Cyramza ® (ramucirumab)

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Cyramza® (ramucirumab) BRAF Status i RAISE

I RAISE-studien hade 41 patienter BRAF-muterade tumörer.



Study Design

The RAISE trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that evaluated FOLFIRI and ramucirumab vs FOLFIRI and placebo in the second-line treatment of patients with mCRC who had progressed on first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomly assigned in a 1:1 ratio (stratified by region, KRAS mutation status, and time to progressive disease after beginning first-line treatment) to receive IV infusions of either FOLFIRI plus ramucirumab 8 mg/kg (n=536) or FOLFIRI plus placebo (n=536) once every 2 weeks.1

BRAF Analysis

Methods

Plasma and tumor tissue collection were mandatory and analyses were performed to assess correlations of baseline individual marker levels with clinical outcomes. KRAS mutational status was determined before randomization and patients were classified into 1 of the 3 categories:

  • BRAF mutant,

  • KRAS/NRAS mutant, or

  • BRAF/KRAS/NRAS wild type.2

Kaplan-Meier and Cox proportional hazards analyses were used to evaluate OS and PFS in  RAS and RAF subgroups. Time-to-event stem-and-leaf plot was used to evaluate the relationships of OS and PFS with VEGF-D level subgroups within RAF-mutant patients.2

Table 1.  Patient Demographics and Baseline Characteristics in RAISE Patients by Subgroup2

Characteristic, % of Patients

RAM + FOLFIRI 
(n=20)

PBO + FOLFIRI
(n=21)

RAM + FOLFIRI
(n=285) 

PBO + FOLFIRI
(n=294)

RAM + FOLFIRI
(n=149)

PBO + FOLFIRI
(n=143)

RAF Mutant

RAS Mutant

Wild-Type

Age group

65 years

30

48

45

38

39

44

70 years

20

29

23

24

18

23

Male

60

57

53

55

55

71

Geographic Region

Japan/East Asia

10

5

19

15

22

22

Rest of World

90

95

81

85

78

78

Race

Black

0

5

3

3

3

1

White

80

81

77

80

72

72

Other

20

10

20

16

23

26

Missing

0

5

0

1

1

1

ECOG PS

0

65 

52

50

50

54

50

1

30

48

50

50

46

50

Missing

5

0

0

<1

0

0

Time to progress after first-line

<6 months

35

52

22

22

27

26

6 months

65

48

78

78

73

74

KRAS statusa

Mutant

0

0

94

89

0

0

Wild-type

100

100

6

11

100

100

Colorectal tumor sidedness

Left

35

29

62

60

74

76

Right

55

67

33

34

19

19

Missing

10

5

4

7

7

6

Plasma VEGF-D levelb 

High

65

67

50

45

53

58

Low

25

14

34

34

29

31

Missing

10

19

16

21

18

11

Baseline CEA level

>10 μg/mL

65

43

68

67

60

68

10 μg/mL

35

52

27

27

30

27

200 μg/mL

15

10

22

22

15

18

<200 μg/mL

85

86

73

72

75

76

Missing

0

5

5

6

10

6

Abbreviations: CEA = carcinoembryonic antigen; ECOG = Eastern Cooperative Oncology Group; FOLFIRI = 5-fluororuracil, leucovorin, and irinotecan; PBO = placebo; PS = performance status; RAM = ramucirumab; VEGF-D = vascular endothelial growth factor D. 

a Determined prior to randomization.

b Cutoff=115 pg/mL.

Results

Efficacy

Efficacy results in RAISE patients by subgroup are presented in Table 2.  Survival Results in RAISE Patients by Subgroup.

Table 2.  Survival Results in RAISE Patients by Subgroup2

Outcome  

RAM + FOLFIRI 
(n=20)

PBO + FOLFIRI
(n=21)

RAM + FOLFIRI
(n=285) 

PBO + FOLFIRI
(n=294)

RAM + FOLFIRI
(n=149)

PBO + FOLFIRI
(n=143)

BRAF Mutant 

KRAS/NRAS Mutant

BRAF/KRAS/NRAS Wild-Type

Median OS, months

9.0 

4.2

12.9

11.5

16.2

15.5

HR (95% CI)

0.54 (0.25-1.13)

0.86 (0.71-1.04) 

 0.86 (0.64-1.14) 

Median PFS, months

5.7

2.7

5.7

4.3

5.7

5.7

HR (95% CI)

0.55 (0.28-1.08)

0.81 (0.68-0.97)

0.78 (0.61-1.00)

Abbreviations: FOLFIRI = 5-fluororuracil, leucovorin, and irinotecan; HR = hazard ratio; OS = overall survival; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab.

In the 41 patients with BRAF-mutated tumors:

  • Ramucirumab treatment effect vs placebo was stronger (OS HR 0.54) than in the other subgroups:

    • RAS mutant: OS HR 0.86 and

    • RAS/RAF wild type: OS HR 0.86.

