Multiple Technology Appraisal Cetuximab

938 Pages·2015·8.36 MB·English

Multiple Technology Appraisal

Cetuximab (review of TA176) and
panitumumab (partial review of TA240) for
the first line treatment of metastatic
colorectal cancer ID794

Committee papers
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

MULTIPLE TECHNOLOGY APPRAISAL

Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer [ID794]

Contents:

1 Pre-meeting briefing

2 Full preceding guidance: TA176, cetuximab for the first-line treatment of
metastatic colorectal cancer
TA240 was published as terminated guidance (“NICE is unable to recommend
the use in the NHS of panitumumab”) because the manufacturer did not make
a submission

3 Assessment Report prepared by Peninsula Technology Assessment Group,
University of Exeter
 Assessment Report
 Appendices A-J
 Erratum

4 Consultee and commentator comments on the Assessment Report from:
 Amgen
 Merck Serono
 NCRI RCP RCR ACP joint comments
 Healthcare Improvement Scotland

The Royal College of Nurses and Department of Health indicated that they
had no comments on this Assessment Report

5 Response to consultee and commentator comments on the Assessment
Report from Peninsula Technology Assessment Group, University of Exeter
 Response
 Addendum

6 Company submission(s) from:
 Amgen (panitumumab)
 Merck Serono (cetuximab)

7 Professional group, patient group and NHS organisation submissions
from:
 Joint submission from Beating Bowel Cancer and Bowel Cancer UK
 NCRI RCP RCR

8 Expert personal statements from:
 Dr Saifee Mullamitha – clinical expert, nominated by Roche
 Dr Vanessa Potter – clinical expert, nominated by
NCRI/RCP/RCR/ACP
 Ben Ashworth – patient expert nominated by Beating Bowel Cancer
 Stuart Barber – patient expert nominated by Beating Bowel Cancer

Any information supplied to NICE which has been marked as confidential, and which
is not related to the patient access scheme, has been redacted. All personal
information has also been redacted.
CONFIDENTIAL UNTIL PUBLICATION
NATIONAL INSTITUTE FOR HEALTH AND CARE
EXCELLENCE
Premeeting briefing
Cetuximab (review of TA176) and panitumumab (partial
review of TA240) for the first line treatment of metastatic
colorectal cancer
This premeeting briefing highlights key issues for discussion at the first
Appraisal Committee meeting and should be read with the full supporting
documents for this appraisal.
Key issues for consideration
Clinical effectiveness
Generalisability
 Considering the information below, are the clinical trials generalisable to the
population and current practice in England?
 Trials included subsequent treatments that are not widely used in England.
 Average age of trial populations was 59–65 years and the majority of
participants had an ECOG performance status of <2, meaning that people were
younger and fitter than the UK population of people with metastatic colorectal
cancer.
 The Assessment Group assumed that the diagnostic tests for RAS wild-type
status used in the clinical trials had the same accuracy as the tests used in
NHS practice (page 307 assessment report). It suggested that if the test were
less accurate in clinical practice than in the trials, this would likely increase the
ICERs for cetuximab and panitumumab.
 Are the diagnostic tests for RAS wild-type status available to all patients in the
NHS?

