Cyramza® (Ramucirumab)

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Ramucirumab: Prior First-Line Therapy in RAINBOW

A post-hoc analysis of RAINBOW found improved OS among patients who received ramucirumab plus paclitaxel vs paclitaxel plus placebo regardless of prior doublet vs triplet therapy regimen.

MX_cFAQ_RAM159_RAINBOW_PRIOR_FIRST_LINE
MX_cFAQ_RAM159_RAINBOW_PRIOR_FIRST_LINE
es-MX

The information contained in this letter may not completely match the current local labeling for RAMUCIRUMAB. Please see local labeling approved in your country. 

RAINBOW Study Design

The RAINBOW trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced nonresectable gastric or GEJ adenocarcinoma following disease progression during or within 4 months after last dose of first-line platinum plus fluoropyrimidine combination chemotherapy with or without an anthracycline and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by region, measurable vs nonmeasurable disease, and TTP on first-line therapy) to receive ramucirumab (8 mg/kg days 1 and 15) plus paclitaxel (80 mg/m2 days 1, 8, and 15) (n=330) or placebo (days 1 and 15) plus paclitaxel (80 mg/m2 days 1, 8, and 15) (n=335) of a 28-day cycle until disease progression, unacceptable toxicity, withdrawal, or death.1

Analysis According to Prior First-Line Therapy

An exploratory, post-hoc analysis was conducted to evaluate the impact of prior first-line therapy on the efficacy, safety, and QoL among patients enrolled in the RAINBOW study. Patients whose first-line therapy could be classified as either a doublet regimen (platinum plus fluoropyrimidine, n=498) or triplet regimen (platinum plus fluoropyrimidine plus anthracycline, n=163) were included in the analysis.2

Baseline Patient Characteristics

Baseline patient characteristics were generally balanced between treatment groups within the doublet and triplet subgroups and are summarized in Baseline Patient Characteristics According to Prior First-Line Therapy in RAINBOW.2

Baseline Patient Characteristics According to Prior First-Line Therapy in RAINBOW2

 Characteristic

RAM + PAC
(n=253)

PBO + PAC
(n=245)

Total
(n=498)

RAM + PAC
(n=76)

PBO + PAC
(n=87)

Total
(n=163)

Doublet Regimen

Triplet Regimen

Male, n (%)

179 (70.8)

177 (72.2)

356 (71.5)

49 (64.5)

64 (73.6)

113 (69.3)

Age <65 years, n (%)

151 (59.7)

146 (59.6)

297 (59.6)

53 (69.7)

64 (73.6)

117 (71.8)

Geographical region, n (%)

Europe/North America/Australia

129 (51.0)

117 (47.8)

246 (49.4)

68 (89.5)

80 (92.0)

148 (90.8)

Rest of the World

18 (7.1)

15 (6.1)

33 (6.6)

5 (6.6)

6 (6.9)

11 (6.7)

Asia

106 (41.9)

113 (46.1)

219 (44.0)

3 (3.9)

1 (1.1)

4 (2.5)

ECOG PS, n (%)

0

88 (34.8)

110 (44.9)

198 (39.8)

29 (38.2)

34 (39.1)

63 (38.7)

1

165 (65.2)

135 (55.1)

300 (60.2)

47 (61.8)

53 (60.9)

100 (61.3)

Time to PD on first-line therapy, n (%)

<6 months

152 (60.1)

146 (59.6)

298 (59.8)

56 (73.7)

53 (60.9)

109 (66.9)

≥6 months

101 (39.9)

98 (40.0)

199 (40.0)

20 (26.3)

34 (39.1)

54 (33.1)

Missing

0

1 (0.4)

1 (0.2)

0

0

0

Number of metastatic sites, n (%)

0-2

153 (60.5)

172 (70.2)

325 (65.3)

55 (72.4)

57 (65.5)

112 (68.7)

≥3

100 (39.5)

73 (29.8)

173 (34.7)

21 (27.6)

30 (34.5)

51 (31.)

Liver metastasis, n (%)

Yes

119 (47.0)

96 (39.2)

215 (43.2)

31 (40.8)

42 (48.3)

73 (44.8)

No

134 (53.0)

149 (60.8)

283 (56.8)

45 (59.2)

45 (51.7)

90 (55.2)

Weight loss in prior 3 months, n (%)

<10%

218 (86.2)

209 (85.3)

427 (85.7)

58 (76.3)

74 (85.1)

132 (81.0)

≥10%

35 (13.8)

36 (14.7)

71 (14.3)

18 (23.7)

11 (12.6)

29 (17.8)

Missing

0

0

0

0

2 (2.3)

2 (1.2)

Presence of ascites, n (%)

Yes

98 (38.7)

79 (32.2)

177 (35.5)

32 (42.1)

26 (29.9)

58 (35.6)

No

155 (61.3)

166 (67.8)

321 (64.5)

44 (57.9)

61 (70.1)

105 (64.4)

Prior gastrectomy, n (%)

Yes

110 (43.5)

99 (40.4)

209 (42.0)

22 (28.9)

25 (28.7)

47 (28.8)

No

143 (56.5)

146 (59.6)

289 (58.0)

54 (71.1)

62 (71.3)

116 (71.2)

Abbreviations: ECOG = Eastern Cooperative Oncology Group; PAC = paclitaxel; PBO = placebo; PD = progressive disease; PS = performance status; RAM = ramucirumab.

