Panitumumab, concentrated solution for infusion, 20 mg per mL, 5 mL, Vectibix®, November 2008
Public summary document for Panitumumab, concentrated solution for infusion, 20 mg per mL, 5 mL, Vectibix® November 2008
Page last updated: 20 March 2009
Public Summary Document
Product: Panitumumab, concentrated solution for
infusion, 20 mg per mL, 5 mL, Vectibix®
Sponsor: Amgen Australia Pty Ltd.
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission sought a Section 85 Authority Required listing (and
inclusion in the Chemotherapy Pharmaceuticals Access Program
(CPAP)) for treatment of K-RAS wild type (WT) metastatic colorectal
cancer (mCRC), after failure of treatment with a fluoropyrimidine,
irinotecan and oxaliplatin.
2. Background
Panitumumab had not previously been considered by the PBAC.
3. Registration Status
Panitumumab was TGA registered on 14 May 2008 for the treatment of
epidermal growth factor receptor (EGFR)-expressing, metastatic
colorectal carcinoma in patients who have disease progression
following treatment with a fluoropyrimidine, oxaliplatin- and
irinotecan-based chemotherapy.
4. Listing Requested and PBAC’s View
Authority required
Initial treatment of a patient with metastatic colorectal cancer
that meets all of the following criteria:
- Bearing the wild-type K-RAS gene;
- With an ECOG performance status of 2 or less; and
- Who has failed treatment with a fluoropyrimidine, irinotecan and oxaliplatin.
The sponsor proposed that a written authority application be
required with inclusion of a copy of the report from an Approved
Pathology Authority providing evidence of the absence of mutations
of the K-RAS gene in tumour material.
Duration of initial supply is 8 weeks of treatment.
Authority required
Continuing treatment of a patient with metastatic colorectal cancer
who has demonstrated a lack of disease progression with previous
treatment with panitumumab.
The sponsor proposed that a written statement that the
patient’s disease has not progressed must be provided.
Duration of continued supply is 14-week cycles.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Colorectal cancer is the second most common type of cancer and the
second-leading cause of cancer-related death in Australia.
Panitumumab would provide a treatment option for patients who have
failed the current standard chemotherapeutic options.
6. Comparator
The submission nominated best supportive care (BSC) comprising
antibiotics, analgesics, radiation therapy, corticosteroids,
transfusions, psychotherapy, growth factors, palliative surgery, or
any other symptomatic therapy as clinically indicated but
excluding active chemotherapy as the comparator. The PBAC
accepted this as appropriate.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented one open-label, randomised controlled
trial (Study 408) as key evidence, comparing panitumumab 6mg/kg
with BSC in the treatment of chemotherapy refractory mCRC. Patients
were randomised to receive panitumumab plus BSC (referred to as the
panitumumab arm) or BSC alone (referred to as the BSC arm).
While K-RAS had not been specifically identified at the time, the
study commenced, the possibility that a biomarker may exist was
foreseen and tumour tissue was prospectively collected for
biomarker analysis according to the trial protocol
Details of the trial and associated reports, published at the time
of the submission are presented in the table below.
| Trial ID/ First author | Protocol Title/ Publication title | Publication citation |
| Study 408 | An open-label, randomised, phase 3 clinical trial of ABX-EGF plus best supportive care versus best supportive care in subjects with metastatic colorectal cancer. 20020408 Clinical study report, 2007. | Not published |
| An open-label, randomised, phase 3 clinical trial of ABX-EGF plus best supportive care versus best supportive care in subjects with metastatic colorectal cancer. 20020408 KRAS Flash Report, 2007. | Not published | |
| Van Cutsem E et al. | Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. | Journal of Clinical Oncology. 2007, 25(13):1658-64 |
| Siena S et al. | Association of progression-free survival with patient-reported outcomes and survival: results from a randomized phase 3 trial of panitumumab. | British Journal of Cancer . 2007. 97(11):1469-74 |
| Sartore-Bianchi A et al. | Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. | Journal of Clinical Oncology. 2007. 25(22):3238-45 |
| Peeters M et al. | Association of progression-free survival, overall survival, and patient-reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy 2009 | Cancer (in press) |
| Gibson TB et al. | Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. | Clinical Colorectal Cancer. 2006. 6(1):29-31 |
8. Results of Trials
The submission presented results for the “all enrolled”
analysis set as well as the “wild-type” (non-mutated)
and “mutant” K-RAS subgroups. The patients bearing the
wild type K-RAS gene were the population for whom PBS listing was
sought. Only the results of the comparative effectiveness of
panitumumab versus BSC in patients expressing the wild-type K-RAS
gene and those bearing the mutant K-RAS gene were presented.
