Overview for healthcare professionals

Advice

Regulatory status of bevacizumab
Evidence statements
Summary of the evidence

Overview for healthcare professionals

Bevacizumab is a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). It is useful in treating certain types of cancer because it stops the growth of new blood vessels, preventing the cancer cells from growing.

Regulatory status of bevacizumab

Bevacizumab (at a recommended dose of 15 mg/kg body weight), in combination with paclitaxel and carboplatin, is licensed for the front-line treatment of adults with advanced (International Federation of Gynaecology and Obstetrics [FIGO] stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer.

Bevacizumab (at a recommended dose of 15 mg/kg body weight), in combination with carboplatin and gemcitabine, is licensed for treating adults with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

Bevacizumab is also licensed at various doses (including 7.5 mg/kg) for metastatic colorectal cancer, metastatic breast cancer, non-small-cell lung cancer and renal cell cancer.

In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using bevacizumab outside its authorised indications.

Evidence statements

One phase III, open-label, randomised controlled trial (ICON7) was identified. It assessed the effect of bevacizumab 7.5 mg/kg on survival in 1528 women with all stages of ovarian cancer and good physical ability.
Quality of life data obtained from 890 of these women 54 weeks after starting treatment was also reported separately (Stark et al. 2013).
The women received either standard chemotherapy (paclitaxel and carboplatin given every 3 weeks for 6 cycles) or the same regimen plus bevacizumab 7.5 mg/kg given every 3 weeks for 5 or 6 cycles and then bevacizumab continued on its own for 12 additional cycles or until progression of disease.
After a median follow-up of 19 months, median progression-free survival was 19 months in the bevacizumab group compared with 17.3 months in the standard chemotherapy group. The ICON 7 authors also reported results from a pre-planned subgroup of 465 women with advanced ovarian cancer whom they termed at 'high risk for progression' (women had either FIGO stage III disease and >1.0 cm of residual disease after debulking surgery or FIGO stage IV disease). For the subgroup at 'high risk for progression', median progression-free survival was15.9 months in the bevacizumab group compared with 10.5 months in the standard chemotherapy group.
An updated analysis performed after a median follow-up of 28 months showed an improvement in median progression-free survival of 2.4 months in the bevacizumab group compared with the standard chemotherapy group. For the subgroup of women termed at 'high risk for progression', an improvement of 5.5 months with bevacizumab was shown.
Full results for overall survival are still awaited but no statistically significant difference was found after a median of either 19 or 28 months' follow-up.
In the subgroup at 'high risk for progression', after a median follow-up of 28 months, interim analysis showed that median overall survival was 36.6 months with bevacizumab compared with 28.8 months with standard chemotherapy alone. However, these results are preliminary and should be interpreted with caution.
Health-related quality of life, assessed by Stark et al. (2013), found that mean global quality of life at 54 weeks was statistically significantly lower in the bevacizumab group compared with the standard chemotherapy group (69.7 points compared with 76.1 points respectively). This statistically significant (p<0.0001) difference of 6.4 points was small but clinically relevant.
A higher proportion of women on standard chemotherapy had a clinically significant improvement (an improvement of at least 10 points) in global quality of life after 54 weeks compared with those on bevacizumab (66% compared with 56% respectively).
Further analyses of subscales showed clinically small but statistically significant reduced quality of life for women in the bevacizumab group for role functioning, financial worries, attitudes to disease or treatment, hormonal symptoms and rash (all p<0.01).
The ICON7 trial reported recognised adverse events of bevacizumab including mucocutaneous bleeding, bleeding within the central nervous system (CNS) grade 3 or more, gastrointestinal perforation grade 3 or more, thrombotic events, complications of wound healing and hypertension. These adverse events occurred more frequently in the bevacizumab group compared with the standard chemotherapy group.

Summary of the evidence

This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.

Efficacy

One open-label, randomised controlled trial (ICON7) was identified that assessed the efficacy of bevacizumab 7.5 mg/kg for treating ovarian cancer. Quality of life results were also reported separately (Stark et al. 2013).

