AVF2107g: safety of Avastin in combination with IFL1
The clinical benefit of Avastin in combination with IFL was accompanied by a relatively modest increase in the incidence of AEs(Symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study), which were easily managed
- The increase in the incidence of grade 3/4 events was mainly due to hypertension(High blood pressure).
AVF2107g: safety overview1
| Event (%) | IFL + placebo (n=397) | Avastin + IFL (n=393) |
|---|---|---|
| Any grade 3/4 event | 74.0 |
84.9* |
| Event leading to study discontinuation |
7.1 | 8.4 |
| Event leading to death | 2.8 | 2.6 |
| 60-day mortality | 4.9 | 3.0 |
| NB: not adjusted for different time on therapy *p<0.01 vs placebo |
||
AVF2107g: review of AEs attributable to Avastin1
Neither grade 3/4 bleeding nor grade 3/4 proteinuria(The presence of an excess of serum proteins in the urine) was significantly increased when Avastin was combined with IFL.
No significant increase in thromboembolic AEs was observed when Avastin was combined with IFL.
The most common AE was hypertension.
AVF2107g: incidence of selected AEs1
| Events (%) | IFL + placebo (n=397) | Avastin + IFL (n=393) |
|---|---|---|
| Bleeding Grade 3/4 |
2.5 |
3.1 |
| Any thromboembolic event | 16.2 | 19.4 |
| Deep thrombophlebitis | 6.3 | 8.9 |
| Pulmonary embolus | 5.1 | 3.6 |
| Any hypertension Grade 3 |
8.3 2.3 |
22.4* 11.0* |
| Any proteinuria Grade 2 Grade 3 |
21.7 5.8 0.8 |
26.5 3.1 0.8 |
| GI perforation | 0.0 | 1.5 |
| NB: not adjusted for different time on therapy *p<0.01 |
||
NO16966: safety of Avastin in combination with oxaliplatin-based chemotherapy2
The safety profile of Avastin in trial NO16966 was similar to that reported in other trials, with no new safety concerns reported.
NO16966: safety overview2
| AE (%) |
FOLFOX4/XELOX + placebo (n=675) | Avastin + FOLFOX4/XELOX (n=694) |
|---|---|---|
| Any grade 3/4 AE | 75 | 80 |
| Grade 3/4 AEs of special interest to Avastin Venous thromboembolic events Hypertension Bleeding Arterial thromboembolic events* GI perforations Wound-healing complication Fistula/intra-abdominal abscess Proteinuria AEs leading to discontinuation Any AE Grade 3/4 AEs of special interest to Avastin |
8 1 1 1 <1 <1 – – 21 15 2 |
16 4 2 2 <1 <1 1 <1 30 21 5 |
| All cause 60-day mortality | 1.6 | 2 |
| Treatment-related mortality up to 28 days after last dose | 1.5 | 2 |
| *Also includes ischaemic cardiac events | ||
BRiTE: safety of Avastin in a large, community-based trial*
The incidence of AEs observed in clinical practice was similar to that observed in clinical trials of Avastin.3
The incidence of Avastin-associated AEs post first progression(A carcinogenic process whereby genetically altered cells undergo a second (non-genetic) cell expansion resulting in uncontrollable growth) was not significantly increased in patients who received Avastin post-progression.4
The majority (27 of 44) of reported arterial thromboembolic events(An event pertaining to or emanating from the formation of a clot (thrombus) in an artery) occurred within the first 6 months after the start of Avastin treatment.3
Of the 833 (42.7%) patients with hypertension at baseline, 183 (22.0%) patients experienced a worsening of their hypertension which was managed with standard classes of antihypertensive medication.3
Of the 1,120 patients without baseline hypertension, 248 (22.1%) patients developed de-novo hypertension requiring medication after starting treatment with Avastin-based chemotherapy.3
*Data from this study has not been submitted for regulatory review and is not included in the Avastin SmPC
BRiTE: incidence of AEs3
| Event (%) | Patients (n=1,953) |
|---|---|
| GI perforation | 1.9 |
| Grade 3/4 bleeding |
2.2 |
| Arterial thromboembolic event | 2.0 |
| Hypertension | 22.0 |
| Post-operative wound-healing complication | 4.4 |
| *New or worsened hypertension requiring medication | |
BRiTE: incidence of arterial thromboembolic events3
| Patients with arterial thromboembolic events (n=40) |
||
|---|---|---|
| Arterial thromboembolic event, n (%) | Events (n=44) | Related deaths (n=8) |
| Cerebrovascular accident | 16 (36) | 3 (8) |
| Myocardial infarction |
12 (27) | 4 (10) |
| Transient ischemic attack |
7 (16) | 0 |
| Other | 9 (20) | 1 (2)* |
| *Sudden cardiac death | ||
First-BEAT: safety of Avastin in a large, community-based trial*
Data from First-BEAT show that the incidence of AEs observed in clinical practice is similar to that seen in clinical trials of Avastin.5
No new safety signals have been identified in this trial.5
The rate of arterial thromboembolic events was lower than expected and may be a result of patient selection.5
*Data from this study has not been submitted for regulatory review and is not included in the Avastin SmPC
First-BEAT: the incidence of AEs of special interest for Avastin5
| Event, n (%) | Any AE or serious AE (n=1,914) | CTC grade 3/4 or serious AE (n=1,914) |
|---|---|---|
| Hypertension | 572 (29.9) | 101 (5.3) |
| Proteinuria | 200 (10.4)* | 21 (1.1) |
| Bleeding | 593 (31.0) | 61 (3.2) |
| Wound healing | 76 (4.0) | 22 (1.1) |
| Arterial thromboembolic events | 29 (1.5) | 28 (1.5) |
| GI perforation | 37 (1.9)‡ | 34 (1.8) |
| At baseline, 8.8% of patients reported CTC grade 1/2 and 0.2% grade 3/4 proteinuria ‡One patient hospitalised for microperforation |
||
First-BEAT: safety of Avastin in elderly patients
The safety of Avastin plus chemotherapy was evaluated by age group (<65, 65–74, and ≥75 years) in patients from First-BEAT.6
A total of 1,286 (67%) patients were <65 years, 499 (26%) were 65–74 years and 129 (7%) were ≥75 years.6
Avastin-associated AEs were similar in those aged <65, 65–74 and ≥75 years6
- Although a higher rate of thromboembolic events and proteinuria was reported in patients aged ≥75 years.