[The results for the “all enrolled” analysis set
indicated a statistically significant improvement in progression
free survival (PFS) in the panitumumab arm compared to the BSC arm
(median 8.0 weeks in panitumumab arm vs. 7.3 weeks BSC arm) and no
difference in overall survival (OS).]
The primary end point of the trial was PFS, with key secondary end
points including OS and best objective response defined as the best
disease status from randomisation through to the end of the study
which included complete response, partial response, stable disease
and progressive disease. The key results of the analysis of PFS for
the K-RAS analysis set are presented in the table below. The
analysis of the K-RAS subgroups (mutant and wild type) in the trial
was post hoc.
Summary of the analysis of progression free survival (K-RAS
efficacy analysis set)
| Wild-type K-RAS efficacy analysis set | Mutant K-RAS efficacy analysis set | |||
| Panitumumab (n = 124) | BSC (n = 119) | Panitumumab (n = 84) | BSC (n = 100) | |
| n (%) | n (%) | n (%) | n (%) | |
| Subjects with events | 115 (93) | 114 (96) | 76 (90) | 95 (95) |
| Disease progression | 93 (75) | 103 (87) | 65 (77) | 78 (78) |
| Death, any cause | 22 (18) | 11 (9) | 11 (13) | 17 (17) |
| Subjects censored | 9 (7) | 5 (4) | 8 (10) | 5 (5) |
| Kaplan-Meier (weeks) | ||||
| Median (95% CI) | 12.3 (8.3, 16.1) | 7.3 (7.0, 7.7) | 7.4 (7.3, 7.9) | 7.3 (6.3, 7.9) |
| Hazard ratio (95% CI) | 0.45 (0.34, 0.59) | 0.99 (0.73, 1.36) | ||
| P-value | <.0001 | 0.9732 | ||
A quantitative interaction test at 5% significance level was used
to compare the magnitude of the relative treatment effect on PFS
between the wild type and mutant K-RAS subgroups. This test was
significant (P<0.0001).
A statistically significant improvement in PFS was observed
favouring the panitumumab group compared with the BSC group in
patients with tumours expressing wild type K-RAS. The median PFS
was significantly longer, at 12.3 weeks, in patients with wild type
K-RAS treated with panitumumab than those with mutant K-RAS (7.4
weeks). This can be compared with 7.3 weeks in both K-RAS subgroups
treated with BSC.
The PBAC noted that there were more deaths in the K-RAS wild type
panitumumab treated group than in the wild type BSC group (18% vs.
9%), despite improved progression free survival in the former
group
The analysis of overall survival showed that, although more
patients were deemed progression free with panitumumab compared to
BSC, this did not translate into differences in OS (median overall
survival: 8.1 months panitumumab wild type vs. 7.6 months BSC wild
type). The submission claimed that this is due to the effect of
early cross over of patients from BSC to panitumumab treatment and
the magnitude of this cross-over (76%). The PBAC acknowledged this
was a possibility but that it was also possible that PFS is not a
valid surrogate for OS, and thus no effect of panitumumab on OS had
been demonstrated.
The PBAC considered that K-RAS status may be an effect modifier but
that considerable uncertainty remains around the circumstances in
which K-RAS status will accurately predict outcome, and the extent
of benefit conferred by it.
For PBAC’s comments on these results, see Recommendation
and Reasons.
The PBAC noted that the analysis of the toxicity profile of
panitumumab, comparing wild type and mutant subgroups suggested
that, relative to BSC, panitumumab is associated with additional
toxicities. The risk of several adverse events, particularly
erythema, pruritus and dermatitis acneiform was found to be
elevated following the addition of panitumumab to BSC. The PBAC
further noted an increased risk of adverse events in patients
receiving panitumumab who have the wild type K-RAS gene. However,
until comparable data emerge from prospective pre-planned analyses,
it was difficult to confidently conclude whether there is a K-RAS
modifying effect for toxicity (in addition to PFS and best
objective response) in mCRC patients.
9. Clinical Claim
The submission described panitumumab as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over BSC. According to the analysis of K-RAS subgroups, the
submission further claimed that the treatment effect associated
with panitumumab is exclusively confined to patients expressing the
wild type K-RAS gene. The PBAC considered that the evidence
provided did not adequately support these descriptions.
10. Economic Analysis
A stepped modelled economic evaluation was presented in the form of
cost-effectiveness and cost-utility analyses. Patients were
modelled using a decision tree approach. Modelling was based upon
the differential survival observed within the various best
objective response categories (complete response, partial response,
stable disease, and progressive disease).
The estimated base case incremental cost per Quality Adjusted Life
Year (QALY) fell in the range of $45,000 to $75,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated a cost per year to the PBS of between
$10-30 million in Year 5. The PBAC considered this uncertain.
