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Cyramza ® (ramucirumab)
Denna information är endast avsedd för sjukvårdspersonal verksam i Sverige och som svar på din fråga. Informationen nedan är på engelska
Information from Summary of Product Characteristics
Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine.1
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.2
The KRAS mutation status (WT vs mutant) of each patient had to be known prior to randomization; however, patients were eligible to enroll irrespective of KRAS mutation status.2 The study was not powered to detect differences between subgroups; however, a prespecified data analysis was conducted to determine if KRAS mutational status had an effect on the efficacy of treatment with ramucirumab. Patients were divided into two subgroups: KRAS WT (n=530) and KRAS mutant (n=542).3
Efficacy Results
The efficacy results according to KRAS mutational subgroups are summarized in Table 1
Table 1. Efficacy Outcomes According to KRAS Mutational Status3
Efficacy Outcomea |
FOLFIRI
+ Ramucirumab |
FOLFIRI
+ Placebo |
FOLFIRI
+ Ramucirumab |
FOLFIRI
+ Placebo |
KRAS Wild-Type |
KRAS Mutant |
|||
Median OS, months (95% CI) |
14.4 (12.7-16.1) |
11.9 (10.8-13.3) |
12.7 (11.6-14.0) |
11.3 (10.6-12.9) |
HR (95% CI); p valueb |
0.82 (0.67-1.0); .049 |
0.89 (0.73-1.09); not significant |
||
Interaction p value |
Not significant |
|||
Median PFS, months (95% CI) |
5.7 (5.5-6.2) |
4.7 (4.2-5.6) |
5.6 (5.1-6.8) |
4.3 (4.1-5.4) |
HR (95% CI); p valueb |
0.77 (0.65-0.92); .004 |
0.84 (0.70-1.00); not significant |
||
Interaction p value |
Not significant |
Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.
a The study was not powered for subgroup analysis.
b Unstratified analysis.
Postdiscontinuation therapy with anti-EGFR therapy was found to be well balanced between treatment groups among KRAS-wild type patients (ramucirumab plus FOLFIRI: 132 patients [49.4%]; FOLFIRI plus placebo: 145 patients [52.7%]).4
Safety Results
All-grade TEAEs that occurred in at least 20% of patients in either treatment arm according to KRAS status are summarized below in Table 2.
Table 2. All-Grade TEAEs in ≥20% of Patients in Either Treatment Arm According to KRAS Status5
Preferred Term |
KRAS
WT |
KRAS
Mutant |
KRAS
WT |
KRAS
Mutant |
FOLFIRI + Ramucirumab |
FOLFIRI + Placebo |
|||
Neutropeniaa |
155 (58.9)b |
156 (58.6)b |
131 (48.7) |
110 (42.5) |
Fatigue |
144 (54.8) |
161 (60.5)b |
143 (53.2) |
132 (51.0) |
Diarrhea |
155 (58.9)b |
161 (60.5) |
132 (49.1) |
139 (53.7) |
Hypertension |
64 (24.3)b |
72 (27.1)b |
18 (6.7) |
27 (10.4) |
Stomatitis |
85 (32.3)b |
78 (29.3) |
45 (16.7) |
65 (25.1) |
Abdominal paina |
66 (25.1) |
74 (27.8) |
70 (26.0) |
69 (26.6) |
Thrombocytopeniaa |
75 (28.5)b |
75 (28.2)b |
39 (14.5) |
33 (12.7) |
Vomiting |
80 (30.4) |
74 (27.8) |
71 (26.4) |
73 (28.2) |
Nausea |
125 (47.5) |
137 (51.5) |
128 (47.6) |
143 (55.2) |
Decreased appetite |
95 (36.1) |
103 (38.7)b |
80 (29.7) |
64 (24.7) |
Anemiaa |
38 (14.4) |
48 (18.0) |
48 (17.8) |
62 (23.9) |
Constipation |
64 (24.3) |
87 (32.7) |
56 (20.8) |
64 (24.7) |
Peripheral edema |
51 (19.4)b |
57 (21.4)b |
25 (9.3) |
23 (8.9) |
Epistaxis |
81 (30.8)b |
96 (36.1)b |
36 (13.4) |
43 (16.6) |
Alopecia |
70 (26.6) |
85 (32.0) |
86 (32.0) |
79 (30.5) |
Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; KRAS = Kirsten rat sarcoma viral oncogene; TEAE = treatment-emergent adverse event; WT = wild-type.
a Consolidated term.
b p<.05 between treatment group comparison, Fisher's exact test.