National Institute for Health and Care Excellence 1 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015
CONFIDENTIAL UNTIL PUBLICATION
 How important are uncertainties and potential for bias in the clinical evidence?
 Evidence in people with RAS wild-type status tumours is mainly based on post
hoc subgroup analyses, not full intention-to-treat trial populations (the subgroup
analysis was pre-planned in 1 trial: PEAK). There are limitations associated
with interpreting subgroup data (for example, no minimising bias by
stratification or randomisation) and reduced power to show statistical
significance.
 The sample size of people with metastases confined to the liver was small and
analyses were post hoc, increasing uncertainty and further reducing power of
studies to show statistical significance.
 The subgroup data are the only available data for the RAS wild-type sub-
population. The European Medicines Agency used these data to inform the
recent change to the licensed indications for the technologies.
 Trials were open-label design (participants and outcomes assessors were not
blinded). However, 2 studies (OPUS and CRYSTAL) performed a blinded
retrospective review of radiological assessment, progression, and best
objective response rate, and 1 study (PRIME) did so for objective response rate
In addition, in 1 study (PRIME) an independent data monitoring committee
reviewed interim analyses of safety and progression free survival. The PEAK
trial did not include any independent assessments.
Treatment pathway
 Patients with colorectal cancer may undergo surgery to resect liver metastases;
for some patients, they are considered for resection only after first line
chemotherapy shrinks the hepatic metastases.
 Are all patients considered for resection of liver metastases in clinical practice
or only people with metastases confined to the liver?
 What is the evidence for increased survival after resection of liver metastases?
Robustness of clinical effectiveness estimates
 The Assessment Group performed a network meta-analysis to compare
cetuximab plus chemotherapy with chemotherapy alone, panitumumab plus
National Institute for Health and Care Excellence 2 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015
CONFIDENTIAL UNTIL PUBLICATION
chemotherapy with chemotherapy alone, and lastly cetuximab plus chemotherapy
with panitumumab plus chemotherapy. Did the Assessment Group use robust
methods and assumptions in its network meta-analysis?
 Was it appropriate for the Assessment Group to use a fixed effect model in its
network meta-analysis?
 The Assessment Group generated 2 discrete networks: 1 evaluating
FOLFOX-containing chemotherapy regimens and the second comparing
FOLFIRI-containing chemotherapy regimens. Was this appropriate, based on the
trial data available (it excluded the CALGB-80405 trial)?
Comparators
 Was it appropriate for the Assessment Group to exclude some comparators from
its base case?
 Which FOLFOX regimen (FOLFOX4 or FOLFOX6) is more commonly used in
clinical practice in England? The Assessment Group used FOLFOX4 in its base
case and FOLFOX6 in a scenario analysis.
 Is XELOX used in clinical practice in England and is it a relevant comparator?
 The Assessment Group also excluded the following comparators from its base
case: bevacizumab, capecitabine monotherapy, tegafur, folinic acid and
fluorouracil.
 The Assessment Group assumed that XELOX had equal efficacy compared with
FOLFOX but that XELOX was cheaper. Is this appropriate, given the tolerability
profile of XELOX?
Cost effectiveness
Generalisability
 The Assessment Group used an every other week dosing schedule for cetuximab
in its base case model, although the trials use weekly dosing. NICE cannot issue
guidance outside of the marking authorisation for cetuximab (which stipulates
weekly dosing). The Assessment Group did a scenario analysis using weekly
dosing of cetuximab; the results are presented in Table 7 and Figures 3–6.
National Institute for Health and Care Excellence 3 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015
CONFIDENTIAL UNTIL PUBLICATION
 ******************************************************************************************
******************************************************************************************
*****************************************
 For the subgroup analysis of people with metastases confined to the liver, the
following parameters were the same as used for the full population who had
metastases not confined to the liver: time of resection, overall survival for patients
who have not undergone resection, overall survival post-resection,
progression-free survival post-resection, utilities, costs, and adverse events.
Parameters that were unique to the subgroup of people with only liver metastases
were: proportion of people who had surgical resection, progression-free survival
for patients who have not undergone resection and treatment duration. Is this
clinically realistic?
 The Assessment Group used an average body surface area of 1.85m2 for people
in its model, meaning that everyone would be treated with the highest dosage of
cetuximab. Does this accurately reflect the distribution of patients?
Treatment duration
 Above all, treatment duration is the most critical issue to explain the difference in
cost effectiveness estimates between the Merck model and Assessment Group
model; the ICERs increase substantially using the Assessment Group estimates.
 Treatment duration affected the total mean cost of drug acquisition and
administration, which were critical drivers of cost effectiveness because they
were by far the largest cost items.
 The Assessment Group ICERs were very sensitive to changes in treatment
duration (deterministic sensitivity analysis).
 ICERs were impacted in a scenario analysis in which the Assessment Group
modelled overall survival from trial data, which in turn changed treatment
duration estimates (pages 379–382 of the assessment report).
Was the Assessment Group’s method of estimating treatment duration (presented
on pages 284–298 of the assessment report) appropriate? Merck acknowledged
that it underestimated treatment duration and submitted revised estimates to
