Cetuximab, solution for I.V. infusion, 100 mg in 20 mL, 100 mg in 50 mL and 500 mg in 100 mL, Erbitux®, November 2008
Public summary document for Cetuximab, solution for I.V. infusion, 100mg in 20mL, 100mg in 50mL and 500mg in 100mL, Erbitux®, November 2008
Page last updated: 24 March 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: November 2008
1. Purpose of Application
The submission sought 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. Background
Cetuximab is currently listed on the PBS for use in squamous cell
cancer of the head and neck. This is the fourth 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 because of uncertain clinical benefit and
unacceptable and uncertain cost-effectiveness. The PBAC considered
that the proposed continuation rule would not be enforceable and
that an element of clinical judgement was required when
distinguishing between partial response and stable disease. The
Committee considered there was likelihood of misclassifications
when assessing patient eligibility under the continuation rule. The
PBAC considered that uncertainty still existed as to the extent of
incremental survival gain with cetuximab. The submission claimed
that cetuximab plus irinotecan was of similar or less toxicity than
“usual care”. The PBAC noted that a comparison across
the single-arm studies provided showed that the proportion of
patients with grades 3 and 4 adverse events of cetuximab plus
irinotecan was greater than those of the components of usual care.
The PBAC considered that there remained uncertainty over the
comparative toxicity of cetuximab plus irinotecan and usual care.
The PBAC also considered that the submission’s assumed
utility prior to progression, and the incremental cost per QALY
gained were biased in favour of cetuximab (See also Public Summary
Document of November 2005).
At the July 2006 meeting, the PBAC considered a minor re-submission
for a Section 100 listing for cetuximab for treatment of mCRC. The
PBAC considered the proposed continuation rule requiring patients
to have regular scans in the last weeks of life to be too onerous.
It was not clear whether the cost of scanning had been included in
the cost-effectiveness ratios. The application was rejected because
of uncertain clinical benefit and unacceptable and uncertain
cost-effectiveness.
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
Initial and Continuing
PBS-subsidised treatment of patients with metastatic colorectal
cancer with a WHO performance status of 2 or less where:
- 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.
- 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
Usual Care (UC) defined as best supportive care (BSC) plus active
chemotherapy. The PBAC considered that the appropriate current
comparator in the setting of metastatic colorectal cancer (mCRC)
was best supportive care, as there was no evidence that patients
with mCRC whose disease had progressed despite treatment with
oxaliplatin, irinotecan and 5-fluorouracil will benefit from
further treatment with the currently available chemotherapeutic
agents. This was a change from the Committee’s finding in
November 2005 that usual care, a composite of active chemotherapy
and best supportive care, was the appropriate comparator and
reflected recent advances in knowledge in this area. This also
meant that no costs for chemotherapy can be validly included in the
comparator arm of the economic evaluation.
For PBAC’s view see Recommendation and
Reasons.
7. Clinical Trials
The re-submission used the two open-label randomised trials (BOND
and CO-17) to conduct an indirect comparison between cetuximab plus
irinotecan and “Usual Care” on the whole mCRC
population via cetuximab as the common reference. The re-submission
also conducted an indirect comparison on the PBS eligible
population (K-RAS wild type) between cetuximab plus irinotecan
(using data from the retrospective studies De Roock/Lievre) and
“Usual Care” (using data from a retrospective analysis
of Study CO-17).