Summary of First-Line Therapies Received

The most common first-line therapies administered to patients in the RAINBOW study are summarized in Prior First-Line Regimens That Were Administered to ≥5% of Patients in Either Arm.

Prior First-Line Regimensa That Were Administered to ≥5% of Patientsb in Either Arm2

Prior First-Line Therapy, % of Patients

RAM + PAC

PBO + PAC

Doublet Regimens

Cisplatin + S1 (SP)

24

24

Cisplatin + 5FU (CF)

23

23

Capecitabine + oxaliplatin (CAPEOX)

18

16

Cisplatin + capecitabine (XP)

17

15

5FU + leucovorin + oxaliplatin (FOLFOX4)

8

6

5FU + leucovorin + cisplatin (FLP)

5

5

5FU + leucovorin + oxaliplatin (FOLFOX6)

4

8

Triplet Regimensc

Epirubicin + oxaliplatin + capecitabine (EOX)

42

45

Epirubicin + cisplatin + 5FU (ECF)

30

28

Epirubicin + cisplatin + capecitabine (ECX)

26

27

Abbreviations: 5FU = 5-fluorouracil; PAC = paclitaxel; PBO = placebo; RAM = ramucirumab.

aTrastuzumab was not considered as part of this classification. 

bSome patients were counted more than once if they received multiple regimens in prior therapy as indicated in the database.

cOnly anthracycline based triplet regimens were studied.

Efficacy According to First-Line Therapy

Numerically higher median OS and PFS was observed among patients who received ramucirumab plus paclitaxel compared with patients who receive paclitaxel plus placebo regardless of first-line treatment regimen.2 Efficacy outcomes are summarized in Efficacy Outcomes According to Prior First-Line Therapy in RAINBOW.

Efficacy Outcomes According to Prior First-Line Therapy in RAINBOW2

Outcome

RAM + PAC
(n=253)

PBO + PAC
(n=246)

RAM + PAC
(n=76)

PBO + PAC
(n=87)

Doublet Regimen

Triplet Regimen

Median OS, months 

9.8

7.8

8.1

5.5

HR (95% CI); p value

0.862 (0.703-1.058); p=.1547

0.685 (0.480-0.979); p=.0374

Median PFS, months

4.4

2.9

4.6

2.9

HR (95% CI); p value

0.650 (0.535-0.788); p<.0001

0.592 (0.413-0.848); p=.0038

ORR, % (95% CI)

29.2 (24.0-35.1)

15.9 (11.9-21.0)

23.7 (15.5-34.4)

17.2 (10.7-26.5)

CR, n (%)

1 (0.4)

1 (0.4)

1 (1.3)

0

PR, n (%)

73 (28.9)

38 (15.5)

17 (22.4)

15 (17.2)

DCR, % (95% CI)

80.6 (75.3-85.0)

65.7 (59.6-71.4)

77.6 (67.1-85.5)

59.8 (49.3-69.4)

Abbreviations: CR = complete response; DCR = disease control rate; HR = hazard ratio; ORR = objective response rate; OS = overall survival; PAC = paclitaxel; PBO = placebo; PFS = progression-free survival; PR = partial response; RAM = ramucirumab.

Safety According to First-Line Therapy

Grade ≥3 TEAEs were reported 72.2% of patients who received first-line doublet therapy and 72.0% of patients who received first-line triplet therapy. A TEAE with an outcome of death was reported in 12.2% of patients who received prior doublet-therapy and 18.6% of patients who received prior triplet therapy.2 A summary of safety is presented in Treatment Emergent Adverse Events That Occurred in >15% of Patients According to Prior First-Line Therapy in RAINBOW.

Treatment Emergent Adverse Events That Occurred in >15% of Patients According to Prior First-Line Therapy in RAINBOW2

TEAE, n (%)

Any Grade

Grade 3/4/5

Any Grade

Grade 3/4/5

Any Grade

Grade 3/4/5

Any Grade

Grade 3/4/5

RAM + PAC
(n=251)

PBO + PAC
(n=241)

RAM + PAC
(n=75)

PBO + PAC
(n=86)

Doublet Regimen

Triplet Regimen

Neutropenia

145 (57.8)

111 (44.2)

88 (36.5)

53 (22.0)

32 (42.7)

22 (29.3)

13 (15.1)

8 (9.3)

Alopecia

100 (39.8)

0 (0.0)

113 (46.9)

1(0.4)

7 (9.3)

0 (0.0)