  • Time-to-event stem-and-leaf plots for OS and PFS by VEGF-D subgroup found that the ramucirumab benefit in the patients with BRAF-mutated tumors did not appear to be impacted by VEGF-D levels.

These results should be interpreted with caution due to the small sample size.2

Safety

Adverse events by BRAF mutational status were not reported. All grade TEAEs that occurred in ≥20% of patients in either treatment arm and grade ≥3 TEAEs are presented in Table 3. Any Grade TEAEs That Occurred in ≥20% of Patients in Either Treatment Arm and Grade ≥3 TEAEs. Grade ≥3 adverse events of special interest are presented in Table 4. Grade ≥3 Adverse Events of Special Interest.

Table 3. Any Grade TEAEs That Occurred in ≥20% of Patients in Either Treatment Arm and Grade ≥3 TEAEs1,3

NCI-CTC Adverse Event

Any Grade

Grade ≥3

FOLFIRI + Ramucirumab
(N=529)

FOLFIRI + Placebo
(N=528)

FOLFIRI + Ramucirumab
(N=529)

FOLFIRI + Placebo
(N=528)

n

%

n

%

n

%

n

%

Neutropeniaab

311

58.8

241

45.6

203

38.4

123

23.3

Anemiab

86

16.3

110

20.8

8

1.5

19

3.6

Thrombocytopeniab

150

28.4

72

13.6

16

3.0

4

0.8

Abdominal painb

140

26.5

139

26.3

18

3.4

19

3.6

Alopecia

155

29.3

165

31.3

NA

NA

NA

NA

Bleeding/hemorrhagic events

232

43.9

120

22.7

13

2.5

9

1.7

Constipation

151

28.5

120

22.7

5

0.9

8

1.5

Decreased appetite

198

37.4

144

27.3

13

2.5

10

1.9

Diarrhea

316

59.7

271

51.3

57

10.8

51

9.7

Epistaxis

177

33.5

79

15.0

0

0

0

0

Fatigueb

305

57.7

275

52.1

61

11.5

41

7.8

Hypertensionb

138

26.1

45

8.5

59

11.2

15

2.8

Nausea

262

49.5

271

51.3

13

2.5

14

2.7

Peripheral edema

108

20.4

48

9.1

1

0.2

0

0

Stomatitis

163

30.8

110

20.8

20

3.8

12

2.3

Vomiting

154

29.1

144

27.3

15

2.8

13

2.5

Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; MedDRA = Medical Dictionary for Regulatory Activities; NA = not applicable; NCI-CTC = National Cancer Institute Common Terminology Criteria; TEAEs = treatment‑emergent adverse events.

a The rate of any grade of febrile neutropenia was 4% in the ramucirumab + FOLFIRI group and 3% in the FOLFIRI + placebo group.

b Consolidated category comprising synonymous MedDRA preferred terms or adverse event of special interest grouping.

Table 4. Grade ≥3 Adverse Events of Special Interest1,3

NCI-CTC Adverse Event

FOLFIRI + Ramucirumab
(N=529)

FOLFIRI + Placebo
(N=528)

n

%

n

%

Arterial thromboembolica

4

0.8

6

1.1

Bleeding/hemorrhage eventa

13

2.5

9

1.7

Congestive heart failurea

4

0.8

3

0.6

GI hemorrhagea

10

1.9

6

1.1

GI perforationa

9

1.7

3

0.6

Hypertensiona

59

11.2

15

2.8

Infusion-related reactiona

4

0.8

2

0.4

Liver injury or liver failure

26

4.9

21

4.0

Proteinuriaa

16

3.0

1

0.2

Renal failurea

7

1.3

5

0.9

Venous thromboembolic eventsa

22

4.2

11

2.1

Abbreviations: FOLFIR = irinotecan, folinic acid, and 5-fluorouracil; GI = gastrointestinal; MedDRA = Medical Dictionary for Regulatory Activities; NCI-CTC = National Cancer Institute Common Terminology Criteria.

a Consolidated category comprising synonymous MedDRA preferred terms or adverse event of special interest grouping.

References

1. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508. http://dx.doi.org/10.1016/S1470-2045(15)70127-0

2. Yoshino T, Obermannova R, Bodoky G, et al. Are BRAF-mutated metastatic colorectal cancer tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study, a global, randomized, double-blind, phase III study. Poster presented at: 2018 Gastrointestinal Cancers Symposium (ASCO-GI); January 18-20, 2018; San Francisco, CA.

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

Glossary

FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil

HR = hazard ratio

IV = intravenous

KRAS = Kirsten rat sarcoma virus 

mCRC = metastatic colorectal cancer

OS = overall survival

PFS = progression-free survival

TEAE = treatment-emergent adverse event

VEGF-D = vascular endothelial growth factor-D

Datum fӧr senaste ӧversyn 2018 M01 18


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