Bevacizumab, solution for I.V. infusion, 100 mg in 4 mL and 400 mg in 16 mL, Avastin® - March 2011
Page last updated: 05 July 2011
Public Summary Document
Product: Bevacizumab, solution for I.V. infusion,
100 mg in 4 mL and 400 mg in 16 mL, Avastin®
Sponsor: Roche Products Pty Limited
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an extension to the current PBS listing for
bevacizumab to include a Section 85 Authority Required listing and
listing under the Section 100 Chemotherapy Pharmaceuticals Access
Program (CPAP) for:
(1) initial treatment, in combination with carboplatin and
paclitaxel, of a patient with advanced or metastatic non-squamous
non-small cell lung cancer who meet certain criteria and;
(2) continuing treatment, as monotherapy, in a patient who does not
have progressive disease.
2. Background
This drug had not been previously considered by the PBAC for this
indication.
3. Registration Status
Bevacizumab was TGA registered on 27 October 2008 for the
first-line treatment of patients with unresectable advanced,
metastatic or recurrent, non-squamous, non-small cell lung cancer,
in combination with carboplatin and paclitaxel.
Bevacizumab is also registered for the following indications:
- In combination with fluoropyrimidine based chemotherapy for the treatment of patients with metastatic colorectal cancer.
- In combination with paclitaxel, for the first line treatment of metastatic breast cancer in patients in whom an anthracycline based therapy is contraindicated.
- In combination with interferon-alfa-2a for the treatment of patients with advanced and/or metastatic renal cell cancer.
- Single agent for the treatment of patients with grade IV glioma after relapse or disease progression after standard therapy, including chemotherapy.
4. Listing Requested and PBAC’s View
Authority required
Treatment, in combination with carboplatin and paclitaxel, of a
patient with advanced or metastatic non-squamous non-small cell
lung cancer with a WHO performance status of 0 or 1, who has not
previously received treatment for their metastatic disease.
The maximum dose that will be approved is 15 mg per kg every three
weeks.
Authority required
Continuing treatment, as monotherapy, of a patient with advanced or
metastatic non-squamous non-small cell lung cancer who has
previously received carboplatin and paclitaxel and who does not
have progressive disease.
The maximum dose that will be approved is 15 mg per kg every three
weeks.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Non-small cell lung cancer is a type of lung cancer that accounts
for the majority of patients (80%) with lung cancer. The aim of
treatment in patients with advanced disease is to improve both the
duration and the quality of the patient’s remaining
life.
6. Comparator
The submission nominated carboplatin and paclitaxel (Carb+P) as the
main comparator for the treatment of previously untreated, advanced
or metastatic non-squamous NSCLC, which was considered reasonable
by the PBAC.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented four randomised controlled trials
comparing the combination of bevacizumab and platinum-based doublet
chemotherapy, with platinum-based doublet chemotherapy alone.
The key clinical trial presented in the submission was Study E4599,
an open-label randomised controlled trial of carboplatin plus
paclitaxel, with or without bevacizumab (15 mg/kg), in patients
with advanced non-squamous NSCLC.
The three supportive studies were:
- Study AVF0757g: an open-label phase II, randomised controlled trial of carboplatin plus paclitaxel, with or without bevacizumab (15 mg/kg or 7.5 mg/kg) in patients with locally advanced or metastatic NSCLC;
- Study JO19907: an open-label randomised controlled trial of carboplatin plus paclitaxel, with or without bevacizumab (15 mg/kg), in Japanese patients with advanced or recurrent non-squamous NSCLC; and
- Study BO17704: a randomised double-blind controlled trial of cisplatin plus gemcitabine with placebo or bevacizumab (15 mg/kg or 7.5 mg/kg), in patients with advanced or recurrent non-squamous NSCLC.
