Cyramza® (Ramucirumab)

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Ramucirumab: Use in Patients With HCC and Treatment-Emergent Peripheral Edema

In the pooled analysis of REACH and REACH-2, more any grade peripheral edema was reported among patients who received ramucirumab compared with those that received placebo.

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Study Designs

REACH-2 and REACH were both global, randomized, placebo-controlled phase 3 trials with similar study eligibility, protocol procedures, treatment regimen, and study endpoints. In both studies, patients were randomized to receive either ramucirumab plus BSC or placebo plus BSC.1

The data from patients enrolled in in REACH study with a baseline AFP ≥400ng/mL were pooled with the data from patients enrolled in the REACH-2 study to form a combined analysis. By using the larger patient population in the pooled analysis, the precision of the estimates of the ramucirumab-treatment benefit and safety assessments in the target population was increased. A brief summary of the study designs for REACH-2 and REACH are provided below.1

REACH-2

A multicenter, randomized, double-blind, placebo-controlled trial was conducted to compare ramucirumab plus BSC vs placebo plus BSC in patients with advanced HCC and elevated baseline AFP following first-line sorafenib.2

Patients were eligible for participation if they had

  • diagnosis of HCC (histological or radiological imaging confirmation) or in the absence of histological confirmation a diagnosis of cirrhosis and HCC with classical imaging characteristics 
  • BCLC stage C or stage B refractory or not amenable to locoregional therapy
  • Child-Pugh Class A
  • ECOG PS score of 0 or 1
  • baseline AFP ≥400 ng/mL
  • prior sorafenib treatment (discontinued due to progression or intolerance), and
  • adequate hematologic and biochemical parameters.2

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).2

Patients were randomly assigned in a 2:1 ratio to receive ramucirumab 8 mg/kg IV 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.2 

REACH

A multicenter, randomized, double-blind, placebo-controlled trial was conducted in patients with advanced HCC following first-line treatment with sorafenib.3

Patients were eligible for participation if they had

  • diagnosis of HCC (histological or radiological imaging confirmation)
  • BCLC stage C or stage B refractory or not amenable to locoregional therapy
  • Child-Pugh Class A
  • ECOG PS score 0 or 1
  • prior sorafenib treatment (discontinued due to progression or intolerance)
  • adequate hematological, and
  • biochemical parameters.3

Patients were randomly assigned in a 1:1 ratio (stratified by geographic region and etiology of liver disease) to receive ramucirumab (8 mg/kg IV every 2 weeks) plus BSC (n=283) or placebo (every 2 weeks) plus BSC (n=282) until disease progression, unacceptable toxicity, withdrawal of consent, or death.3

Treatment-Emergent Peripheral Edema

Incidence and Duration of Peripheral Edema

An exploratory analysis of patients in REACH and REACH-2 was conducted to assess outcomes based on the development of treatment-emergent peripheral edema. The incidence of peripheral edema among patients enrolled in REACH and REACH-2 is summarized in Incidence of Treatment-Emergent Peripheral Edema Among Patients in REACH and REACH-2. When adjusted for the duration of exposure to study treatment, the incidence rate per 100 person-year of any-grade peripheral edema was similar between the ramucirumab (82.3) and placebo (82.7) treatment groups.4 The median time to onset and duration of peripheral edema are summarized in Time to Onset and Duration of Peripheral Edema According to Treatment Received in the Pooled REACH-2 and REACH Study Population.

 

Incidence of Treatment-Emergent Peripheral Edema Among Patients in REACH and REACH-21,4

Peripheral Edemaa

RAM + BSC
(n=119)

PBO+ BSC
(n=128)

RAM + BSC
(n=197)

PBO + BSC
(n=95)

RAM + BSC
(n=316)

PBO + BSC
(n=223)

REACH (Baseline AFP ≥400 ng/mL)

REACH-2

Pooled (REACH [Baseline AFP ≥400 ng/mL] + REACH-2)

Any grade, n (%)

41 (34.5)

20 (15.6)

50 (25.4)

13 (13.7)

92 (29.1)

38 (17.0)

IRb

NA

NA

NA

NA

82.3

82.7

Grade ≥3, n (%)

0

0

3 (1.5)

0

3 (0.9)

0

IRb

NA

NA

NA

NA

2.7

0

Abbreviations: AFP = alpha-fetoprotein; BSC = best supportive care; IR = incidence rate; MedDRA = Medical Dictionary for Regulatory Activities; NA = not available; PBO = placebo; PY = person-year (sum of individual patient treatment durations, converted to the unit of year); RAM = ramucirumab. 

aMedDRA preferred term.

bAn exposure-adjusted incidence rate was calculated to account for the observed difference in exposure (eg, treatment duration) between treatment groups using the following formula: Incidence rate/100 PY = n/PY x 100. Ramucirumab PY=111.7 and BSC PY=45.9.