The trials published at the time of the submission were:
| Trial ID | Protocol/Publication title | Publication citation |
| Study 007 (BOND) | Open, randomised, multicentre, Phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal adenocarcinoma expressing the epidermal growth factor receptor (EGFR) and progressing on a defined irinotecan-based regimen. November 27 2006. | Cunningham, DHY., Siena, S., et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine 2004; 351:337-345. |
| CO-17 Jonker DJ et al Karapetis C et al | Cetuximab for the treatment of colorectal cancer. Cetuximab plus BSC versus BSC alone in the treatment of metastatic EGFR-positive colorectal cancer. | New England Journal of Medicine 2007; 357(20):2040-8. Signal 2005;6 (1): 15-7. |
| De Roock et al | KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. | Annals of Oncology 2008:19(3); 508-515 |
| Lievre et al | KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. | Journal of Clinical Oncology 2008:26(3);374-379 |
8. Results of Trials
Whole mCRC population
For progression free survival (PFS), there was a statistically
significant difference favouring (1) cetuximab plus irinotecan over
cetuximab monotherapy in BOND [4.1 vs. 1.5 months, HR=0.54 (95%CI:
0.42, 0.71; p<0.0001)] and (2) cetuximab monotherapy over best
supportive care in Study CO-17 [1.9 vs. 1.8 months, HR=0.68 (95%CI:
0.57, 0.80; p<0.0001)]. For overall survival (OS), there was no
statistically significant difference for cetuximab plus irinotecan
over cetuximab monotherapy in BOND [8.6 vs. 6.9 months, HR=0.91
(95%CI: 0.68, 1.21; p=0.48). There was a statistically significant
difference favouring cetuximab monotherapy over best supportive
care in Study CO-17 [6.1 vs. 4.6 months, HR=0.77 (95%CI: 0.64,
0.92; p=0.0046)]. It was possible that the results for overall
survival in BOND were indicative of confounding by cross-over (56
of 111 (50.5%) patients received cetuximab plus irinotecan
combination therapy upon documented disease progression with
cetuximab monotherapy). The usefulness of PFS where there was a
relatively short interval between recurrence and death was
uncertain and its interpretation as a composite clinical endpoint
(the definition of which can be inconsistent across different
trials) can be problematic. There appeared to be important
differences in treatment survival effects (in weeks) between the
cetuximab monotherapy arms across the studies. An examination of
the Kaplan-Meier plots also suggested that the assumption on which
the calculation of hazard ratios was based did not hold in the
current context, i.e. the curves indicated that the ratio of the
hazards was not constant over time or the individual hazard
functions were not proportional to each other – an assumption
that underpins the log-rank statistical test that has been
used.
The clinical evaluation of cetuximab plus irinotecan versus Usual
Care for the population for whom PBS listing was sought (K-RAS wild
type) was based on indirect comparisons across retrospective
studies of combined data from single arm studies.
K-RAS status as a treatment effect modifier
The data from the studies indicated that K-RAS status was a
treatment effect modifier; however these results were interpreted
with caution given that the data were derived from post hoc
retrospective analyses of single arm studies and the approach of
combining the response data was uncertain. There was considerable
potential for selection bias, ascertainment bias and confounding to
have affected the results.
The results from De Roock indicated that the majority of the
clinical benefit in K-RAS wild type patients (for example in terms
of median OS) was derived from the addition of irinotecan to
cetuximab (difference between cetuximab plus irinotecan and
cetuximab monotherapy approximates 20 weeks). There were no
important differences between the mutant groups regardless of
treatment type; however, the wild type patients demonstrated
important clinical benefit upon addition of irinotecan.
The inconsistency of treatment effect in the ‘common
reference’ group (cetuximab monotherapy) across the studies
made the interpretation of the results problematic. Median overall
survival appeared to be different between the K-RAS wild type
cetuximab monotherapy ‘arms’.
K-RAS wild type population: indirect comparison between
cetuximab plus irinotecan and BSC via cetuximab monotherapy as the
common reference
The re-submission concluded that in the all patient group the
incremental survival comparing cetuximab plus irinotecan to Usual
Care was approximately 25 weeks. This increased to approximately 40
weeks in the WT patients. The use of absolute differences in
treatment effect rather than relative treatment effects across
studies, to conduct an indirect comparison, was problematic.
Relative effects were ‘more stable’ across different
studies and more appropriate for use in an indirect comparison
context where there were differences between the treatment effects
of the common reference arms. However, an indirect comparison in
the current setting was difficult. The median and mean estimates
did not describe the whole survival experience and it was uncertain
whether the difference in treatment effects was constant across the
different studies.