ICON7 was a multicentre trial including 1528 women who had undergone surgery for epithelial ovarian, fallopian tube or primary peritoneal cancer. The majority of women (94%) had good physical ability as measured by the Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and the rest were ambulatory for more than 50% of the time and did not require nursing care, with an ECOG performance status of 2. Women who had all stages of ovarian cancer were recruited. The trial reported overall results, but also results for a pre-specified subgroup of women with advanced ovarian cancer who had FIGO stage III disease and more than 1.0 cm of residual disease after debulking surgery or who had FIGO stage IV disease. They termed these 465 women at 'high risk for progression'.

Women were randomised to either standard chemotherapy with paclitaxel and carboplatin every 3 weeks for 6 cycles (the standard chemotherapy group), or the same regimen plus bevacizumab 7.5 mg/kg every 3 weeks for 5 or 6 cycles, followed by bevacizumab on its own for an additional 12 cycles or until disease progression or unacceptable toxicity occurred (the bevacizumab group). Allocation to treatment was concealed by central randomisation using an interactive telephone or web-based system.

In the primary analysis, median progression-free survival in the intention-to-treat population estimated after a median follow-up of 19 months showed an improvement of 1.7 months for the bevacizumab group compared with the standard chemotherapy group (19.0 months compared with 17.3 months respectively). The Kaplan‑Meier curves for progression-free survival crossed over demonstrating non-proportional hazards. A test for non-proportional hazards confirmed this (p<0.0001). The conventional hazard ratio is not meaningful when calculated using data that demonstrates non-proportional hazards. To better estimate the effect of bevacizumab on progression-free survival, restricted mean values were estimated. Using all data up to 36 months after randomisation, an improvement in restricted mean progression-free survival of 1.5 months was found for bevacizumab compared with standard chemotherapy (21.8 months compared with 20.3 months respectively).

An updated analysis after a median follow-up of 28 months was performed. This showed an improvement in median progression-free survival of 2.4 months for the bevacizumab group compared with the standard chemotherapy group (19.8 months compared with 17.4 months respectively). Restricted mean values for progression-free survival, estimated using data up to 36 months and up to 42 months after randomisation, showed an improvement of 1.9 months and 1.7 months respectively for bevacizumab compared with standard chemotherapy.

In women at 'high risk for progression', after a median follow-up of 19 months median progression-free survival was improved by 5.4 months with bevacizumab compared with standard chemotherapy (15.9 months compared with 10.5 months respectively). In this same subgroup of women, the restricted mean values for progression-free survival, estimated using data up to 36 months after randomisation, showed an improvement of 3.4 months for bevacizumab compared with standard chemotherapy (16.5 months compared with 13.1 months respectively).

In the updated analysis in women at 'high risk for progression', after a median follow-up of 28 months median progression-free survival was improved by 5.5 months with bevacizumab compared with standard chemotherapy (16.0 months compared with10.5 months respectively). In the same subgroup of women, restricted mean values for progression-free survival, estimated using data up to 36 months and up to 42 months after randomisation, showed an improvement of 3.5 months and 3.6 months respectively for bevacizumab compared with standard chemotherapy.

Further subgroup analysis of the group at 'high risk for progression' was performed. These analyses were reported in the NICE technology appraisal guidance on bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. After 28 months, women with stage III suboptimally debulked disease had an improvement in progression-free survival of 6.8 months on bevacizumab compared with those on standard chemotherapy (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.52 to 0.87), but no statistically significant difference was reported for stage III women with optimally debulked cancer (difference of 1.6 months favouring bevacizumab) or stage IV cancer (difference of 3.4 months favouring bevacizumab). Only the hazard ratio is provided for the subgroup of women with inoperable stage III or IV cancer, which showed a statistically significant improvement in progression-free survival with bevacizumab (HR 0.66, 95% CI 0.48 to 0.91; p=0.011).

The protocol-specified final overall survival analysis for ICON7 is expected at the end of 2013. An interim overall survival analysis was conducted in the subgroup who were at 'high-risk for progression': approximately 47% of women in the standard chemotherapy group and 34% in the bevacizumab group had died. This showed a statistically significant increase in the median overall survival of 7.8 months in the bevacizumab group (36.6 months compared with 28.8 months). However, these results are preliminary and should be interpreted with caution.

Health-related quality of life was measured using the European Organisation for the Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30) with a translated scale from 0 (worst) to 100 (best). All questionnaires were requested in the Stark et al. (2013) study from the ICON7 trial. At baseline 684 (90%) of women in the standard chemotherapy group and 691 (90%) of those in the bevacizumab group had completed quality of lifequestionnaires. At week 54, 388 (51%) women in the standard chemotherapy group and 502 (66%) women in the bevacizumab group provided quality of life data. It is unclear what impact this may have had on the results.