12. Recommendation and Reasons
The Committee agreed that there is no evidence that patients with
metastatic colorectal cancer (mCRC) whose disease has progressed
despite treatment with oxaliplatin, irinotecan and 5-fluorouracil
will benefit from further treatment with the currently available
chemotherapeutic agents. Thus, best supportive care (BSC) is an
appropriate comparator in this setting.
The Committee noted that although K-RAS had not been identified
a-priori as a predictive marker in the key trial (Study 408), the
possibility that biomarkers might exist was predicted and tumour
tissues were prospectively collected according to the trial
protocol with about 90 % of patients having samples analysed for
K-RAS mutations. The Committee considered that K-RAS status might
be an effect modifier but that considerable uncertainty remains
around the circumstances in which K-RAS status will accurately
predict outcome, and of the extent of benefit conferred by it. For
example, the available evidence does not allow discernment of
whether K-RAS status is a prognostic factor in its own right or a
predictor of responsiveness to treatment. In trial 408, there were
more deaths in the K-RAS wild type panitumumab treated group than
in the wild type BSC group (18 % vs. 9 %) despite improved
progression free survival in the former group. Additionally data
from the CAIRO2 cetuximab trial are not supportive of K-RAS status
as a predictive indicator of responsiveness to treatment.
However the largest area of concern to the PBAC was the inadequacy
of the evidence from trial 408 to support the claim of a better
therapeutic effect for panitumumab over BSC, with the Committee
agreeing with its Economic Sub-Committee that the large proportion
of patients in the BSC arm (76 %) that crossed over to panitumumab
made the endpoints difficult to interpret for a number of
reasons.
Firstly, the primary outcome of progression free survival is likely
to be highly confounded by this crossover and other aspects of the
trial design. For example, the open label design together with the
possibility for patients in the BSC arm to switch to active
treatment upon progression, and for all patients receiving active
treatment to cease that treatment upon (further) progression, is
likely to have biased patients and investigators to making an
earlier determination of progression in the BSC arm (thus allowing
patients to switch to active treatment) and a later determination
of progression in the panitumumab arm (thus allowing patients to
continue on active treatment for longer). This is particularly so
as the determination of disease status, (assessment of progression
using radiographic and clinical data) treatment and withdrawal from
the study was as the discretion of the investigator and even though
the assessment of disease progression was undertaken by a blinded
independent review committee, the decision to make an assessment
was unblinded. It is also probable that it was the sickest patients
with the most rapidly progressing disease in the BSC arm that would
not have crossed over to active treatment. The cumulative effect of
these factors will be to overestimate the extent of progression
free survival which can be attributed to panitumumab.
Secondly, because the majority of “BSC” patients were
on panitumumab for almost all the study period, this group of
patients is likely to have derived similar benefits, if any, to
active treatment as the group initially randomised to panitumumab.
This is reflected in the lack of difference in overall survival
between the two groups (median overall survival: 8.1 months
panitumumab wild type vs. 7.6 months BSC wild type). The submission
attempts to deal with the uncertainty introduced by the cross-over
design by censoring all the cross-over patients from the overall
survival estimate, however the implication of this censoring is
that the BSC arm is shrinking both by deaths as well as by
censoring after progression. This results in a much smaller sample
size in the BSC arm for the time from progression to death, so the
mean overall survival value in the BSC arm is highly
uncertain.
Consequently, the PBAC concluded that there is considerable
uncertainty around the extrapolated survival data in the modelled
economic evaluation, with survival in the BSC arm likely to be
underestimated and that in the panitumumab arm likely to be
overestimated.
Further, the Committee also did not accept the use of the mean
progression free survival (PFS) rather than median PFS in the
modelled economic evaluation, given the likely reason for treatment
effect was cross-over at progression and the sample size is smaller
and thus the mean value is more likely to be affected by outliers.
The Committee furthermore agreed with ESC that step 4 of the
economic evaluation is very dependent on the mix of outcomes in the
Australian population being the same as in the pivotal trial. This
is highly unlikely due to the issues of cross over and the
treatment pathways which will change with the listing of
bevacizumab.
The PBAC considered the subjective nature of the assessment upon
which the decision to cease treatment is based, means that in
practice, not all patients with progressive disease will cease
treatment after 8 weeks. This uncertainty, together with those
described above and with uncertainties around the estimation of
eligible patients results in high uncertainty in the total
financial cost.
Thus, overall the PBAC rejected the application because of
uncertainty about the extent of clinical benefit over best
supportive care, both in terms of progression free and overall
survival, 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
The sponsor has no comments.