Grade ≥3 TEAEs (graded by NCI-CTCAE v4.0) that occurred in at least 5% of patients in either treatment arm according to KRAS status are summarized below in Table 3.
Table 3. Grade ≥3 TEAEs in ≥5% of Patients in Either Treatment Arm According to KRAS Status5
Preferred Term |
KRAS
WT |
KRAS
Mutant |
KRAS
WT |
KRAS
Mutant |
FOLFIRI + Ramucirumab |
FOLFIRI + Placebo |
|||
Neutropeniaa |
96 (36.5)b |
107 (40.2)b |
65 (24.2) |
58 (22.4) |
Fatigue |
30 (11.4) |
31 (11.7)b |
24 (8.9) |
17 (6.6) |
Diarrhea |
28 (10.6) |
29 (10.9) |
26 (9.7) |
25 (9.7) |
Hypertension |
25 (9.5)b |
32 (12.0)b |
5 (1.9) |
10 (3.9) |
Stomatitis |
13 (4.9) |
7 (2.6) |
7 (2.6) |
5 (1.9) |
Abdominal paina |
8 (3.0) |
10 (3.8) |
11 (4.1) |
8 (3.1) |
Thrombocytopeniaa |
10 (3.8)b |
6 (2.3) |
2 (0.7) |
2 (0.8) |
Vomiting |
6 (2.3) |
9 (3.4) |
6 (2.2) |
7 (2.7) |
Nausea |
7 (2.7) |
6 (2.3) |
4 (1.5) |
10 (3.9) |
Decreased appetite |
6 (2.3) |
7 (2.6) |
6 (2.2) |
4 (1.5) |
Anemiaa |
2 (0.8)b |
6 (2.3) |
13 (4.8) |
6 (2.3) |
Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; KRAS = Kirsten rat sarcoma viral oncogene; TEAEs = treatment-emergent adverse events; WT = wild-type.
a Consolidated term.
b p<.05 between treatment group comparison, Fisher’s exact test.
1. Cyramza [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2. 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
3. Obermannová R, Van Cutsem E, Yoshino T, et al. Subgroup analysis in RAISE: a randomized, double-blind phase 3 study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016;27(11):2082-2090. http://dx.doi.org/10.1093/annonc/mdw402. Accompanied by supplementary appendix available at: http://annonc.oxfordjournals.org/content/suppl/2016/08/28/mdw402.DC1/mdw402supp_table5.docx.
4. Obermannová R, Van Cutsem E, Yoshino T, et al. Subgroup analysis in RAISE: a randomized, double-blind phase 3 study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016;27(11):2082-2090. http://dx.doi.org/10.1093/annonc/mdw402
5. Van Cutsem E, Obermannová R, Bodoky G, et al. Subgroup analysis by KRAS status in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression during or following first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine [abstract and poster]. Eur J Cancer. 2015;51 (suppl 3):S365. http://dx.doi.org/10.1016/S0959-8049(16)31030-9
Glossary
CTCAE = Common Terminology Criteria for Adverse Events
EGFR = epidermal growth factor receptor
FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil
IV = intravenous
KRAS = Kirsten rat sarcoma viral oncogene
mCRC = metastatic colorectal cancer
NCI = National Cancer Institute
OS = overall survival
TEAE = treatment-emergent adverse event
WT = wild-type
Datum fӧr senaste ӧversyn 2019 M10 31