Cyramza® (Ramucirumab)

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Ramucirumab: Use in Patients With Intermediate Stage HCC

In the pooled analysis of REACH and REACH-2, patients who received ramucirumab had improved OS regardless of BCLC stage compared with patients who received placebo.

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MX_cFAQ_RAM149_HCC_COMBINED_ANALYSIS_BCLC_STAGE
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Study Design

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

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

BCLC Staging System

Background Information

The BCLC Staging system categorizes patients into 4 main prognostic groups (Stage A, B, C, and D) based on

  • tumor burden
  • severity of liver disease, and
  • ECOG PS.4

Intermediate-stage HCC, as defined as BCLC Stage B, is a heterogeneous disease in terms of liver function and tumor burden.4

BCLC Staging in REACH-2 and REACH

Patients with BCLC Stage C disease or BCLC Stage B disease not amenable or refractory to locoregional therapy were included in both REACH and REACH-2.4

For this analysis, BCLC staging was based on individual patient

  • radiographic
  • lab, and
  • baseline characteristic data.4

Outcomes According to BCLC Stage in Combined Analysis of REACH-2 and REACH

Baseline Demographics and Disease Characteristics

Baseline demographics and disease characteristics for the pooled analysis of patients in REACH-2 and REACH according to BCLC stage are summarized in Baseline Demographics and Disease Characteristics in Pooled Analysis of Patients in REACH-2 and REACH According to BCLC Stage .

Baseline Demographics and Disease Characteristics in Pooled Analysis of Patients in REACH-2 and REACH According to BCLC Stage4 

 

Ramucirumab
(n=30)

Placebo
(n=22)

Ramucirumab
(n=286)

Placebo
(n=204)

BCLC Stage B

BCLC Stage C

Male, n (%)

27 (90)

19 (86)

219 (77)

170 (83)

Median age, years

65

65

63

62

ECOG PS 0, n (%)

30 (100)

22 (100)

143 (50)

96 (47)

Geographical region, n (%)

Region 1 (Americas, Europe, Australia, Israel)

14 (47)

12 (55)

140 (49)

96 (47)

Region 2 (Asia excluding Japan)

3 (10)

2 (9)

98 (34)

76 (37)

Region 3 (Japan)

13 (43)

8 (36)

48 (17)

32 (16)

Child-Pugh score A-5, n (%)

22 (73)

12 (55)

168 (59)

123 (60)

Prior TACE, n (%)

22 (73)

11 (50)

157 (55)

112 (55)

Intolerant to sorafenib, n (%)

27 (90)

19 (86)

247 (86)

179 (88)

Macrovascular invasion present, n (%)

0

0

113 (40)

77 (38)

Extrahepatic spread present, n (%)

0

0

226 (79)

171 (84)

Median duration of prior sorafenib, months

4.8

5.2

3.6

3.9

Median AFP (IQR), ng/mL

1817 (1000-6425)

2958 (1591-12317)

4472 (1283-24494)

4375 (1174-23120)

Etiology of liver disease, n (%)

Hepatitis B virus

12 (40)

6 (27)

112 (39)

96 (47)

Hepatitis C virus

10 (33)

10 (46)

73 (26)

46 (23)

Significant alcohol use

4 (13)

4 (18)

67 (23)

39 (19)

Steatohepatitis

2 (7)

1 (5)

24 (8)

10 (5)

Other

6 (20)

3 (14)

37 (13)

27 (13)

Abbreviations: AFP = alpha-fetoprotein; BCLC = Barcelona Clinic Liver Cancer; ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; PS = performance status; TACE = transarterial chemoembolization.

Efficacy Results

The pooled analysis of REACH-2 and REACH data found that BCLC staging trended as an independent prognosis factor for OS (B v C; HR=0.756; 95% CI: 0.546-1.046).4 Efficacy outcomes according to BCLC stage are summarized in Efficacy Results in the Pooled Analysis of Patients in REACH-2 and REACH According to BCLC Stage.

Efficacy Results in the Pooled Analysis of Patients in REACH-2 and REACH According to BCLC Stage4

Ramucirumab
(n=30)

Placebo
(n=22)

Ramucirumab
(n=286)

Placebo
(n=204)

BCLC Stage B

BCLC Stage C

Median OS, months

13.7

8.2

7.7

4.8

HR (95% CI)

0.43 (0.23-0.83)

0.72 (0.59-0.89)

Median PFS, months

4.2 

2.8

2.8

1.5

HR (95% CI)

0.33 (0.17-0.64)

0.60 (0.49-0.74)

ORRa, n (%)

5 (17)

1 (5)

12 (4)

1 (1)

DCRa, n (%)

24 (80)

13 (59)

154 (54)

71 (35)

Abbreviations: BCLC = Barcelona Clinic Liver Cancer; DCR = disease control rate; HR = hazard ratio; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors.

aAll response assessments were done locally by investigators according to Modified RECIST (version 1.1).