13 (15.1)

0 (0.0)

Decreased appetite

111 (44.2)

9 (3.6)

80 (33.2)

10 (4.1)

20 (26.7)

1 (1.3)

25 (29.1)

3 (3.5)

Fatigue

101 (40.2)

14 (5.6)

79 (32.8)

9(3.7)

29 (38.7)

9 (12.0)

25 (29.1)

4 (4.7)

Anemia

88 (35.1)

24 (9.6)

81 (33.6)

25(10.4)

23 (30.7)

6 (8.0)

35 (40.7)

8 (9.3)

Nausea

85 (33.9)

4 (1.6)

81 (33.6)

6 (2.5)

30 (40.0)

2 (2.7)

27 (31.4)

2 (2.3)

Leukopenia

94 (37.5)

52 (20.7)

61 (25.3)

20 (8.3)

16 (21.3)

5 (6.7)

7 (8.1)

2 (2.3)

Diarrhea

79 (31.5)

9 (3.6)

61 (25.3)

4 (1.7)

27 (36.0)

3 (4.0)

14 (16.3)

1 (1.2)

Vomiting

66 (26.3)

7 (2.8)

47 (19.5)

6 (2.5)

22 (29.3)

3 (4.0)

21 (24.4)

6 (7.0)

Abdominal pain 

63 (25.1)

10 (4.0)

46 (19.1)

6 (2.5)

38 (50.7)

8 (10.7)

21 (24.4)

5 (5.8)

Constipation

54 (21.5)

0 (0.0)

48 (19.9)

2 (0.8)

16 (21.3)

0 (0.0)

23 (26.7)

0 (0.0)

Epistaxis

78 (31.1)

0 (0.0)

18 (7.5)

0 (0.0)

22 (29.3)

0 (0.0)

5 (5.8)

0 (0.0)

Peripheral edema

62 (24.7)

3 (1.2)

32 (13.3)

2 (0.8)

20 (26.7)

2 (2.7)

12 (14.0)

0 (0.0)

Peripheral sensory neuropathy 

51 (20.3)

5 (2.0)

32 (13.3)

3 (1.2)

6 (8.0)

1 (1.3)

4 (4.7)

0 (0.0)

Asthenia

47 (18.7)

9 (3.6)

32 (13.3)

4 (1.7)

22 (29.3)

9 (12.0)

13 (15.1)

2 (2.3)

Stomatitis

56 (22.3)

2 (0.8)

20 (8.3)

1 (0.4)

8 (10.7)

0 (0.0)

3 (3.5)

1 (1.2)

Pyrexia

45 (17.9)

1 (0.4)

27 (11.2)

0 (0.0)

14 (18.7)

2 (2.7)

10 (11.6)

1 (1.2)

Hypertension

59 (23.5)

34 (13.5)

11 (4.6)

6 (2.5)

19 (25.3)

12 (16.0)

5 (5.8)

2 (2.3)

Proteinuria

44 (17.5)

4 (1.6)

16 (6.6)

0 (0.0)

10 (13.3)

0 (0.0)

4 (4.7)

0 (0.0)

Malignant neoplasm progression

31 (12.4)

28 (11.2)

34 (14.1)

33 (13.7)

21 (28.0)

19 (25.3)

26 (30.2)

26 (30.2)

Ascites

20 (8.0)

5 (2.0)

16 (6.6)

8 (3.3)

13 (17.3)

7 (9.3)

11 (12.8)

5 (5.8)

Rash

21 (8.4)

0 (0.0)

19 (7.9)

0 (0.0)

14 (18.7)

0 (0.0)

7 (8.1)

0 (0.0)

Abbreviations: PAC = paclitaxel; PBO = placebo; RAM = ramucirumab; TEAE = treatment-emergent adverse event.

QoL According to First-Line Therapy

At baseline, QoL scores as assessed by EORTC QLQ-C30 were similar between treatment arms within subgroups; however, the mean scores were more than 5 points worse for the prior triplet subgroup for

  • role functioning
  • fatigue
  • pain, and
  • appetite loss.2

Changes in QoL scores, which were assessed every 6 weeks, were similar between treatment arms and within first-line regimen.2

References

1Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. http://dx.doi.org/10.1016/S1470-2045(14)70420-6

2Klempner SJ, Wainberg Z, Muro K, et al. Impact of frontline doublet versus triplet therapy on clinical outcomes: exploratory analysis from the RAINBOW study. Poster presented at: 56th Annual Meeting of the American Society of Clinical Oncology (ASCO Virtual); May 29-31, 2020. Accessed May xx, 2020.

Glossary

ECOG = Eastern Cooperative Oncology Group

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer quality-of-life questionnaire

GEJ = gastroesophageal junction

OS = overall survival

PFS = progression-free survival

PS = performance status

QoL = quality of life

TEAE = treatment-emergent adverse event

TTP = time-to-progression

Fecha de la última revisión: 2020 M05 15


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