Cetuximab, solution for I.V. infusion, 100 mg in 20 mL, 100 mg in 50 mL and 500 mg in 100 mL, Erbitux®, March 2009
Public summary document for Cetuximab, solution for I.V. infusion, 100 mg in 20 mL, 100 mg in 50 mL and 500 mg in 100 mL, Erbitux®, March 2009
Page last updated: 03 July 2009
Public Summary Document
Product:Cetuximab, solution for I.V. infusion, 100
mg in 20 mL, 100 mg in 50 mL and
500 mg in 100 mL, Erbitux®
Sponsor: Merck Serono Australia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
1) To request an Authority required listing (and inclusion in the
Chemotherapy Pharmaceuticals Access Program (CPAP)) of cetuximab
for the treatment of patients with metastatic colorectal cancer
following failure of irinotecan and failure of or intolerance to
oxaliplatin.
2) To provide further information to address the PBAC’s
concerns from the November 2008 meeting regarding the economic
evaluation and KRAS diagnostic testing.
2. Background
Cetuximab is currently listed on the PBS for use in squamous cell
cancer of the head and neck. This is the fifth application for
listing of cetuximab for the treatment of metastatic colorectal
cancer (mCRC).
At the March 2005 meeting, the PBAC rejected an application to list
cetuximab for treatment of epidermal growth factor receptor (EGFR)
expressing metastatic colorectal cancer in patients who have failed
irinotecan based therapies, and either failed or are unsuitable for
oxaliplatin based therapies, to be used in combination with
irinotecan because of uncertain extent of clinical benefit and
uncertain but unacceptable cost-effectiveness.
At the November 2005 meeting, the PBAC once again rejected an
application for cetuximab for the treatment of metastatic
colorectal cancer (MCRC) where the current standard
chemotherapeutic options have failed, because of uncertain clinical
benefit and unacceptable and uncertain cost-effectiveness.
At the July 2006 meeting, the PBAC rejected a minor
re-submission for a Section 100 listing for cetuximab for treatment
of mCRC because of uncertain clinical benefit and unacceptable and
uncertain cost-effectiveness.
At the November 2008 meeting, the PBAC rejected an application for
third-line treatment of mCRC in patients whose tumour has wild type
KRAS because of uncertainty about the extent of survival benefit
over best supportive care and because of the resultant high and
highly uncertain cost effectiveness ratio.
3. Registration Status
Cetuximab solution for I.V. infusion 2 mg/mL was TGA registered on
4 February 2005. Additional strengths (50 mg/10 mL, 100 mg/20 mL,
250 mg/50 mL and 500 mg/100 mL) were TGA registered on 25 September
2007.
All strengths are registered for the following indications:
- Treatment of patients with metastatic colorectal cancer that has been demonstrated to express epidermal growth factor receptor (EGFR) 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, 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
PBS-subsidised treatment of patients with metastatic colorectal
cancer with a WHO performance status of 2 or less, in combination
with irinotecan, where:
a) Patients have received and failed 5-fluorouracil or
capecitabine, received and failed an irinotecan based therapy and
received and failed or are unsuitable for an oxaliplatin based
therapy.
b) There is evidence that the patient has KRAS wild type in the
tumour material.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Cetuximab provides a treatment option for patients with metastatic
colorectal cancer who have failed the current standard
chemotherapeutic options.
6. Comparator
The submission nominated best supportive care (BSC) as the
comparator.
At the November 2008 meeting, the PBAC agreed that BSC is the
appropriate comparator, as there was no evidence that patients with
metastatic colorectal cancer (mCRC), whose disease had progressed
despite treatment with oxaliplatin, irinotecan and 5-fluorouracil,
would benefit from further treatment with the currently available
chemotherapeutic agents.
7. Clinical Trials
No new clinical data were presented in this submission compared to
the November 2008 submission. See November 2008 Public Summary
Document (PSD) for details.
8. Results of Trials
For the key results, see November 2008 PSD.
In this submission, the treatment effect (overall survival) was
derived using data from Study C017, as reported by Karapetis
(2008), for KRAS wild type patients receiving cetuximab plus best
supportive care versus best supportive care alone.
The overall survival curve from Karapetis et al. (2008), for
cetuximab plus BSC and BSC alone, was used to calculate the area
under extrapolated survival curves and derive a mean overall
survival, which was between 5 – 6 months in the BSC arm and
10-11 months for the cetuximab plus BSC arm.
For PBAC’s view, see Recommendation and
Reasons.
9. Economic Analysis
A modelled economic evaluation was presented in the form of a
cost-effectiveness analysis.
The submission presented a “worse case” scenario
analysis as part of the modelled economic evaluation for the KRAS
sub-group in which the treatment effect came from the CO17 study
cetuximab versus BSC but the costs are those of cetuximab and
irinotecan.
The sensitivity analyses showed that the economic model is
sensitive to the overall survival time and that varying the cost of
the KRAS test has only a minor impact on the incremental
cost-effectiveness ratio (ICER) but that the inclusion of costs for
irinotecan substantially increases the ICER.
In the November 2008 submission, the cost for irinotecan per
patient was derived from a progression-free survival period of
approximately 35.3 weeks sourced from Lievre et al. 2008. The cost
for irinotecan in the present submission is less as the mean
progression-free survival from Study C017 for cetuximab monotherapy
is used to derive a time on treatment.
The “worst case” ICER is estimated to be in the range
of $75,000 - $200,000 (evaluation calculation) per QALY. No adverse
events or cost of adverse events for irinotecan treatment are
factored into the ICERs and therefore the new cost of irinotecan
therapy may be underestimated.
For PBAC’s view, see Recommendation and
Reasons.
