During the observation period, 12 patients discontinued ramucirumab therapy because of progressive disease (PD) (n = 4) or AEs (n = 8), and 3 patients died from HCC progression. There was no treatment-related death in this study. The median OS and PFS were not reached, and PFS at 3 months was 68.2% (Figure 1). In Child-Pugh A patients without macrovascular invasion (n = 8), 1 patient died from HCC progression with bone metastasis. Radiological evaluation after ramucirumab administration was performed in 11 patients. With regard to the best antitumor response according to modified RECIST, no patient had complete response (CR), 3 patients had partial response (PR), 6 patients had stable disease (SD), and 2 patients had PD. The objective response rate (ORR) was 27.2% and disease control rate (DCR) was 81.8%. With regard to the best antitumor response according to RECIST, no patient had CR, 1 patient had PR, 7 patients had SD, and 3 patients had PD. ORR and DCR were 9.1% and 72.7%, respectively. AFP level decreased in 4 of 13 patients within 8 weeks after ramucirumab administration. Among 4 patients with decreased AFP, 2 patients showed PR and the remaining 2 patients were diagnosed as having SD by modified RECIST criteria. According to RECIST criteria, 1 patient showed PR and the remaining 3 patients were diagnosed as having SD. Among 4 patients with decreased AFP, AFP level at 4 weeks was decreased in 2 patients and the other 2 patients showed higher AFP at 4 weeks than pretreatment and decreased at 8 weeks after ramucirumab administration.
Changes in liver function
The changes in the ALBI score within 8 weeks are presented in Figure 2. The median ALBI scores at baseline and at 2, 4, and 8 weeks were −2.02 (range, −2.99 to −1.60), −1.91 (range, −2.69 to −1.31), −2.04 (range, −2.91 to −1.26), and −1.93 (range, −2.73 to −1.43), respectively. There were no significant differences in median ALBI score between baseline and at 4 weeks (P = 0.29) and between at baseline and at 8 weeks (P = 0.43).
Adverse events during ramucirumab therapy
AEs observed during ramucirumab therapy are presented in Table 2. Any grades of total AEs are observed in all patients. No infusion reaction was reported in all patients. Percentages of patients manifesting CTCAE grade 3 or more AEs were 43.8% for ascites and edema and 6.2% for increased total bilirubin (T-Bil). During the observation period, 8 patients discontinued ramucirumab therapy owing to AEs, as follows: 3 patients with edema, 3 patients with ascites, 1 patient with increased T-Bil, and 1 patient with cerebral infarction. In terms of cerebral infarction, the patient was male at the age of 80 years, received ramucirumab as fourth-line, and showed mild gait disorder after 2 courses of ramucirumab. Magnetic resonance imaging revealed multiple cerebral infarcts. The size of infarcts was small, and antithrombotic therapy and rehabilitation improved the patient to his condition before disease onset.
