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 was 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 as

  • BRAF mutant

  • RAS mutant, or

  • BRAF/RAS wild type.2

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

Patient demographics and baseline patient characteristics according to RAS/BRAF subgroup are summarized in Table 1.

Table 1. Patient Demographics and Baseline Characteristics in RAISE Patients According to RAS/BRAF 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)

BRAF Mutanta

RAS Mutant

RAS/BRAF 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 progression after first-line

<6 months

35

52

22

22

27

26

6 months

65

48

78

78

73

74

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 ng/mL

65

43

68

67

60

68

10 ng/mL

35

52

27

27

30

27

200 ng/mL

15

10

22

22

15

18

<200 ng/mL

85

86

73

72

75

76

Missing

0

5

5

6

10

6

Abbreviations: BRAF = B-rapidly accelerated fibrosarcoma; CEA = carcinoembryonic antigen; ECOG = Eastern Cooperative Oncology Group; FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; PBO = placebo; PS = performance status; RAM = ramucirumab; RAS = rat sarcoma viral oncogene; VEGF-D = vascular endothelial growth factor-D. 

a A single patient was found to have mutations in both RAS and BRAF and this patient was included only in the BRAF mutant sub-group for this table and all summaries and analyses.

b VEGF-D high ≥115 pg/mL; VEGF-D low<115 pg/mL.

Results

Efficacy

Efficacy results in RAISE patients by subgroup are presented in Table 2.

Table 2. Survival Results in RAISE Patients According to RAS/BRAF 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

RAS Mutant

BRAF/RAS Wild-Type

Median OS, months

9.0

4.2

12.9

11.5

16.2

15.5

HR (95% CI)a

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)a

0.55 (0.28-1.08)

0.81 (0.68-0.97)

0.78 (0.61-1.00)

Abbreviations: BRAF = B-rapidly accelerated fibrosarcoma; FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; HR = hazard ratio; OS = overall survival; PBO = placebo; PFS = progression-free survival; RAM = ramucirumab; RAS = rat sarcoma viral oncogene.

a HRs and 95% CI were estimated from an unstratified Cox model adjusted for covariates (stratification factors).

In the 41 patients with BRAF-mutated tumors,

  • Ramucirumab treatment effect vs placebo was stronger (OS: HR=0.54; 95% CI:0.25-1.13) than in the other subgroups (RAS mutant [OS: HR=0.86; 95% CI: 0.71-1.04] and RAS/BRAF wild type [OS: HR=0.86; 95% CI: 0.64-1.14]), and

  • Time-to-event stem-and-leaf plots for OS and PFS by VEGF-D subgroup found that the ramucirumab benefit did not appear to be impacted by VEGF-D levels.2

These results should be interpreted with caution since this is a retrospective analysis, may be underpowered, and utilizes a 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. Grade ≥3 adverse events of special interest are presented in Table 4.

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, Portnoy DC, Obermannova R, et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE - a global phase III study. Ann Oncol. 2019;30(1):124-131. https://doi.org/10.1093/annonc/mdy461

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

Glossary

BRAF = B-rapidly accelerated fibrosarcoma

FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil

HR = hazard ratio

IV = intravenous

KRAS = Kirsten rat sarcoma viral oncogene

mCRC = metastatic colorectal cancer

OS = overall survival

PD = progressive disease

PFS = progression-free survival

RAS = rat sarcoma viral oncogene

TEAE = treatment-emergent adverse event

VEGF-D = vascular endothelial growth factor-D

Datum fӧr senaste ӧversyn 2019 M10 01


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