Safety Results

Treatment-emergent adverse events that occurred in ≥15% of patients in the ramucirumab arm according to BCLC stage are summarized in TEAEs in ≥15% Patients in Ramucirumab Arm in the Combined Analysis of Patients in REACH-2 and REACH According to BCLC Stage.

TEAEsa in ≥15% Patients in Ramucirumab Arm in the Combined Analysis of Patients in REACH-2 and REACH According to BCLC Stage4

TEAE, n (%)

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Ramucirumab
(n=30)

Placebo
(n=22)

Ramucirumab
(n=286)

Placebo
(n=201)

BCLC Stage B

BCLC Stage C

Peripheral edema

15 (50)

0 (0)

6 (27)

0 (0)

77 (27)

3 (1)

32 (16)

0 (0)

Ascites

9 (30)

2 (7)

2 (9)

2 (9)

57 (20)

13 (5)

31 (15)

7 (4)

Decreased appetite

9 (30)

 0 (0)

5 (23)

0 (0)

61 (21)

4 (1)

41 (20)

1 (1)

Proteinuria

8 (27)

1 (3)

2 (9)

0 (0)

48 (17)

3 (1)

10 (5)

0 (0)

Diarrhea

7 (23)

0 (0)

4 (18)

0 (0)

51 (18)

1 (0)

22 (11)

1 (1)

Fatigue

7 (23)

0 (0)

3 (14)

0 (0)

69 (24)

8 (3)

36 (18)

6 (3)

Hypertension

7 (23)

5 (17)

4 (18)

 1 (5)

59 (21)

33 (12)

16 (8)

7 (4)

Increased blood bilirubin

6 (20)

2 (7)

1 (5)

0 (0)

25 (9)

8 (3)

23 (11)

17 (9)

Headache

6 (20)

0 (0)

0 (0)

0 (0)

47 (16)

1 (0)

14 (7)

1 (1)

Abdominal pain

5 (17)

0 (0)

3 (14)

0 (0)

56 (20)

5 (2)

38 (19)

9 (5)

Arthralgia

5 (17)

0 (0)

0 (0)

0 (0)

9 (3)

2 (1)

7 (4)

0 (0)

Asthenia

5 (17)

1 (3)

0 (0)

0 (0)

32 (11)

8 (3)

14 (7)

1 (1)

Hypoalbuminemia

5 (17)

0 (0)

2 (9)

1 (5)

31 (11)

2 (1)

9 (5)

0 (0)

Nasopharyngitis

5 (17)

0 (0)

2 (9)

0 (0)

10 (3)

0 (0)

7 (4)

0 (0)

Nausea

5 (17)

0 (0)

0 (0)

0 (0)

57 (20)

0 (0)

36 (18)

0 (0)

Pruritus

5 (17)

0 (0)

0 (0)

0 (0)

22 (8)

0 (0)

17 (9)

1 (1)

Pyrexia

5 (17)

0 (0)

1 (5)

0 (0)

35 (12)

0 (0)

13 (7)

0 (0)

Abbreviations: BCLC = Barcelona Clinic Liver Cancer; CTCAE = Common Terminology Criteria for Adverse Events; TEAE = treatment-emergent adverse event. 

aAdverse events were graded according to the CTCAE (version 4.0).

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. Accessed February 17, 2021. 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

4Kudo M, Finn R, Morimoto M, et al. Ramucirumab for patients with intermediate-stage hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): pooled results from two phase 3 studies (REACH and REACH-2). Talk presented at: American Society of Clinical Oncology Gastrointestinal Symposium (ASCO GI); January 23-25, 2020; San Francisco, CA. https://meetinglibrary.asco.org/record/182363/abstract

Glossary

AFP = alpha-fetoprotein

BCLC = Barcelona Clinic Liver Cancer

BSC = best supportive care

ECOG = Eastern Cooperative Oncology Group

HCC = hepatocellular carcinoma

HR = hazard ratio

IV = intravenous

OS = overall survival

PS = performance status

Fecha de la última revisión: 2020 M01 08


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