The re-submission did not present any uncertainty around the
estimates of incremental survival gain. The survival data were
derived using simple weighting by size of sub-group. The survival
data for the cetuximab plus irinotecan were also obtained by
combining data from single arm open-label studies. These did not
form an evidentiary basis adequate enough to provide support for
the re-submission’s claim.
Therefore considerable uncertainty surrounded the extent of
incremental survival benefit of cetuximab plus irinotecan compared
to Usual Care for use in the stepped economic evaluation.
Furthermore, the assumption that the BSC arm from Study CO-17 was
equivalent to “Usual Care” in terms of effectiveness
was not adequately justified in the re-submission.
Cetuximab in combination with irinotecan tended to have more
serious adverse events (AEs) and Grade 3/4 AEs compared to
cetuximab monotherapy. The most common treatment related grade 3 or
4 AEs were diarrhoea, neutropenia, asthenia and rash in the
combination therapy group compared to asthenia, dyspnea, rash and
abdominal pain in the cetuximab monotherapy group. These AEs were
expected to be less in the BSC group. Cetuximab monotherapy had a
greater incidence of any adverse event of grade 3 or higher
compared to the BSC group (p<0.001). Patients in the cetuximab
monotherapy group had a higher incidence of rash, infection without
neutropenia, confusion and other pain as well as hypomagnesemia and
infusion reactions. Many of these reactions were known and expected
reactions of cetuximab.
9. Clinical Claim
The re-submission described cetuximab plus irinotecan as superior
in terms of comparative effectiveness compared to cetuximab
monotherapy which was in turn superior compared to best supportive
care (considered equivalent to Usual Care) but associated with more
toxicity. Based on the supporting data the PBAC did not accept this
claim.
For PBAC’s view see Recommendation and
Reasons.
10. Economic Analysis
A stepped economic evaluation was presented in the re-submission.
The incremental cost per extra QALY gained was in the range of
$45,000 - $75,000 for the base case K-RAS wild-type patients and in
the range of $105,000 - $200,000 for all patients.
The results of the sensitivity analyses indicated that the
incremental cost effectiveness ratio (ICER) values were most
sensitive to clinical benefit in terms of survival. The magnitude
of survival benefit associated with cetuximab plus irinotecan over
‘Usual Care’ used in the stepped economic evaluation
was derived from absolute rather than relative treatment effects in
an indirect comparison across single arm studies. The economic
evaluation also failed to examine any overall impact of the
reliability, sensitivity and specificity and accessibility of K-RAS
testing. The PBAC was of the opinion that the above aspects of the
economic evaluation tended to bias the clinical benefit in favour
of the proposed drug combination.
11. Estimated PBS Usage and Financial Implications
The likely number of prescriptions per year was estimated to be
< 10,000 and the financial cost to the PBS (excluding
co-payments) minus any savings in use of other drugs was estimated
to be between $10 million - $30 million in Year 5.
12. Recommendation and Reasons
The Committee considered that the appropriate current comparator in
the setting of metastatic colorectal cancer (mCRC) was best
supportive care, as there was no evidence that patients with mCRC
whose disease had progressed despite treatment with oxaliplatin,
irinotecan and 5-fluorouracil will benefit from further treatment
with the currently available chemotherapeutic agents. This was a
change from the Committee’s finding in November 2005 that
usual care, a composite of active chemotherapy and best supportive
care, was the appropriate comparator and reflected recent advances
in knowledge in this area. This also meant that no costs for
chemotherapy can be validly included in the comparator arm of the
economic evaluation.
The PBAC noted that, although not made explicit by the requested
restriction, the relevant comparison for this application was that
of cetuximab plus irinotecan against best supportive care, and that
if this was the intent of the restriction and the evidence base
used to justify the listing then the restriction should be amended
to specify that cetuximab must be used in combination with
irinotecan. The Committee also noted that, in an update to the last
submission for cetuximab in mCRC, the restriction now sought to
limit treatment to patients whose tumour had wild type K-RAS.