The mean global quality of life score was higher in the standard chemotherapy group (76.1, standard deviation [SD] 18.2) at 54 weeks compared with the bevacizumab group (69.7, SD 19.1), with a difference of 6.4 points (95% CI 3.7 to 9.0, p<0.0001).

The number of women whose global quality of life improved by at least 10 points between baseline and 54 weeks was higher in the standard chemotherapy group at 66% (221 of 333) compared with 56% (250 of 444) in the bevacizumab group (odds ratio 0.58, 95% CI 0.42 to 0.80, p=0.001).

Analyses of subscales of the QLQ-C30 and the additional QLQ-OV28 questionnaire showed small but statistically significant lower quality of life for women in the bevacizumab group for role functioning, financial worries, attitudes to disease or treatment, hormonal symptoms and rash (all p<0.01).

The reason for the small reduction in quality of life in the bevacizumab group remains unclear, and was not shown to be due to resolution timing of ascites, abdominal wall wound healing, or life disruption with continued chemotherapy.

Table 1 Summary of the primary analyses from the ICON7 trial and the Stark et al. (2013) quality of life report

	Standard chemotherapy (paclitaxel and carboplatin)	Standard chemotherapy + bevacizumab	Analysis
ICON7 : a phase III trial of bevacizumab in ovarian cancer. Results after a median follow-up of 19 months
Regimen	Paclitaxel (175 mg/m²) and carboplatin (area under the curve, 5 or 6) every 3 weeks for 6 cycles	Paclitaxel (175 mg/m²) and carboplatin (area under the curve, 5 or 6) every 3 weeks for 6 cycles with concurrent IV bevacizumab (7.5 mg/kg) for 5 or 6 cycles and continued as sole therapy for 12 additional cycles or until disease progression
Randomised	n=764	n=764
Efficacy	n=764	n=764
Progression-free survival: percentage of women who had disease progression or died	51.3% (392/764)	48.0% (367/764)
Progression-free survival: median number of months	17.3	19.0	HR 0.81, 95% CI 0.70 to 0.94, p=0.004^a
Overall survival: percentage of women who died	17.0% (130/764)	14.5% (111/764)	HR 0.81, 95% CI 0.63 to 1.04, p=0.098^a
Progression-free survival in women at high risk for progression: percentage of women who had disease progression or died	67.5% (158/234)	74.9% (173/231)
Progression-free survival in women at high risk for progression: median number of months	10.5	15.9	HR 0.68, 95% CI 0.55 to 0.85), p<0.001^a
Overall survival in women at high risk for progression^b: percentage of women who died	46.6% (109/234)	34.2% (79/231)
Overall survival in women at high risk for progression^b: median number of months	28.8	36.6	HR 0.64, 95% CI 0.48 to 0.85), p=0.002^a
Quality of life	n=727/764 (at baseline) Mean global quality of life score: Baseline 55.7 18 weeks 71.1 54 weeks 74.5 76 weeks 73.7	n=724/764(at baseline) Mean global quality of life score: Baseline 53.6 18 weeks 66.9 54 weeks 69.5 76 weeks 72.6	Quality of life differences between bevacizumab and standard chemotherapy were statistically significant at 18 and 54 week time points only (p<0.01)
Safety: percentage of women that had any adverse event	Grade 1 or 2: 44% (331/753) Grade 3 or 4: 54% (410/753) Grade 5: 1% (9/753)	Grade 1 or 2: 34% (254/745) Grade 3 or 4: 65% (483/745) Grade 5: 1% (8/745)	p value not reported
Adverse events: mucocutaneous bleeding	Grade 1 or 2: 7% (55/753) Grade ≥3: 0% (0/753)	Grade 1 or 2: 36% (271/745) Grade ≥3: 1% (5/745)	p value not reported
Adverse events: bleeding within the central nervous system (CNS) grade ≥3	0% (0/753)	<1% (2/745)	p value not reported
Adverse events: gastrointestinal perforation grade ≥3	<1% (3/753)	1% (10/745)	p value not reported
Adverse events: hypertension	Grade 1: 4% (31/753) Grade 2: 2% (14/753) Grade ≥3: <1% (2/753)	Grade 1: 8% (57/745) Grade 2: 12% (90/745) Grade ≥3: 6% (46/745)	p value not reported
Adverse events: any thrombotic event	Grade 1 or 2: 3% (22/753) Grade ≥3: 3% (23/753)	Grade 1 or 2: 4% (29/745) Grade ≥3: 7% (51/745)	p value not reported
Complication of wound healing	Grade 1 or 2: 2% (13/753) Grade ≥3: <1% (3/753)	Grade 1 or 2: 4% (27/745) Grade ≥3: 1% (10/745)
Stark et al. (2013) : quality of life outcomes from ICON7
Randomised	n=764	n=764
Number of women with data at week 18	n=662 (87%)	n=693 (91%)
Number of women with data at week 54	n=388 (51%)	n=502 (66%)
Mean global quality of life score at baseline	58.6 (SD 20.6)	55.1 (SD 20.8)
Mean global quality of life score at week 18 (end of chemotherapy)	64.4 (SD 20.3)	59.2 (SD 19.4)	Difference favoured standard chemotherapy group −5.1 (95% CI −7.4 to −2.9), p<0.0001
Mean global quality of life score at week 54 (end of continuation bevacizumab)	76.1 (SD 18.2)	69.7 (SD 19.1)	Difference favoured standard chemotherapy group -6.4 (95% CI -9.0 to -3.7), p<0.0001
Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intention to treat; IV: intravenous; n, number of women; p, p value; RR, relative risk; SD, standard deviation. ^ap value obtained using the unadjusted log-rank test. ^b No overall survival analyses were performed for the subgroup at high risk for progression after a median follow-up of 19 months and so data presented are interim analyses performed after a median follow-up of 28 months.

