Cyramza ® (ramucirumab)

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Cyramza® (ramucirumab): Adverse Events Leading to Treatment Discontinuation in REACH-2

Treatment discontinuation due to TEAE occurred in 17.8% patients who received ramucirumab plus BSC, and 10.5% of patients who received placebo plus BSC.

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

Date of Last Review: October 01, 2018

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