Cetuximab, solution for IV infusion, 100mg in 50mL, Erbitux®, March 2007
Public summary document for Cetuximab, solution for IV infusion, 100mg in 50mL, Erbitux®, March 2007
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Public Summary Document
Product: Cetuximab, solution for IV infusion,
100mg in 50mL, Erbitux®
Sponsor: Alphapharm Pty Limited
Date of PBAC Consideration: March 2007
1. Purpose of Application
To seek an Authority required listing for the treatment, in
combination with radiotherapy, of patients with locally advanced
squamous cell cancer of the larynx, oropharynx or hypopharynx in
whom the use of cisplatin is either contraindicated or cannot be
tolerated.
2. Background
This is the first submission considered by the PBAC for cetuximab
for the treatment of squamous cell carcinoma of the head and neck.
Previous applications have sought the listing of cetuximab for the
treatment of metastatic colorectal cancer.
3. Registration Status
Erbitux is registered:
- for the treatment of patients with metastatic colorectal cancer that has been demonstrated to be epidermal growth factor receptor (EGFR) positive and whose disease has progressed or is refractory to irinotecan based therapy. Cetuximab can be used at the doses recommended either in combination with irinotecan or as a single agent.
- in combination with radiation therapy is indicated for the treatment of patients with locally advanced squamous cell cancer of the head and neck.
4.Listing Requested and PBAC’s View
Authority required
Treatment in combination with radiotherapy, of patients with UICC
Stage III, IVa or IVb squamous cell cancer of the larynx,
oropharynx or hypopharynx in whom the use of cisplatin is either
contraindicated or cannot be tolerated.
Please see the Recommendation and Reasons for the PBAC
view
5. Clinical Place for the Proposed Therapy
Cetuximab will provide a treatment option for patients with locally
advanced squamous cell cancer of the larynx, oropharynx or
hypopharynx in whom use of cisplatin is either contraindicated or
cannot be tolerated.
6. Comparator
The submission nominated placebo, as an add-on to radiotherapy
alone, as the comparator. The PBAC considered the comparator
appropriate.
7. Clinical Trials
An open label head-to-head randomised comparative trial (Bonner
Study) comparing cetuximab and radiotherapy with radiotherapy alone
was presented. The study’s planned follow-up was 5 years. The
submission reported the results based on median duration of
follow-up of 45.7 months for the radiotherapy alone group, and 45
months for the combined radiotherapy plus cetuximab group.
The trial forming the basis of the submission is detailed
below.
| Trial | Publication citation |
| Bonner study | Bonner JH, PM, Giralt J, Azarnia N, Shin D, Cohen R, Jones C, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England Journal of Medicine 2006;354(6):567-578 |
8. Results of Trials
The results of the key trial are summarised in the tables below.
Results of the comparative randomised trial- loco-regional control (primary outcome)
| Cetuximab + radiotherapy n = 211 | Radiotherapy alone n = 213 | |
| Median duration LRC months (95% CI) | 24.4 (15.7 to 45.1) | 14.9 (11.8 to 19.9) |
| Hazard Ratio (95% CI) | 0.68 (0.52 to 0.89) p = 0.005 | |
| Patients with LRC % (95% CI) | ||
| One year | 63.2 (56.5 to 69.8) | 55.3 (48.5 to 62.2) |
| Two year | 50.3 (43.4 to 57.3) | 40.7 (33.8 to 47.5) |
There was a statistically significant difference in loco-regional control favouring
cetuximab in the Bonner trial’s primary analysis.
Results of the comparative randomised trial- overall survival (secondary outcome)
| Cetuximab +Radiotherapy n = 211 | Radiotherapy alone n = 213 | |
| Median survival months (95% CI) | 49.0 (32.8 to 62.6*) | 29.3 (20.6 to 42.8) |
| Hazard Ratio (95% CI) | 0.74 (0.56 to 0.97) p = 0.032 | |
| Patients alive % (95% CI) | ||
| One year | 77.6 (72.0 to 83.3) | 73.8 (67.9 to 79.8) |
| Two year | 62.2 (55.6 to 68.7) | 55.2 (48.4 to 62.0) |
| Three year | 56.1 (49.3 to 62.8) | 45.0 (38.2 to 51.9) |
- median survival had not been reached at the time of the assessment. Months shown are those for duration of follow-up for the relevant groups.
The PBAC noted that there was a large difference between the population enrolled in
the Bonner study and the Australian patients who might receive cetuximab, with the
trial having a higher proportion of patients with oropharyngeal disease than is observed
in Australia, as patients with oropharyngeal disease are generally considered to respond
better to treatment than those with disease of the larynx or hypopharynx. The Committee
however agreed with the sponsor that there is currently no evidence to suggest that
this difference would result in a significant difference in effectiveness for cetuximab
if listed on the PBS as requested compared to that observed in the Bonner study. The
impact of tumour location on the effectiveness of cetuximab in the Bonner study was
subject to a predefined subgroup analysis and the confidence intervals of the hazard
ratios for these subgroups overlapped for both the primary (locoregional control)
and the secondary (survival, progression free survival) outcomes.
