Capecitabine, tablets 150 mg and 500 mg, Xeloda®, November 2008
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Public Summary Document
Product: Capecitabine, tablets 150 mg and 500 mg, Xeloda®
Sponsor: Roche Products Pty Ltd.
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission sought PBS listing for the combination treatment of
metastatic colorectal cancer (mCRC) with capecitabine and
oxaliplatin (XELOX regimen). This required a change to the PBS
listing for oxaliplatin to include the treatment in combination
with capecitabine.
2. Background
Capecitabine was first listed on the PBS on 1 November 1999, for
the treatment of advanced metastatic breast cancer after failure of
standard therapy which includes a taxane and an anthracycline, or
where those agents are clinically inappropriate.
At its December 2000 meeting, the PBAC recommended the additional
listing for capecitabine for treatment of advanced or metastatic
colorectal cancer. At its November 2005 meeting, the PBAC
recommended further extending the listing for capecitabine to
include the adjuvant treatment of patients with Dukes C colon
cancer.
Oxaliplatin was recommended by the PBAC at its June 2001 meeting
for use as second-line therapy in metastatic colorectal cancer. At
its meeting in December 2003, the PBAC recommended extending the
listing of oxaliplatin to include first-line treatment of
metastatic colorectal cancer in patients with a WHO performance
status of 2 or less, to be used in combination with 5-fluorouracil
and folinic acid.
3. Registration Status
Capecitabine was first registered by the TGA on 4 September 2000. It is indicated for:
- adjuvant treatment of patients with Dukes’ stage C and high-risk stage B colon cancer;
- treatment of patients with advanced or metastatic colorectal cancer;
- treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline containing chemotherapy regimen unless therapy with these and other standard agents are clinically contraindicated;
- in combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.
4. Listing Requested and PBAC’s View
The sponsor proposed that the current PBS restriction for
capecitabine in the treatment of advanced or metastatic CRC remain
unchanged as this is consistent with the wording of the
TGA-approved indication:
Authority Required
Advanced breast cancer after failure of prior therapy which
includes a taxane and an anthracycline;Advanced breast cancer where
therapy with a taxane and/or an anthracycline is
contraindicated;Advanced breast cancer in combination with
docetaxel after failure of prior anthracycline-containing
chemotherapy;
Treatment of advanced or metastatic colorectal cancer;
Adjuvant treatment of stage III (Dukes C) colon cancer, following
complete resection of the primary tumour.
NOTE:
In the adjuvant setting, the recommended treatment duration is 24
weeks.
Capecitabine is not PBS-subsidised for the treatment of patients
with stage II (Dukes B) colon cancer.
Capecitabine is not PBS-subsidised for the adjuvant treatment of
patients with rectal cancer.
The sponsor requested a change to the PBS listing of oxaliplatin to
allow combination use with capecitabine, as follows:
Authority Required
Metastatic colorectal cancer in combination with capecitabine
OR
Metastatic colorectal cancer in patients with a WHO performance
status of 2 or less, to be used in combination with capecitabine or
5-fluorouracil and folinic acid.
5. Clinical Place for the Proposed Therapy
Colorectal cancer is the second most commonly diagnosed cancer in
Australia and is a significant cause of morbidity and mortality.
The aim of treatment in patients with advanced disease is to
improve both the duration and quality of the patient’s
remaining life.
Capecitabine in combination with oxaliplatin will provide an
alternative for first- and second- line treatment of patients with
metastatic colorectal cancer.
6. Comparator
The submission nominated 5-fluorouracil (5-FU) with or without
leucovorin in combination with oxaliplatin as the comparator. The
PBAC considered that 5-FU in combination with oxaliplatin in the
regimen modified FOLFOX6 was the appropriate comparator as this is
the therapy most likely to be replaced in clinical practice.
7. Clinical Trials
The submission presented five randomised trials comparing
combination capecitabine plus oxaliplatin chemotherapeutic regimens
with 5-fluorouracil plus oxaliplatin regimens for first-line
treatment in patients with metastatic colorectal cancer (mCRC), and
one randomised trial comparing combination capecitabine plus
oxaliplatin chemotherapeutic regimens with 5 fluorouracil plus
oxaliplatin regimens for second-line treatment in patients with
metastatic colorectal cancer. Details of the studies published at
the time of submission are presented in the table below.
