Study
Design
A
global, randomized, double-blind, placebo-controlled study compared
ramucirumab plus BSC and placebo plus BSC in patients with advanced
HCC and elevated baseline AFP following first-line sorafenib.1
Patients
were stratified by
geographic
region (Americas, Europe, Israel, and Australia vs Asia [except
Japan] vs Japan)
baseline
ECOG PS (0 vs 1), and
macrovascular
invasion (yes vs no).1
Patients
were randomly assigned (2:1) to receive ramucirumab 8 mg/kg plus
BSC (n=197) or placebo plus BSC (n=95) every 14 days until disease
progression or unacceptable toxicity, or until discontinuation
criteria were met.1
Treatment
Discontinuation and Death Due to Adverse Events
Adverse
events leading to treatment discontinuation occurred in
17.8%
of patients who received ramucirumab plus BSC, and
10.5%
of patients who received placebo plus BSC.2
Adverse
events that resulted in death occurred in
3.0%
of patients who received ramucirumab plus BSC, and
3.2%
of patients who received placebo plus BSC.2
Treatment
Discontinuation Due to Adverse Event
The
overall incidence of TEAEs leading to the discontinuation of study
treatment was higher in the ramucirumab arm compared to the placebo
arm (17.8% vs 10.5%, respectively), with no predominant AE or AEs
identified which led to discontinuation of ramucirumab.2
In
REACH-2, patients discontinued study treatment in the event of
grade
3 or 4
IRR
ATE
VTE
bleeding
or hemorrhage events, or
CHF
uncontrolled
hypertension, hypertensive crisis, or hypertensive encephalopathy
(grade 4)
proteinuria
>3 g/24 h or in the setting of nephrotic syndrome
GI
perforation
RPLS,
or
hepatic
encephalopathy and/or hepatorenal syndrome.2
The
TEAEs leading to discontinuation of study treatment are summarized in
Table 1.
Table
1. Treatment-Emergent Adverse Events Reported as Reason for Study
Treatment Discontinuation Occurring in ≥2 Patients in the
Ramucirumab Arm Safety Population2
|
MedDRA
Preferred Term
|
Any
Grade
|
Grade
≥3
|
Any
Grade
|
Grade
≥3
|
|
RAM
+ BSC
(n=197)
n (%)
|
PBO
+ BSC
(n=95)
n (%)
|
|
Patients
discontinued study treatment due to TEAE
|
35
(17.8)
|
28
(14.2)
|
10
(10.5)
|
8
(8.4)
|
|
Proteinuria
|
4
(2.0)
|
1
(0.5)
|
0
|
0
|
|
Hepatic
encephalopathy
|
3
(1.5)
|
2
(1.0)
|
0
|
0
|
|
Platelet
count decreased
|
3
(1.5)
|
3
(1.5)
|
0
|
0
|
|
Hepatorenal
syndrome
|
2
(1.0)
|
2
(1.0)
|
0
|
0
|
|
Esophageal
varices hemorrhage
|
2
(1.0)
|
2
(1.0)
|
0
|
0
|
|
Pneumonia
|
2
(1.0)
|
2
(1.0)
|
0
|
0
|
Abbreviations:
BSC = best supportive care; MedDRA = Medical Dictionary for
Regulatory Activities; PBO = placebo; RAM = ramucirumab; TEAE =
treatment-emergent adverse event.
Treatment
Discontinuation Due to Death
Overall,
the incidence of deaths that occurred while on treatment and up to 30
days after discontinuation from study treatment were similar in both
treatment arms (19.8% in the ramucirumab arm vs 16.8% in the placebo
arm) with the majority of the deaths reported by the investigator as
due to disease progression.2 Deaths
on therapy and within 30 days of treatment discontinuation are
summarized in Table 2
and deaths due to AEs are summarized in Table
3.
Table
2. Deaths on Therapy or Within 30 Days of Treatment Discontinuation2
|
|
RAM
+ BSC
n=197
n (%)
|
PBO
+ BSC
n=95
n (%)
|
|
Deaths
on therapy or within 30 days of treatment discontinuation
|
39
(19.8)
|
16
(16.8)
|
|
Adverse
eventsa
|
7
(3.6)
|
3
(3.2)
|
|
Adverse
events related to study treatment
|
3
(1.5)
|
0
|
|
Study
disease
|
32
(16.2)
|
13
(13.7)
|
Abbreviations:
BSC = best supportive care; PBO = placebo; RAM = ramucirumab.
a
Adverse events as reasons for death include "Adverse
events related to study treatment."
Table
3. Deaths Due to Adverse Events on Treatment or Within 30 Days
of Treatment Discontinuation, Regardless of Causality in
the Safety Population2
|
MedDRA
Preferred Term
|
RAM
+ BSC
n=197
n (%)
|
PBO
+ BSC
n=95
n (%)
|
|
Patients
who died due to an AE
|
7
(3.6)
|
3
(3.2)
|
|
Acute
kidney injury
|
1
(0.5)
|
0
|
|
Generalized
edema
|
1
(0.5)
|
0
|
|
Hepatorenal
syndrome
|
1
(0.5)
|
0
|
|
Lung
disorder
|
0
|
1
(1.1)
|
|
Myocardial
infarction
|
1
(0.5)
|
1
(1.1)
|
|
Pneumonia
|
2
(1.0)
|
0
|
|
Renal
failure
|
1
(0.5)
|
0
|
|
Respiratory
tract infection
|
0
|
1
(1.1)
|
Abbreviations:
AE = adverse event; BSC = best supportive care; MedDRA = Medical
Dictionary for Regulatory Activities; PBO = placebo; RAM =
ramucirumab.
References
1.
Zhu AX, Kang YK, Yen CJ, et al. REACH-2: A randomized, double-blind,
placebo-controlled phase 3 study of ramucirumab versus placebo as
second-line treatment in patients with advanced hepatocellular
carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP)
following first-line sorafenib. Presented as an oral presentation at:
54th Annual Meeting of the American Society of Clinical Oncology
(ASCO); June 1-5, 2018; Chicago, IL. Abstract #4003.
https://meetinglibrary.asco.org/record/159169/abstract
2.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Glossary
AE =
adverse event
AFP
= alpha-fetoprotein
ATE
= arterial thromboembolic event
BSC
= best supportive care
CHF
= congestive heart failure
ECOG
= Eastern Cooperative Oncology Group
GI =
gastrointestinal
HCC
= hepatocellular carcinoma
IRR
= infusion-related reaction
PS =
performance status
RPLS
= reversible posterior leukoencephalopathy syndrome
TEAE
= treatment-emergent adverse event
VTE
= venous thromboembolic event