reflect the actual mean treatment durations from the CRYSTAL and OPUS studies
National Institute for Health and Care Excellence 4 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015
CONFIDENTIAL UNTIL PUBLICATION
(pages 11–12 of Merck’s comments on the assessment report); these have not
been fully critiqued by the Assessment Group because they were submitted as
consultation comments but the Assessment Group noted that Merck did not
explain its method for calculating mean treatment duration in CRYSTAL and
OPUS.
Costs
 The cost of drug administration (comprising drug delivery, pharmacy costs,
infusion pump and line maintenance) was one of the largest cost items and is
affected by another key issues: treatment duration. Did the Assessment Group
use NHS Reference costs appropriately to estimate the cost of drug
administration? Refer to page 322–329 of the assessment report and page 8 of
Merck’s consultation comments (which have not been critiqued by the
Assessment Group).
 Did the Assessment Group use an appropriate estimate for the cost of resection
surgery? Costs were estimated as follows:
 Merck: £2707
 Assessment Group: £10,440
 NICE technology appraisal 176: £8929.
Proportion of patients who undergo resection
 What is the likely proportion of patients who undergo surgical resection in clinical
practice? The Assessment Group’s ICERs were very sensitive to changes in this
parameter (deterministic sensitivity analysis).
 The Assessment Group considered that the company (Merck) estimates were
not appropriate (see table 92 of the assessment report).
 The Assessment Group stated that its estimated proportion of patients who
undergo resection with CET+FOLFOX ******* is subject to uncertainty because
it is based on an indirect comparison (pages 251–258 of the assessment
report). Is it realistic to assume that the proportion of patients who undergo
resection with CET+FOLFOX ******* is higher than the proportion with
PAN+FOLFOX *******?
National Institute for Health and Care Excellence 5 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015
CONFIDENTIAL UNTIL PUBLICATION
 In Merck’s consultation comments on the assessment report (which have not
been critiqued by the Assessment Group), it referred to data which suggests
that a higher proportion of patients undergo surgical resection in clinical
practice than in clinical trials (including the CELIM trial by Folprecht et al, the
Ye et al study and the Adam et al study). It noted that during NICE technology
appraisal 176, clinical specialists stated that a realistic rate for potentially
curative resection with chemotherapy in general was approximately 12–15%,
which could rise to approximately 30–35% with the addition of cetuximab.
Overall survival and progression-free survival
 The Assessment Group ICERs were very sensitive to changes in the
post-resection overall survival and progression-free survival estimates
(deterministic sensitivity analysis). In addition, the Assessment Group
acknowledged a number of uncertainties in their progression-free survival
estimates (see section 5.8).
 In its base-case model, the Assessment Group assumed that survival after first
line progression is independent of first line treatment (that is to say, treatment
effect from first line drugs stopped when disease progressed). Is this
appropriate?
 Was it appropriate for the Assessment Group to use the Weibull model to
extrapolate post-resection progression due to any other cause? See pages
260–265 of the assessment report for details.
 Was it appropriate for the Assessment Group to use the log logistic model to
extrapolate overall survival post-resection? It rejected the Weibull model
because progression free survival exceeded overall survival after 13 years,
which is not possible. See pages 260–266 of the assessment report for details.
 Was it appropriate for the Assessment Group to use the French study by Adam
et al. 2004 to estimate progression-free survival and overall survival
post-resection? How generalisable is the population in the Adam et al. study?
 Was the Assessment Group’s method of estimating progression-free survival for
patients who did not undergo resection appropriate (pages 273–277 of the
assessment report)?
National Institute for Health and Care Excellence 6 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015
CONFIDENTIAL UNTIL PUBLICATION
Utility values
 Are the Assessment Group’s utility values appropriate (Table 1)? Although the
utility values are derived from trial-based EQ-5D data, the data were from the
broader KRAS wild-type population (not specific to RAS wild-type patients). Note
that changing the utility values had little impact on the ICERS.
Table 1. Base case utility values in company (Merck) and Assessment Group
model (table 83 and 111 assessment report)
Parameter Company Assessment Assessment Group source
Group
1st line (PFS) 0.778 0.767 Bennett et al. (2011); average of the
PAN+FOLFOX and FOLFOX arms of
the PRIME trial (EQ-5D data)
2nd line 0.769 0.762 Bennett et al. (2011) l FOLFIRI arm of
the PRIME trial (EQ-5D data)
3rd line (PD) 0.663 0.6407 Wang et al. (2011); people receiving
BSC who are in disease progression
from the PRIME study (EQ-5D data)
PFS post resection 0.789 0.831 (age 63) Age related general population utility
(method by Ara and Brazier 2010,
updated to use Health Survey for
England 2012 data)
PD post resection 0.107 0.142 Average of 2nd and 3rd line utilities,
disutility weighted by time spent in 2nd or 3rd
line
Key: PD, progressive disease; PFS, progression free survival

Cost-effectiveness results
 Do cetuximab and panitumumab meet the NICE criteria for end of life treatments?
 Cetuximab in combination with FOLFOX or FOLFIRI was shown to be cost
effective in the previous appraisal (with ICERS of £26,700–£33,300 and £23,500
per QALY compared with FOLFOX or FOLFIRI alone, respectively). What
explains the differences in the ICERs in the current appraisal? Refer to pages
417–423 of the assessment report for a comparison of the 2 models.
National Institute for Health and Care Excellence 7 of 36
Premeeting briefing – Cetuximab (review of TA176) and panitumumab (partial review of TA240) for
the first line treatment of metastatic colorectal cancer
Issue date: October 2015