Table 2. Adverse events
|
Any grade
n (%)
|
Grade≥3
n (%)
|
Hypertension
|
8 (50.0)
|
0 (0)
|
HFSR
|
3 (18.8)
|
0 (0)
|
Diarrhea
|
4 (25.0)
|
0 (0)
|
Ascites
|
6 (37.5)
|
4 (25.0)
|
Edema
|
11 (68.8)
|
4 (25.0)
|
Decreased appetite
|
8 (50.0)
|
0 (0)
|
Nausea
|
1 (6.2)
|
0 (0)
|
Fatigue
|
9 (56.2)
|
0 (0)
|
Increased NH3
|
3 (18.8)
|
0 (0)
|
Increased AST
|
1 (6.2)
|
0 (0)
|
Increased ALT
|
1 (6.2)
|
0 (0)
|
Increased T-Bil
|
1 (6.2)
|
1 (6.2)
|
Proteinuria
|
6 (37.5)
|
0 (0)
|
Thromboembolism
|
1 (6.2)
|
0 (0)
|
Infusion reaction
|
0 (0)
|
0 (0)
|
Factors associated with adverse events during ramucirumab therapy
To investigate the higher incidence of AEs in this study compared with the REACH-2 study, we analyzed the baseline characteristics between patients with and without discontinuation of ramucirumab owing to AEs. Pretreatment age, creatinine (Cr), and estimated glomerular filtration rate (eGFR) were significant factors associated with discontinuation owing to AEs. Pretreatment albumin, ALBI score, AFP, des-gamma-carboxy prothrombin (DCP), and extrahepatic metastasis were not significantly different (Table 3). Taking these results into account, we focused on pretreatment renal function. In the REACH-2 study, creatinine clearance of ≥60 mL/min was one of the inclusion criteria. We used eGFR instead of creatinine clearance. In this study, 10 patients with eGFR at 60 mL/min/1.73 m2 did not experience ascites during ramucirumab therapy. In contrast, all of 6 patients with impaired renal function (eGFR < 60 mL/min/1.73 m2) discontinued ramucirumab because of AEs such as severe ascites (n = 3), severe edema (n = 1), moderate edema with general fatigue (n = 1), and cerebral infarction (n = 1). There were no significant differences in age, body weight, pretreatment ALBI score, and pretreatment AFP between patients with preserved and impaired renal function. Six patients with impaired renal function discontinued ramucirumab because of AEs, and 3 of 4 patients with radiological evaluation were diagnosed as having SD by RECIST criteria. Pretreatment urine protein-to-creatine ratios between patients with preserved and impaired renal function were not significantly different; however, urine protein-to-creatine ratios were significantly higher in patients with impaired renal function than patients with preserved renal function at 4 weeks after ramucirumab administration (0.93 vs. 0.14, P = 0.017).
Table 3. The comparison of baseline characteristics between patients with and without the discontinuation owing to AEs
|
Patients without discontinuation owing to AEs (n = 8)
|
Patients with discontinuation owing to AEs (n = 8)
|
P value
|
Age (median)
|
67 (53–86)
|
72 (70–88)
|
0.04
|
Gender (male, %)
|
5 (62)
|
6 (75)
|
1.00
|
BW (kg, median)
|
58.0 (51.9–91.8)
|
60.0 (49.6–73.7)
|
1.00
|
Alb (g/dL, median)
|
3.3 (2.9–3.9)
|
3.2 (2.8–4.3)
|
0.39
|
ALBI score (median)
|
−2.03 (−2.57 to −1.65)
|
−2.02 (−2.99 to −1.60)
|
0.59
|
Cr (mg/dL, median)
|
0.65 (0.44–0.88)
|
1.12 (0.65–1.77)
|
0.01
|
eGFR (mL/min/1.73 m2,
median)
|
81.1 (66.2–109.9)
|
51.1 (30.4–95.0)
|
0.02
|
Urine protein-to-creatine ratios (median)
|
0.15 (0.03–0.63)
|
0.14 (0.02–5.61)
|
0.56
|
Pretreatment AFP (ng/mL, median)
Pretreatment DCP
(mAU/mL, median)
|
3349 (502.9–13372.8)
7643 (37.8–41717.3)
|
1221 (447.2–34327.7)
2169 (266–8035.6)
|
0.96
0.57
|
Extrahepatic metastasis
(yes, %)
|
4 (50)
|
2 (25)
|
0.68
|
Efficacy and safety of ramucirumab as third-line or fourth-line therapy
To reveal the efficacy and safety of ramucirumab as second-line after lenvatinib, third-line, and fourth-line, we compared radiological findings and the incidence of discontinuation caused by AEs with the treatment background (Table 4).
Table 4. Radiological findings and incidence of discontinuation owing to AEs
|
PR by RECIST
|
SD by RECIST
|
PD by RECIST
|
Number of patients without radiological evaluation
|
Number of discontinuation owing to AEs
|
Second-line after lenvatinib (n = 4)
|
1
|
2
|
0
|
1
|
0
|
Third-line (n = 2)
|
0
|
1
|
0
|
1
|
1
|
Fourth-line (n = 10)
|
0
|
4
|
3
|
3
|
7
|