Time to Onset and Duration of Peripheral Edema According to Treatment Received in the Pooled REACH-2 and REACH Study Population4

 

RAM + BSC

PBO + BSC

Time to onset of peripheral edema

Number of patients with peripheral edema

92

38

Median (IQR), days

36.00 (15.00-70.50)

45.50 (27.00-64.00)

Mean, days

66.80

51.05

Range, days

1.00-510.00

2.00-187.00

Duration of peripheral edema

na

48

8

Median (IQR), days

21.50 (13.50-44.50)

19.00 (12.00-36.00)

Mean, days

41.44

25.50

Range, days

2.00-276.00

1.00-69.00

Abbreviation: BSC = best supportive care; IQR = interquartile range; PBO = placebo; RAM = ramucirumab.

aNumber of peripheral edema records with outcome resolved/recovered.

Management of Peripheral Edema

In REACH and REACH-2, the management of treatment-emergent peripheral edema was at the discretion of the treating physician and done in accordance with local practice guidelines. The relevant protocol procedures for management of adverse events that were not considered AESI are summarized in Management of Adverse Events in REACH-2.

Management of Adverse Eventsa in REACH-22

If the clinical AE was...

And...

Then...

And...

Grade 2

Reversible and not life-threatening

Study treatment may have been delayed for up to 21 days, at the discretion of the investigator

Dose reduction was not required.

Grade 3

At least possibly related to study treatment

Study treatment was delayed for up to 21 days

  • Study treatment was resumed at a reduced doseb if the event resolved to grade <2 or patient's baseline level within 21 days.
  • Study treatment was discontinued if the event did not resolve to grade <2 or patient's baseline level within 21 days. 

Grade 4

At least possibly related to study treatment

Study treatment was to be discontinued

NA

Abbreviations: AE = adverse event; AESI = adverse event of special interest; NA = not applicable.

aAdverse events that were not considered AESI.

bThe starting dose of ramucirumab was 8 mg/kg. After the first dose reduction, the new dose was 6 mg/kg. After the second dose reduction, the dose was 5 mg/kg.

Efficacy Outcomes According to the Development of Peripheral Edema

Efficacy outcomes according to the development of peripheral edema are summarized in Efficacy Outcomes in the Pooled REACH-2 and REACH Study Population According to the Development of Peripheral Edema. Kaplan-Meier estimate was used to derive the median for PFS and OS. Multivariate Cox regressions stratified by study were used to derive the stratified HR.4

Efficacy Outcomes in the Pooled REACH-2 and REACH Study Population According to the Development of Peripheral Edema4

RAM + BSC
(n=92)

PBO + BSC
(n=38)

RAM + BSC
(n=224)

BSC + PBO
(n=188)

With Peripheral Edema

Without Peripheral Edema

Median PFS, months

4.14

1.97

2.69

1.48

Stratified HR (95% CI); p valuea

0.419 (0.271-0.647); p<.0001

0.661 (0.531-0.824); p=.0002

Median OS, months

9.17

3.55

7.62

5.85

Stratified HR (95% CI); p valuea

0.389 (0.250-0.605); p<.0001

0.810 (0.648-1.012); p=.0639

Abbreviations: BSC = best supportive care; HR = hazard ratio; OS = overall survival; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.

aStratified log-rank p-value.

Potential Mechanism for the Development of Peripheral Edema

The exact mechanism by which peripheral edema may occur in patients with HCC is unknown. The majority of patients with HCC have underlying liver disease. These patients are susceptible to a variety of liver-related complications. Peripheral edema could be caused by either progression of HCC or worsening of liver function as a natural course of chronic liver disease. In addition, peripheral edema is considered an adverse drug reactions for ramucirumab in the HCC indication; therefore, ramucirumab treatment could also play a role in the etiology of this event besides progression of HCC or cirrhosis.4

References

1Zhu AX, Finn RS, Galle PR, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: pooled efficacy and safety across two global randomized phase 3 studies (REACH-2 and REACH). Poster presented at: 20th Annual Meeting of the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer; June 20-23, 2018; Barcelona, Spain. https://www.postersessiononline.eu/173580348_eu/congresos/20wcgic/aula/-LB_1_20wcgic.pdf

2Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. http://dx.doi.org/10.1016/S1470-2045(18)30937-9

3Zhu AX, Park JO, Ryoo BY et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859-870. http://dx.doi.org/10.1016/S1470-2045(15)00050-9

4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AESI = adverse event of special interest

AFP = alpha-fetoprotein

BCLC = Barcelona Clinic Liver Cancer

BSC = best supportive care

ECOG = Eastern Cooperative Oncology Group

HCC = hepatocellular carcinoma

IV = intravenous

OS = overall survival

PFS = progression-free survival

PS = performance status

VEGF = vascular endothelial growth factor

VEGF-A = vascular endothelial growth factor-A

VEGF-C = vascular endothelial growth factor-C

VEGF-D = vascular endothelial growth factor-D

VEGFR-2 = vascular endothelial growth factor receptor 2

Fecha de la última revisión: 2020 M10 15


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