Avastin is well tolerated when combined with platinum-doublet chemotherapy
By excluding patients with a history of gross haemoptysis, the incidence of life-threatening pulmonary haemorrhage was reduced from 9.1% in the phase II trial1 to 1.9% (1.2% fatal) in ECOG 4599.2
ECOG 4599: Summary of severe (grade ≥3) selected AEs of special interest in ECOG 45992
|
Carboplatin/paclitaxel |
Avastin 15mg/kg + carboplatin/paclitaxel (n=427) n (%) |
|||||
|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 |
Grade 5 |
Grade 3 | Grade 4 |
Grade 5 |
|
| Hypertension | 2 (0.5) | 1 (0.2) | – | 29 (6.8) | 1 (0.2) | – |
| Proteinuria |
– | – |
– | 11 (2.6) | 2 (0.5) | – |
| Bleeding events (all types) | Grade 3–5 AEs 3 (0.7) |
Grade 3–5 AEs 19 (4.4) |
||||
Pulmonary haemorrhage |
1 (0.2) | – | – | 2 (0.5) | 1 (0.2) | 5 (1.2) |
| Copyright © 2006 Massachusetts Medical Society. All rights reserved. | ||||||
The safety of Avastin in the AVAiL trial was comparable to that observed in ECOG 4599.2,3
There was no evidence that thromboembolic events, GI(Complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity) perforations, cardiac disorders or wound-healing complications were increased with Avastin-based therapy versus chemotherapy alone.
Grade ≥3 haemoptysis occurred in 0.9%, 0.9% and 0.3% of patients in the 7.5mg/kg Avastin, 15mg/kg Avastin and placebo arms, respectively.
The overall incidence of grade ≥3 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) was comparable across all arms.
Clinically significant(A measure of the importance of a therapy, treatment or a related side effect that may impact clinical practice) events were infrequent.
Summary of severe (grade ≥3) AEs of special interest3
| Placebo + cisplatin/gemcitabine (n=327) |
Avastin 7.5mg/kg + cisplatin/gemcitabine (n=330) |
Avastin 15mg/kg + cisplatin/gemcitabine (n=329) |
|
|---|---|---|---|
| Bleeding (%) |
2 | 4 | 4 |
| Haemoptysis (all grades; %) |
5.2 | 7 | 9.7 |
| Hypertension (%) | 2 | 6 | 1 |
| Proteinuria (%) | – | < 1 | 1 |
| GI perforation (%) | < 1 | – | < 1 |
| Ischemic events (%) | 5 | 2 | 3 |
| Venous thromboembolic events (%) |
6 | 7 | 7 |
| Adapted from Reck M, von Pawel J, Zatloukal P, et al. J Clin Oncol;27:1227-34 | |||
The SAiL trial provides an insight into the safety and efficacy(The capacity for beneficial change (or therapeutic effect) of a given intervention) of Avastin in combination with a range of standard first-line chemotherapy regimens in a population of NSCLC patients representative of clinical practice.
The safety data from the SAiL trial are consistent with the safety profile of Avastin established in earlier randomised(How subjects are assigned to a treatment arm in a study. The treatment a subject receives is determined by chance alone) phase III trials.2,3,4
SAiL also offers further confirmation of the benefit of Avastin when used in combination with a range of chemotherapies.4
SAiL: first-line Avastin-based therapy is well tolerated in clinical practice
The majority of AEs of special interest related to Avastin were grade ≤2.
The incidence of grade ≥3 pulmonary haemorrhage/haemoptysis was low (<1%).
Five cases of CNS haemorrhage were reported in patients diagnosed with CNS metastases during the course of the study.