Overall the adverse events associated with radiation therapy appear to be similar
in the cetuximab + radiotherapy arm compared to those in the radiotherapy alone arm.
The incidence of the acne, rash, headache, fever, pruritus and chills was higher in
patients who received cetuximab and radiotherapy compared to those who received radiotherapy
alone.
9. Clinical Claim
The submission claimed that cetuximab plus radiotherapy has
significant clinical advantages over radiotherapy alone but has
more toxicity.
For PBAC’s view see Recommendation and Reasons
10. Economic Analysis
A preliminary economic evaluation adopting a cost-effectiveness
approach was presented. The resources included the overall
comparative costs and outcomes for each alternative.
The trial-based incremental discounted cost/extra life year gained
was estimated to be between $45,000 – $75,000 and the
trial-based incremental discounted cost/extra year of loco-regional
control gained was estimated to be between $15,000- $45,000.
A modelled economic evaluation was presented. The resources
included were similar to the preliminary economic evaluation with
the only difference being ongoing consultations with an
oncologist.
The base case modelled incremental discounted cost/extra life year
gained was estimated to be between $15,000- $45,000 as was the base
case modelled incremental discounted cost/extra year of
loco-regional control gained.
11. Estimated PBS Usage and Financial Implications
The submission estimates that the number of patients treated would
be <1,000 and that the estimated gross cost to the PBS would be,
< $3 million in Year 4 of listing.
12. Recommendation and Reasons
The PBAC recommended listing for use in Stage III, IVa or IVb
squamous cell cancer on the larynx, oropharynx or hypopharynx in
combination with radiotherapy, on the basis of acceptable
cost-effectiveness against radiotherapy alone, at the price
proposed in the submission. The Committee accepted that
loco-regional control was a more relevant end-point in head and
neck cancers than in other cancers, and considered that the
incremental cost of treatment with cetuximab in these patients was
acceptable at between $15,000-$45,000 per extra life year gained,
even though the survival gains were not quality adjusted.
The PBAC noted that there was a large difference between the
population enrolled in the Bonner study and the Australian patients
who might receive cetuximab, with the trial having a higher
proportion of patients with oropharyngeal disease than is observed
in Australia, as patients with oropharyngeal disease are generally
considered to respond better to treatment than those with disease
of the larynx or hypopharynx. The Committee however agreed with the
sponsor that there is currently no evidence to suggest that this
difference would result in a significant difference in
effectiveness for cetuximab if listed on the PBS as requested
compared to that observed in the Bonner study. The impact of tumour
location on the effectiveness of cetuximab in the Bonner study was
subject to a predefined subgroup analysis and the confidence
intervals of the hazard ratios for these subgroups overlapped for
both the primary (locoregional control) and the secondary
(survival, progression free survival) outcomes.
The Committee agreed with the restriction wording proposed by the
Restrictions Working Group with the following amendments: (1)
cetuximab should not be subsidised in patients who have completed
cisplatin treatment; (2) the contraindications to cisplatin should
be those in the TGA approved product information; and (3) lifetime
subsidised treatment should be limited to a maximum of 8 supplies
per treatment site, on the basis that a normal treatment course
requires 8 supplies, but with a proviso that the maximum can be
increased to 10 in a patient in whom radiotherapy is suspended.
Furthermore, the Committee requested that Medicare Australia
formulate questions for prescribers to ensure that cetuximab is
used in combination with radiotherapy, ie not as monotherapy or in
combination with cisplatin
The PBAC requested the sponsor provide the Committee with updates
of the results of clinical trials in this indication, and that
usage be monitored by the DUSC for any evidence that cetuximab is
being used first line.
Recommendation
CETUXIMAB, solution for IV infusion, 100mg in 50mL
Restriction: Authority required
Initial treatment of stage III, IVa or IVb squamous cell cancer of
the larynx, oropharynx or hypopharynx for the week prior to
radiotherapy, where cisplatin is contraindicated according to the
TGA approved Product Information.
Initial treatment of stage III, IVa or IVb squamous cell cancer of
the larynx, oropharynx or hypopharynx in combination with
radiotherapy, where cisplatin is not tolerated.
Maximum Quantity: 6
Repeats: nil
NOTE: No applications for repeats will be authorised
Restriction: Authority required
Continuing treatment of stage III, IVa or IVb squamous cell cancer
of the larynx, oropharynx or hypopharynx, in combination with
radiotherapy, where cisplatin is either contraindicated or not
tolerated.NOTE: A maximum lifetime supply for this indication is
limited to a maximum of 8 treatments per site and to 10 treatments
per site for patients in whom radiation is suspended
Maximum Quantity: 4
Repeats: 6
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 chose not to make a comment.