- The increase in thromboembolic events in this age group may have been due at least in part to existing disease at trial entry.
First-BEAT: safety by age group in patients with mCRC treated with first-line Avastin6
| Age group, years |
||||
|---|---|---|---|---|
| All (n=1,914) | <65 (n=1,286) | 65–74 (n=499) | ≥75 (n=129) | |
| Safety, n (%) GI perforation Arterial thromboembolism Venous thromboembolism All grades Grade 3–5 Grade 3–5 bleeding Hypertension Wound-healing complications Proteinuria All grades Grade 3–5 |
193 (10) |
21 (2) 14 (1) 123 (10) 82 (6) 37 (3) 354 (28) 55 (4) 124 (10) 8 (1) |
11 (2) 10 (2) 51 (10) 31 (6) 11 (2) 180 (36) 19 (4) 58 (12) 9 (2) |
4 (3) 5 (4) 19 (15) 16 (12) 3 (2) 38 (30) 2 (2) 18 (14) 4 (3) |
| Reprinted with the kind permission of the author |
||||
E3200: safety of second-line Avastin in combination with FOLFOX4
The safety profile of Avastin in the E3200 trial was consistent with that reported in other Avastin studies in mCRC, confirming that in second-line mCRC, Avastin plus FOLFOX4 is generally well tolerated.7
E3200: grade 3–4 toxicity with Avastin alone or in combination with FOLFOX47
| Event (%) | FOLFOX4 (n=285) |
Avastin + FOLFOX4 (n=287) |
Avastin (n=234) |
p value (FOLFOX4 vs Avastin + FOLFOX4) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 | Grade 3 | Grade 4 | Grade 3 | Grade 4 | ||||||
| Hypertension | 1.4 |
0.4 |
5.2 | 1.0 | 7.3 | 0 | 0.008 |
||||
| Bleeding | 0.4 | 0 |
3.1 | 0.3 | 2.1 | 0 | 0.011 |
||||
| Vomiting | 2.8 | 0.4 |
8.7 | 1.4 | 4.7 | 0 | 0.001 |
||||
| Proteinuria | 0 | 0 |
0.7 | 0 | 0 | 0 | 0.50 |
||||
| Neuropathy | 8.8 | 0.4 | 16.0 | 0.3 | 0.4 | 0.4 | 0.011 |
||||
GI perforation |
0 | 1.0 | 1.3 | ||||||||
| Thromboembolism | 1.1 | 1.4 | 3.1 | 0.3 | 0 | 0.4 | 0.62 |
||||
Cardiac ischaemia |
0 | 0.4 | 0.3 | 0.3 | 0 | 0 | 0.62 |
||||
| Cerebrovascular ischaemia |
0 | 0 | 0.3 | 0 | 0 | 0.4 | |||||
| Any AE AE leading to treatment discontinuation All-cause 60 day mortality |
36.1 | 23.9 5.0 |
24.9 | 49.5 |
23.4 4.0 |
25.8 | 27.8 | 12.0 6.0 |
8.1 | ||
*Cardiac ischaemia and cerebrovascular ischaemia combined
Reprinted with permission. © 2007 American Society of Clinical Oncology. All rights reserved. |
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Avastin in combination with first- or second-line chemotherapy is well tolerated and AEs are easily managed
Avastin has a well established safety profile in patients with mCRC.
Avastin-based therapy is well tolerated, with manageable AEs.
The addition of Avastin does not increase the incidence or severity of AEs associated with chemotherapy.
Common AEs associated with Avastin include hypertension, proteinuria and bleeding, but are generally of low grade and easily managed.
Serious AEs attributable to Avastin therapy occur infrequently, but include GI(Complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity) perforation(Complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity) and arterial thromboembolism.
Safety data from large community-based trials (First-BEAT and BRiTE) were similar to those reported in phase III trials, indicating a consistent safety profile regardless of the chemotherapy regimen with which Avastin is combined.
References
- Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med 2004;350:2335–42.
- Saltz L, Clarke S, Díaz-Rubio E, et al. J Clin Oncol 2008;26:2013–9.
- Kozloff M, Yood MU, Berlin J, et al. Oncologist 2009;14:862–70.
- Grothey A, Sugrue M, Purdie DM, et al. J Clin Oncol 2008;26:5326–34.
- Van Cutsem E, Rivera F, Berry S, et al. Ann Oncol 2009;20:1842–7.
- Van Cutsem E, Rivera F, Berry S, et al. Eur J Cancer Suppl 2009;45:349 (Abstract 6088).
- Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol 2007;25:1539–44.