SAiL: incidence of AEs of special interest (all grades and grade ≥3)4
| Grade 1 n (%) |
Grade 2 n (%) |
Grade 3 n (%) |
Grade 4 n (%) |
Grade 5 n (%) |
Grade ≥3* n (%) |
|
|---|---|---|---|---|---|---|
| Overall bleeding Epistaxis Pulmonary haemorrhage‡ CNS bleeding§ |
714 (32%) 528 (24%) 149 (7%) 5 (<1%) |
129 (6%) 67 (3%) 32 (1%) 0 |
56 (3% 26 (1%) 5 (<1%) 1 (<1%) |
8 (<1%) 3 (<1%) 2 (<1%) 0 |
17 (1%) 0 8 (<1%) 1 (<1%) |
80 (4%) 28 (1%) 15 (1%) 2 (<1%) |
| Hypertension |
364 (16%) | 300 (14) | 120 (5%) | 6 (<1%) | 0 |
125 (6%) |
| Proteinuria | 466 (21%) | 231 (10%) | 56 (3%) | 11 (<1%) | 0 |
67 (3%) |
| Thromboemoblism | 39 (2%) | 79 (4%) | 104 (5%) | 54 (2%) | 26 (1%) | 172 (8%) |
| GI perforation | 1 (<1%) | 2 (<1%) | 13 (1%) | 6 (<1%) | 8 (<1%) | 27 (1%) |
| Wound-healing complications | 14 (1%) | 10 (<1%) | 1 (<1%) | 1 (<1%) | 0 |
2 (<1%) |
| CHF | 2 (<1%) | 4 (<1%) |
3 (<1%) | 2 (<1%) | 6 (<1%) | 11 (<1%) |
| Data are number of patients (%) *Patients could have had more than one grade of the same event ‡Pulmonary haemorrhage or haemoptysis §Cerebral haemorrhage or haematoma Reprinted from Lancet Oncology, 11, Crinò L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Pages 733–40. Copyright (2010). With permission from Elsevier. |
||||||
The majority of AEs of special interest either resolved or improved during the SAiL study.4
SAiL: incidence of AEs of special interest by outcome and action taken4
No. of events n |
Outcome |
Action taken |
|||||
|---|---|---|---|---|---|---|---|
| Resolved n (%) |
Improved n (%) |
Persistent n (%) |
Led to death n (%) |
Treatment temporarily interrupted n (%) |
Treatment permanently discontinued n (%) |
||
| Bleeding | 1,347 | 1,154 (86) | 39 (3) | 137 (10) | 17 (1) | 28 (2) | 110 (8) |
| Hypertension |
1,025 |
778 (76) | 94 (9) | 153 (15) | 0 | 72 (7) |
40 (4) |
| Proteinuria | 1,046 | 717 (69) | 102 (10) | 227 (22) | 0 | 38 (4) |
31 (3) |
| Thromboembolism | 324 | 156 (48) | 57 (18) | 85 (26) |
26 (8) |
34 (11) |
140 (43) |
| GI perforation | 30 | 18 (60) | 3 (10) | 1 (3) | 8 (27) |
0 | 26 (87) |
| Wound-healing complications | 31 | 22 (71) | 2 (6) | 7 (23) | 0 | 8 (26) | 1 (3) |
| CHF | 18 | 6 (33) | 2 (11) | 4 (22) | 6 (33) |
2 (11) | 9 (50) |
| Data are number of events (%). Analysis is based on a total of 3,821 AEs in the ITT population (2,212 patients). Percentages are based on total number of events within each category, not on number of patients Reprinted from Lancet Oncology, 11, Crinò L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Pages 733–40. Copyright (2010). With permission from Elsevier. |
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The favourable and well-established safety profile of Avastin has been confirmed
Avastin-based therapy is well tolerated, with manageable AEs in patients with NSCLC.
Combining Avastin with platinum-doublet chemotherapy has not raised any new safety signals.
Safety data from phase III trials E4599 and AVAiL were mirrored in the large phase IV trial SAiL, further confirming the favourable safety profile of first-line Avastin-based therapy in the clinical setting.
References
- Johnson DH, Fehrenbacher L, Novotny WF, et al. J Clin Oncol 2004;22:2184–91.
- Sandler A, Gray R, Perry MC, et al. N Engl J Med 2006;355:2542–50.
- Reck M, von Pawel J, Zatloukal P, et al. J Clin Oncol 2009;27:1227–34.
- Crinò L, Dansin E, Garrido P, et al. Lancet Oncol 2010;11:733–40.