Safety

The manufacturer of bevacizumab (Avastin, Roche) warned about the risk of necrotising fasciitis associated with bevacizumab in May 2013 in information sent to healthcare professionals about the safety of medicines.

The summary of product characteristics (SPC) lists adverse reactions that may be associated with bevacizumab treatment. These include gastrointestinal perforations, fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, neutropenia and infections, hypersensitivity or infusion reactions, osteonecrosis of the jaw, eye disorders, and ovarian failure.

The safety and efficacy of bevacizumab has not been studied in children, or in people with renal or hepatic impairment. It is contraindicated in people with hypersensitivity to the active substance, Chinese hamster ovary (CHO) cell products, or other recombinant human or humanised antibodies. Bevacizumab is also contraindicated in pregnancy. The SPC advises that women of childbearing potential should use effective contraception during and up to 6 months after treatment and breastfeeding should be avoided during and for at least 6 months after treatment.

Adverse drug reactions have been reported with sunitinib, platinum- or taxane-based therapies and epithelial growth factor receptor (EGFR) monoclonal antibodies when used in combination with bevacizumab.

For full details of adverse reactions and contraindications, see the summary of product characteristics.

The ICON7 trial reported recognised adverse events of bevacizumab including mucocutaneous bleeding (n=276 [37%] with bevacizumab compared with n=55 [7%] with standard chemotherapy respectively), bleeding within the CNS grade 3 or more (n=2 [<1%] compared with n=0 respectively), gastrointestinal perforation grade 3 or more (n=10 [1%] compared with n=3 [<1%] respectively), any thrombotic event (n=80 [11%] compared with n=55 [7%] respectively), complications of wound healing (n=37 [5%] compared with n=16 [2%] respectively) and hypertension (n=193 [26%] compared with n=47 [6%] respectively).

Cost effectiveness and cost

No studies on the cost effectiveness of bevacizumab 7.5 mg/kg for advanced ovarian cancer were identified.

For women whose weight is in the range of 53.4 kg to 66.6 kg, the 'drug-only' cost of bevacizumab at a dose of 7.5 mg/kg would be £1167.06 per cycle at the current (July 2013) price listed in MIMS. The suggested regimen would be in combination with paclitaxel and carboplatin for 6 cycles and then up to an additional 12 cycles or until disease progression. This would equate to between £7002.36 (for the first 6 cycles) and £21,007.08 (for the first 6 cycles plus an additional 12 cycles). This does not include the cost of administration by intravenous infusion in hospital. This additional cost would be greater during the extended treatment phase when standard chemotherapy has finished.