The trials published at the time of submission are presented in the following table:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Study E4599 | ||
| Sandler A et al | Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. | The New England Journal of Medicine 2006; 355 (24): 2542-2550. |
| Sandler A et al | Treatment outcomes by tumour histology in eastern cooperative group study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. | Journal of Thoracic Oncology 2010; 5 (9): 1-8. |
| Study VF0757g | ||
| Johnson D et al | Randomized Phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer . | Journal of Clinical Oncology 2004; 22 (11): 2184-2191. |
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Study JO19907 Nishio M et al | Randomized, open-label, multicenter phase II study of bevacizumab in combination with carboplatin and paclitaxel in chemotherapy-naive Japanese patients with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC): JO19907. | Journal of Clinical Oncology 2009; 27:15s (Abstract; Poster 8036). |
| Study BO17704 (AVAiL) | ||
| Reck M et al | Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). | Annals of Oncology 2010; 21 (9): 1804-1809. |
| Reck M et al | Phase III Trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. | Journal of Clinical Oncology 2009; 27 (8): 1227-1234. Errata DOI: 10.1200/JCO.2009.23.1373. |
8. Results of Trials
Key Study E4599 (Bevacizumab+Carboplatin+Paclitaxel vs Carboplatin+Paclitaxel):
Overall survival (OS):
The overall survival results for randomised patients (ITT) for
Study E4599 showed that the addition of bevacizumab 15 mg/kg to
carboplatin plus paclitaxel resulted in a two months absolute
increase in the median duration of overall survival (12.3 months
for bevacizumab plus carboplatin plus paclitaxel versus 10.3 months
for carboplatin plus paclitaxel) corresponding to a statistically
significant 20% relative decrease in the risk of death
(unstratified analysis: HR=0.800; 95% CI: 0.689, 0.929).
Results for the stratified analysis of overall survival and from a
per protocol analysis conducted by the Eastern Cooperative Oncology
Group (ECOG) (HR=0.77, 95% CI: 0.66, 0.91), are consistent with
those for the stratified ITT analysis.
Progression-free survival (PFS):
The results of the secondary endpoint of progression free survival
(time to disease progression or death) in Study E4599 (ITT)
indicated a statistically significant difference (p <0.0001) in
median duration of PFS favouring patients in the bevacizumab plus
carboplatin plus paclitaxel treatment arm (median PFS = 6.4 months)
over patients in the carboplatin plus paclitaxel treatment arm
(median PFS = 4.8 months).
The supporting evidence presented in the submission was also
generally consistent across the studies with overall median
survival increased by about 2 months and median progression-free
survival increased by around one month.
Study AVF0757 (Bevacizumab+Carboplatin+Paclitaxel vs. Carboplatin+Paclitaxel):
The PBAC noted the median survival in the non-squamous group of
14.3 vs 12.2 months, was not statistically significant; the median
time to progression (non-blinded assessment) of 7.4 vs 4.3 months
(p=0.02); and the HR for time to progression (blinded review) 0.67
(p=0.152), 7.0 months vs 6.0 months.
Study J019907 (background chemotherapy with Carboplatin+Paclitaxel)
The PBAC noted the median progression-free survival of 6.9 vs. 5.9
months; and
HR of risk of progression or death of 0.61 (95%CI: 0.42 to
0.89).
For PBAC’s view, see Recommendation and
Reasons.
The safety profile of bevacizumab for the treatment of non-squamous
NSCLC is similar to that previously established for other
indications, eg metastatic colorectal cancer, recurrent or
metastatic breast cancer.
The PBAC noted that in trial E4599, the risk of fatal adverse
events in bevacizumab patients was more than 2.5 times that of
patients in the carboplatin+paclitaxel alone arm (5% vs 2%, RR:
2.65 [1.24, 5.65]). Bevacizumab+carboplatin+paclitaxel was
associated with higher rates of all grade ≥ 3 adverse events
(77% vs 65%, relative risk (RR): 1.18 [1.09, 1.29]) and grade ≥
3 adverse events of interest (haemorrhage, thromboembolism,
hypertension, proteinuria, gastrointestinal perforation, wound
healing problems and congestive heart failure) than
carboplatin+paclitaxel alone (20% vs 6%, RR: 3.56 [2.33,
5.45]).
The principal significant risk associated with bevacizumab was an
increase in grade ≥ 3 haemorrhage when compared with the doublet
chemotherapy only arms (2% to 5% vs 0% to 2%).
