Cyramza ® (ramucirumab)

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Cyramza® (ramucirumab): Dosminskning i REACH-2

Dosreduktioner och förseningar var låga och liknande mellan behandlingsarmarna. Förekomsten av biverkningar som ledde till dosjusteringar var högre i ramucirumab-armen.

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 

Dose Adjustments

Dose reductions were low and similar between treatment arms. Dose adjustments of ramucirumab and placebo were specified for AEs by the protocol and included dose reductions, dose omissions, and dose delays. All dose reductions, irrespective of study drug, were permitted only due to AEs. The most common reason for dose delays in both treatment arms were scheduling conflicts (ie, holidays or administrative reasons), reported for 8.6% of patients in the ramucirumab arm and 4.2% of patients in the placebo arm. The most common reason for dose omissions in both treatment arms was "others," reported for 6.6% of patients in the ramucirumab arm and 10.5% of patients in the placebo arm. Dose adjustments are summarized in Table 1.

Table 1. Summary of Dose Adjustments in the Safety Population2


RAM + BSC
n=197
n (%)

PBO + BSC
n=95
n (%)

Patients with at least 1 dose adjustment

84 (42.6)

26 (27.4)

Patients with dose reductions

9 (4.6)

2 (2.1)

1 dose reduction

7 (3.6)

2 (2.1)

2 dose reductions

2 (1.0)

0

Patients with dose delaysa

29 (14.7)

7 (7.4)

1 dose delay

19 (9.6)

6 (6.3)

2 dose delays

4 (2.0)

1 (1.1)

3 dose delays

6 (3.0)

0

Patients with dose omissionsb

70 (35.5)

20 (21.1)

1 dose omission

43 (21.8)

17 (17.9)

2 dose omissions

17 (8.6)

3 (3.2)

3 dose omissions

10 (5.1)

0

Abbreviations: BSC = best supportive care; eCRF = electronic case report form; PBO = placebo; RAM = ramucirumab. 

a Dose delay was derived as “dose was delayed” reported in the eCRF with dose delay ≤11 days.

b Dose omitted was derived as “dose not administered” or “dose was delayed” reported in the eCRF with dose delay >11 days. 

Adverse Events Leading to Dose Adjustments

The overall incidence of AEs leading to dose adjustment was higher in the ramucirumab arm as compared to the placebo arm (34.0% vs 12.6%, respectively). Dose adjustments for AEs included dose

  • reduction of ramucirumab/placebo: ramucirumab arm 4.6% vs placebo arm 2.1%

  • delay of ramucirumab/placebo: ramucirumab arm 6.1% vs placebo arm 3.2%, and 

  • omission of ramucirumab/placebo: ramucirumab arm 28.9% vs placebo arm 10.5%.2

Adverse events reported as the reason for dose adjustment are summarized in Table 2.

Table 2. Adverse Events Reported as Reason for Dose Adjustment Occurring in ≥2 Patients in the Ramucirumab Arm in the Safety Population2

MedDRA Preferred Term

RAM + BSC
n=197
n (%)

PBO + BSC
n=95
n (%)

Patients with dose adjustment due to AE (any grade)

67 (34.0)

12 (12.6)

AEs leading to dose reduction

9 (4.6)

2 (2.1)

Proteinuria

3 (1.5)

0

Neutrophil count decreased

2 (1.0)

0

AEs leading to dose delaya

12 (6.1)

3 (3.2)

Hypertension

3 (1.5)

1 (1.1)

Proteinuria

2 (1.0)

0

AEs leading to dose omissionb

57 (28.9)

10 (10.5)

Hypertension

9 (4.6)

0

Proteinuria

7 (3.6)

0

Neutrophil count decreased

4 (2.0)

0

Platelet count decreased

4 (2.0)

1 (1.1)

Blood bilirubin increased

3 (1.5)

0

Hyponatremia

3 (1.5)

0

Aspartate aminotransferase increased

2 (1.0)

0

Asthenia

2 (1.0)

0

Neutropenia

2 (1.0)

0

Abbreviations: AE= adverse event; BSC = best supportive care; eCRF = electronic case report form; MedDRA = Medical Dictionary of Regulatory Activities; PBO = placebo; RAM = ramucirumab.   

a Dose delay was derived as “dose was delayed” reported in the eCRF with dose delay ≤11 days.

b Dose omitted was derived as “dose not administered” or “dose was delayed” reported in the eCRF with dose delay >11 days.

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

BSC = best supportive care

ECOG = Eastern Cooperative Oncology Group

HCC = hepatocellular carcinoma

PS = performance status

Datum fӧr senaste ӧversyn 2018 M10 01

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