The safety profile of Avastin is well established
Over 1 million patients have been treated with Avastin worldwide, across a range of different tumour(An abnormal growth of cells, forming a mass of tissue) types.1 This includes the large, community-based studies BEAT, BRiTE and SAiL, in which investigation of Avastin’s safety profile was the primary objective.2–4
The safety profile of Avastin has therefore been extremely well characterised. 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) of special interest for Avastin include5 bleeding, wound-healing delay, hypertension(High blood pressure), proteinuria(The presence of an excess of serum proteins in the urine), thromboembolic events and fistulae and GI(Complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity) perforations.
Investigation of the underlying molecular mechanisms behind these toxicities has revealed their direct relationship to inhibition of VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) by Avastin.6,7
Possible molecular mechanisms in the toxicity of VEGF inhibition7
| Toxicity | Possible underlying mechanism |
|---|---|
| Bleeding, disturbed wound healing | Platelet dysfunction Decreased expression of endothelial tissue factor |
| Thrombotic events |
Endothelial cell apoptosis Lack of endothelial cell renewal leading to exposure of the extracellular matrix to the circulating blood (results in platelet activation) Increased tissue factor expression Reduced thrombomodulin and nitric oxide Direct platelet activation |
| Hypertension | Decreased nitric oxide and/or prostacyclin production Inappropriate density of vessels (arterioles and capillaries) Vascular stiffness Disturbed endothelin function |
| Proteinuria and oedema | Podocyte dysfunction owing to VEGF blockade Hypertension |
| Adapted by permission from Macmillan Publishers Ltd: Nat Rev Cancer 7(6):475–85, copyright 2007. | |
In general, the AEs attributed to Avastin either occur infrequently or are mild to moderate in severity and clinically manageable.5,8
The safety profile of Avastin does not generally overlap with those of concomitant therapies
Anticancer agents such as cytotoxic(Refers to an agent that acts by causing the death of cells in the body, thus causing a reduction in cell numbers) chemotherapy and immunotherapy also have toxicity profiles related to their MoA.
Depending on the specific therapy, AEs may include
- Myelosuppression
- Diarrhoea, nausea and vomiting
- Mucositis/stomatitis
- Hand-foot syndrome
- Alopecia
- Fatigue(A state of awareness describing a range of afflictions, usually associated with mental and/or physical and/or weakness (tiredness))
Due to its precise action against VEGF, the side effects associated with the use of Avastin do not generally overlap with those of concomitant agents. Some such toxicities have been reported at higher frequencies in Avastin-treated patients in randomised(How subjects are assigned to a treatment arm in a study. The treatment a subject receives is determined by chance alone) trials; this is likely to result from increased exposure to concomitant therapy in patients receiving efficacy(The capacity for beneficial change (or therapeutic effect) of a given intervention) benefit from Avastin.9,10
Non-specific VEGF targeting by anti-angiogenic agents of different design to Avastin (e.g. TKIs) can produce AEs typically observed with chemotherapy, such as myelosuppression, hand-foot syndrome and fatigue, potentially making the combination of these agents with other therapies problematic.11
An analysis of more than 600 patients with CNS metastases demonstrates that the risk of cerebral haemorrhage is independent of bevacizumab(A recombinant humanised monoclonal antibody that specifically inhibits vascular endothelial growth factor (VEGF) and is used for the treatment of various cancer types) therapy12
In a selected population, patients with CNS metastases were found to be at similar risk of developing cerebral haemorrhage, independent of Avastin therapy.12
This finding is based on a retrospective, exploratory analysis that assessed safety data of more than 600 patients with CNS metastases from12
- 13 phase II/III, randomised, controlled trials across several tumour types (NSCLC, pancreatic cancer, mBC, mCRC and mRCC)
- Two open-label(A type of clinical trial in which both the researchers and participants know which treatment is being administered), single-arm, safety studies in metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part) NSCLC (SAiL) and mBC (ATHENA)
- Two recent prospective studies (ATLAS, PASSPORT) including patients with NSCLC and treated CNS metastases.
Analysis results
Incidence of cerebral haemorrhage in patients with CNS metastases, by Avastin treatment
Dataset A (n=8,443): CRC (n=3,382), NSCLC (n=1,952), BC (n=1,885), RCC (n=641), Pancreas (n=583) with cut-off date of March 2008; Dataset B (n=4,382): BC (ATHENA, n=2,216), NSCLC (SAiL, n=2,166) with cut-off date of March 2009; Dataset C (n=845): NSCLC (PASSPORT, n=115) with cut-off date of June 2008 and NSCLC (ATLAS, n=730) with cut-off date of October 2007
In the randomised, controlled trials, occult brain metastases were identified in 187 of 8,443 patients (91 in Avastin arms and 96 in non-Avastin arms)12
- Three Avastin-treated patients (3.3%) developed grade 4 cerebral haemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral haemorrhage.
In SAiL and ATHENA, 321 of 4,382 patients had initially occult CNS metastases, of whom three (0.9%) experienced cerebral haemorrhage
- Two cases of grade 1 and one of grade 3 cerebral haemorrhage were reported.
In ATLAS and PASSPORT, one of 131 Avastin-treated patients (0.8%) with treated cerebral metastases developed grade 2 cerebral haemorrhage.12
There was no difference in the rate of cerebral haemorrhage in patients with treated or untreated CNS metastases.12
Patients with CNS metastases from advanced BC, NSCLC, CRC or RCC should therefore not generally be excluded from Avastin therapy or clinical trials.
Summary: precise VEGF inhibition by Avastin limits toxicity
The side effects of biological agents are related to their MoA and specificity.
Avastin inhibits only the VEGF pathway through extracellular ligand(A substance that forms a complex with a biomolecule to serve a biological purpose) binding. Side effects attributed to Avastin can be directly linked to inhibition of the VEGF pathway.
The safety profile of Avastin is well known and based on experience in a large number of patients. This profile does not generally overlap with those of other types of therapy, thereby making Avastin an excellent combination partner for a wide spectrum of standard therapies.
References
- Avastin PSUR 2011 [RDR 1041900] submitted to EMA on April 27, 2011
- Kozloff M, Hainsworth J, Badarinath S, et al. Presented at: 2007 Gastrointestinal Cancers Symposium; 19–21 January 2007; Orlando Fl. Abstract 375; poster presentation. Available at: http://www.asco.org.
- Van Cutsem E, Rivera F, Berry S, et al. Ann Oncol 2009;20:1842–7.
- Wu Y, Jiang G, Reck M, et al. Proceedings of the International Union Against Cancer (UICC), Geneva, Switzerland; August 2008:POS-B174.
- Avastin Summary of Product Characteristics. Available at: http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm.
- Kamba T, McDonald DM. Br J Cancer 2007;96:1788–95.
- Verheul HMW, Pinedo HM. Nat Rev Cancer 2007;7:475–85.
- Gordon MS, Cunningham D. Oncology 2005;69(Suppl. 3):25–33.
- Escudier B, Pluzanska A, Koralewski P, et al. Lancet 2007;370:2103–11.
- Miller K, Wang M, Gralow J, et al. N Engl J Med 2007;357:2666–76.
- Kollmannsberger C, Soulieres D, Wong R, et al. Can Urol Assoc J 2007;1(Issue 2 Suppl.):S41–54.
- Besse B, Lasserre SF, Compton P, et al. Clin Cancer Res 2010;16:269–78.