10. Estimated PBS Usage and Financial Implications
The likely number of prescriptions per year for cetuximab was
estimated to be less than 10,000 in year 5.
11. Other Relevant Factors
KRAS diagnostic test
The submission presented updated information relating to the
accuracy of the KRAS test.
The submission also claimed a retrospective KRAS analysis of tumour
samples from Study C017 (Karapetis et al.), as evidence for the
predictive value of KRAS testing to determine which patients would
best benefit from cetuximab therapy.
The sponsor has set up a national KRAS testing program.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC noted that the submission nominated best supportive care
as the comparator, agreed by the PBAC as appropriate at the
November 2008 meeting, as there was no evidence that patients with
metastatic colorectal cancer (mCRC), whose disease had progressed
despite treatment with oxaliplatin, irinotecan and 5-fluorouracil,
would benefit from further treatment with the currently available
chemotherapeutic agents. However, the PBAC noted that the requested
restriction in the current re-submission includes use of cetuximab
with irinotecan.
The PBAC noted that no new clinical data were presented in the
re-submission but additional information in relation to KRAS
mutation testing; a revised economic evaluation; and a revised risk
sharing arrangement with the Department was presented. The
treatment effect (overall survival) was derived using data from
Study C017, as reported by Karapetis (2008), for KRAS wild type
patients receiving cetuximab plus best supportive care versus best
supportive care alone. However, because the BOND trial appears to
suggest that cetuximab + irinotecan is superior to cetuximab alone
in the whole mCRC population, a “worse case” scenario
analysis was presented as part of the modelled economic evaluation
for the KRAS sub-group in which the treatment effect came from the
CO17 study cetuximab versus BSC but the costs are those of
cetuximab and irinotecan.
The PBAC noted that using a Weibull extrapolation over a time
horizon of five years, fitted to the Karapetis et al. (2008) data,
mean overall survival estimated during the evaluation was 7.3
months (31.6 weeks) for the BSC arm and 10.9 months (47.6 weeks)
for the cetuximab plus BSC arm. The PBAC also noted that the
difference in mean overall survival presented in the submission was
approximately 22 weeks compared to the evaluation’s estimate
of 16 weeks. The PBAC considered that the submission’s
estimate likely overestimated the overall survival and that the
very small number of patients alive by 14 months suggested that
there may not be a need to extrapolate the treatment effect beyond
the duration of the trial.
Therefore, the PBAC considered that the extent of overall survival
benefit of cetuximab over best supportive care in the KRAS
sub-group remained uncertain as it is based on a post-hoc analysis;
and the method of extrapolation of the treatment effect beyond the
trial period (14 months to 5 years) is uncertain. The PBAC noted
that the Pre-PBAC response estimated the mean survival for KRAS
wild type patients receiving BSC using the Kaplan-Meier curve to be
approximately 24 weeks and that the ICERs were estimated to be in
the range of $45,000 - $75,000 per QALY, depending on whether the
estimate was trial based, submission based or evaluation
based.
The PBAC noted that the modelled economic evaluation presented a
cost-effectiveness analysis, and that the “worst case”
(cost is cetuximab and irinotecan and BSC but effectiveness is
cetuximab and BSC versus BSC) assumes a treatment period based on
progression-free survival data for cetuximab monotherapy KRAS
wild-type group from Study CO17. The PBAC also noted that the
economic model is sensitive to the overall survival time and that
varying the cost of the KRAS test has only a minor impact on the
ICER but the inclusion of costs for irinotecan substantially
increases the ICER.
In the November 2008 submission the cost for irinotecan per patient
was based on an estimated time on treatment derived from a
progression-free survival period of approximately 35.3 weeks
sourced from Lievre et al. 2008. The PBAC noted that the cost for
irinotecan in the present submission is less as the mean
progression-free survival from Study C017 for cetuximab monotherapy
is used to derive a time on treatment. The PBAC noted that the
“worst case” ICER is estimated to be in the range of
$75,000 to $200,000 (evaluation calculation) per QALY and that no
adverse events or cost of adverse events for irinotecan treatment
are factored into these ICERs and therefore the cost of irinotecan
therapy is underestimated.
The PBAC noted that data on the sensitivity and specificity of the
available KRAS tests was not available and considered that the
potential impact of false positive and false negative outcomes to
the economic evaluation is unknown and remains an area of
uncertainty. The criteria for entry into the trial was EGFR
positivity and the PBAC considered that the effect of patients
being treated with cetuximab on the PBS without this pre-requisite
is unknown as the requested restriction does not select for EGFR
positive patients alone. The trial based ICER of between $45,000 -
$75,000 per QALY as calculated in the Pre-PBAC response includes
only patients that are EGFR positive and therefore the PBAC
considered this ICER to be uncertain.
The PBAC noted that the presence of the V600E B-RAF mutation may
also be a marker for resistance in colorectal cancer as per the
published paper by Di Nicolantonio, F et al in the Journal of
Clinical Oncology, Dec 10 2008, 5705-5712, and noted that KRAS and
B-RAF are mutually exclusive. The PBAC considered that the
inclusion of these and other molecular markers may lead to better
targeting of patients.
Therefore, the PBAC rejected the submission for cetuximab on the
basis of high and uncertain cost-effectiveness. Without further
information, the PBAC considered that a price decrease would be
necessary to alleviate the uncertainty of the cost-effectiveness
and to protect against the high cost of use with irinotecan.
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 identification of the K-Ras oncogene represents an important
advancement in personalised medicine. Merck Serono Australia
remains committed to working together with the PBAC to address
their remaining uncertainties and ensure that patients with
metastatic colorectal cancer will have appropriate access to
treatment with cetuximab.