Although PBAC considered that it was quite possible that K-RAS
status was likely to be an effect modifier, considerable
uncertainty remains around the circumstances in which K-RAS status
will predict outcome, and the extent of benefit conferred by it. It
was possible that K-RAS status might predict the natural course of
mCRC independent of treatment with cetuximab, in addition to being
an effect-modifier for cetuximab. Data from the CAIRO2 cetuximab
trial were not supportive of K-RAS status as a predictive indicator
of responsiveness to treatment. Furthermore there are likely to be
other molecular markers which predict response to cetuximab and the
use of K-RAS alone requires further justification. Garassino et al.
(2008) and Lievre et al. (2008) proposed that a randomised,
controlled study, specifically aimed to examine the possible
predictive and prognostic role of K-RAS mutations, was needed to
definitively resolve whether K-RAS mutations were an independent
prognostic factor for cetuximab treatment (Garassino et al.
Should KRAS mutations be considered an independent prognostic
factor in patients with advanced colorectal cancer treated with
cetuximab? J Clin Oncol 2008
DOI:10.1200/JCO.2008.16.8195., Lievre et al. (2008) KRAS
mutations as an independent prognostic factor in patients with
advanced colorectal cancer treated with cetuximab. J Clin Oncol
2008; 26:374-379..)
The Committee noted that there were no direct comparative studies
of cetuximab plus irinotecan against best supportive care in mCRC
patients with wild type K-RAS and that the evidentiary basis for
the K-RAS population was based on analyses of retrospective data
extracted from four studies. The indirect comparison between
cetuximab plus irinotecan and best supportive care using the
results from the open-label randomised BOND and CO-17 trials was
considered by the Committee to have limited relevance to this
population, primarily because no information on K-RAS status was
available for the BOND study.
In the absence of evidence from a proper randomised comparison,
PBAC considered that the claim of an overall survival benefit of
approximately 40 weeks was not well substantiated, as was based on
non-experimental evidence that was likely to be subject to
selection bias (confounding). The Committee considered the response
rate from study CO17 likely to be more reliable as it was
collected, albeit retrospectively, from an RCT, whereas the De
Roock result was derived from a retrospective analysis of mCRC
patient K-RAS data that were lumped from four different trials, and
was likely to overestimate the benefit of cetuximab
treatment.
The modelled economic evaluation presented thus relied upon an
estimate of overall survival that was highly uncertain. The most
reliable results were those derived from study CO17 in which the
group with wild type K-RAS mCRC treated with cetuximab monotherapy
demonstrated a statistically significant improvement in overall
survival of around 20 weeks over the same group treated with BSC.
However, the modelled evaluation assumed a benefit of approximately
40 weeks for the combination of cetuximab with irinotecan; thus
most of the uncertainty arose from the additional benefit assumed
to accrue from the addition of irinotecan to cetuximab. This,
together with the drug price proposed in the submission, resulted
in an incremental cost effectiveness ratio (ICER) that was both
high and highly uncertain.
The PBAC also identified the model’s inclusion of the costs
but not the clinical benefit of active chemotherapy for 60 % of
patients in the BSC arm as favouring cetuximab. The use of the QoL
estimates derived from the MABEL (Monoclonal Antibody Erbitux
in a European Pre-License Study.) study and Petrou and
Campbell (The utility values obtained by Petrou and Campbell
(1997) were used in the July 2005 PBAC submission; the utility
values by Petrou and Campbell have also been used in NICE reviews
for irinotecan, oxaliplatin and raltitrexed for the treatment of
advanced mCRC (Jones, L et al 2001).) were considered to add
to the uncertainty in the ICER. Although quality of life were
collected in Study CO-17, these were not used in the economic
evaluation as the interpretation of QoL data was complicated by
differences in compliance rates between the cetuximab monotherapy
and best supportive arms. Lastly, the submission failed to assess
the impact of the accuracy of K-RAS testing on the incremental
cost-effectiveness of treatment.
Thus, overall the PBAC rejected the application 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.
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
Merck Serono Australia is disappointed with this recommendation and
will continue to work with the PBAC to ensure access to this
targeted therapy for patients with metastatic colorectal
cancer.