The most common bevacizumab-related bleeding events were of
pulmonary origin, with a higher incidence of all grades of
haemoptysis in the bevacizumab arm than in the
carboplatin+paclitaxel arm (6.3% vs 3.9%) in trial E4599.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission described bevacizumab, when used in combination with
carboplatin plus paclitaxel, as superior in terms of comparative
effectiveness and inferior in terms of comparative safety over
carboplatin plus paclitaxel alone.
This claim was considered by the PBAC reasonable and was consistent
with the evidence in the clinical trials.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A stepped economic evaluation was presented with a model developed
from the results of study E4599.
The incremental cost/additional year of quality adjusted overall
survival was estimated to be greater than $200,000.
The PBAC noted that the net incremental cost is largely due to
bevacizumab drug cost, and incremental outcomes are due to the
progression delay (and overall survival gains) seen in bevacizumab
patients in study E4599.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost/year to the PBS was estimated by the
submission to be in the range of $10 – $30 million in Year
5.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The addition of bevacizumab 15 mg/kg to carboplatin plus paclitaxel
resulted in a two months absolute increase in the median duration
of overall survival (12.3 months for bevacizumab plus carboplatin
plus paclitaxel versus 10.3 months for carboplatin plus paclitaxel)
corresponding to a statistically significant 20% relative decrease
in the risk of death (unstratified analysis: HR = 0.800; 95% CI:
0.689, 0.929). The PBAC noted that the data also indicate a
statistically significant difference (p <0.0001) in median
duration of PFS favouring patients in the bevacizumab plus
carboplatin plus paclitaxel treatment arm (median PFS = 6.4 months)
over patients in the carboplatin plus paclitaxel treatment arm
(median PFS = 4.8 months). The supporting evidence presented in the
submission was also generally consistent across the studies with
overall median survival increased by about 2 months and median
progression-free survival increased by around one month.
The PBAC considered that carboplatin in combination with paclitaxel
was a reasonable comparator and the use of this regimen aided the
interpretation of the incremental benefit of bevacizumab. However,
the PBAC considered that the incremental benefit of the monotherapy
component of the regimen had not been quantified.
The PBAC considered that the clinical claim of the submission that
bevacizumab, when used in combination with carboplatin plus
paclitaxel is superior in terms of comparative effectiveness and
inferior in terms of comparative safety over carboplatin plus
paclitaxel alone was reasonable and consistent with the evidence in
the clinical trials. However, the PBAC was concerned that the
combination of carboplatin plus paclitaxel was more toxic than the
doublet chemotherapy regimen carboplatin in combination with
gemcitabine. The PBAC considered that the addition of bevacizumab
to carboplatin and paclitaxel resulted in only a marginal gain in
overall survival of 2 months, and was at a cost of
treatment-related deaths. The PBAC noted that in Trial E4599, there
was greater than a 2.5 fold increase in fatal adverse events for
the bevacizumab plus carboplatin plus paclitaxel arm versus the
carboplatin plus paclitaxel arm.
A stepped economic evaluation was presented with a model developed
from the results of study E4599. The PBAC noted that the net
incremental cost is largely due to bevacizumab drug cost, and
incremental outcomes are due to the progression delay (and overall
survival gains) seen in bevacizumab patients in study E4599. The
results of the sensitivity analyses indicate that the model is most
sensitive to the treatment effect of bevacizumab, adenocarcinoma
histology and the choice and application of utility weights. The
PBAC noted that the inclusion of the higher administration cost in
the economic model did not have a material impact on the
ICER.
The PBAC noted that the utility values in the base case are applied
generally to the progression-free and progressed health states and
did not capture treatment-related differences in quality of life
(eg due to adverse events and/or additional infusions due to
bevacizumab treatment). A sensitivity analysis including
disutilities for bevacizumab-related adverse events increases the
ICER. The utilities for progression and progression-free health
states are based on a patient population on second-line treatment
for metastatic lung cancer, therefore, were considered conservative
for patients on first-line treatment.
The PBAC considered the total financial cost to be high and
uncertain as the estimated respective market shares for each drug
are highly uncertain and may impact the total cost
considerably.
The PBAC therefore rejected the submission on the basis of an
unacceptably high and uncertain cost-effectiveness ratio.
The PBAC also acknowledged and noted the consumer comments on this
item.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor had no further comment.