Trials and associated reports presented in the
submission
| Trial ID | Protocol title/ Publication title | Publication citation |
| Direct randomised trial(s) | ||
| NO 16966 | Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. | Cassidy et al . Journal of Clinical Oncology 2008; 26: 2006-2012. |
| NO 16967 | Phase III trial of capecitabine + oxaliplatin (XELOX) vs 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2 nd -line treatment for patients with metastatic colorectal cancer (MCRC). | Rothenberg et al . Journal of Clinical Oncology 2007; 25, No 18S: 4031 (abstract). |
| Diaz-Rubio 2007 | Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: Final report of the Spanish Cooperative Group for the treatment of digestive tumors trial. | Diaz-Rubio et al. 2007. Journal of Clinical Oncology 2007; 25 (27): 4224-4230. |
| Ducreux 2007 | Efficacy and safety findings from a randomised phase III study of capecitabine (X) and oxaliplatin (O) (XELOX) vs. infusional 5-FU/LV + O (FOLFOX-6) for metastatic colorectal cancer (MCRC). | Ducreux et al . 2007. Journal of Clinical Oncology 2007; ASCO Annual Meeting Proceedings Part I 25: 18s (suppl): Abstract 4029. |
| Hochster 2006 | Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first line treatment for metastatic colorectal cancer (mCRC): TREE-1 and 2 studies. | Hochster et al . 2006. Journal of Clinical Oncology 2006; 23:249s (suppl): Abstract 3515. |
| Porschen 2007 | Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: A final report of the AIO colorectal study group. | Porschen et al . 2007. Journal of Clinical Oncology 2007; 25 (27): 4217-4223. |
Abbreviations 5-FU = 5-fluorouracil; LV=leucovorin=folinic acid;
AIO = Arbeitsgemeinschaft Internistische Onkologie; CPT-11 =
irinotecan; FOLFOX = 5-FU+LV+oxaliplatin; mCRC = MCRC = metastatic
colorectal cancer; O/F = oxaliplatin/fluoropyrimidine
8. Results of Trials
First-line therapy of mCRC
The results of progression free survival (PFS) across the direct randomised trials
in the first-line treatment of metastatic CRC are presented in the table below.
| Trial ID | Population for analysis | XELOX median PFS mths (days) | FOLFOX median PFS mths (days) | Hazard Ratio various CIs | Non-inferiority criteria |
| NO16966 Investigator assessment | EPP ITT PPP | 7.2 (220) 7.3 (222) 7.6 (232) | 7.9 (241) 8.0 (245) 8.5 (260) | 97.5% CI 1.06 (0.92,1.22) 1.05 (0.92,1.20) 1.09 (0.94,1.26) | Upper limit of 97.5% CI <1.23 |
| Diaz-Rubio Investigator assessment | PPP | 8.9 | 9.5 | 95% CI 1.18 (0.9,1.5) a | Hazard ratio < 1.27 |
| Ducreux Investigator assessment | ITT | 8.8 | 9.3 | 90% CI 1.00 (0.82, 1.22) | Not tested for non-inferiority |
| Hochster bc Investigator assessment | As treated participants | 5.9 | 8.7 | NR | Not designed as non-inferiority trial |
| Porschen Investigator assessment | Analysed patient population | 7.1 | 8.0 | 95% CI 1.17 (0.96,1.43) | Hazard ratio <1.29 |
| Pooled result c | 1.09 (0.99,1.19) | Upper limit of 95% CI <1.23 | |||
| Chi-square for heterogeneity: P=0.67 I 2 statistic with 95% uncertainty interval =0% | |||||
a p=0.153.
b PFS censored for second-line treatment.
c Hochster (2006) not included in meta-analysis of results.
CI=confidence interval; EPP=eligible patient population; ITT=intent-to-treat (population);
NR=not reported; PPP=per protocol population.
Second-line therapy of mCRC
The results of efficacy outcomes for the direct randomised trial of second-line treatment
of metastatic CRC are presented in the table below.
| Trial ID 16967 | Population for analysis | XELOX | FOLFOX | Hazard Ratio | Non-inferiority Criteria |
| Progression free survival – investigator assessment | |||||
| Median duration, mths | PPP ITT | 5.1 4.7 | 5.5 4.8 | 1.04 (0.87,1.24) 0.97 (0.83,1.14) | UL, 95% CI <1.30 |
| Overall survival | |||||
| Median duration, mths | PPP ITT | 12.9 11.9 | 13.2 12.5 | 1.05 (0.88,1.27) 1.02 (0.86,1.21) | Not tested |
UL = upper limit; CI=confidence interval; ITT=intent-to-treat population; PPP=per
protocol population
The PBAC accepted the non-inferiority claim for the second-line therapy based on clinical
trial study NO16967 (CI < 1.30), as the preset non-inferiority criteria were met.
However, the PBAC considered that the claim of non-inferiority in the first-line setting
is uncertain because all the point estimates of the hazard ratio for progression free
survival (PFS) suggest XELOX might be inferior to FOLFOX. For the key randomised clinical
trial for first-line treatment of metastatic colorectal cancer (study NO 16966), the
point estimate for the blinded Independent Review Committee (IRC) assessment of PFS
for the per protocol population (PPP) did not meet the non-inferiority criterion,
suggesting a statistically significant inferiority of XELOX in comparison with FOLFOX.
However, the PBAC noted that the unblinded investigator’s assessment of PFS demonstrated
non-inferiority but this was determined in the eligible patient population (EPP) and
based on a subjective measure and an inappropriate population set.
The PBAC took into account the sponsor’s pre-Sub-Committee and pre-PBAC responses
concerning non-inferiority and accepted the non-inferiority of XELOX in both the first
and second-line settings.
For PBAC’s comments on these results, see Recommendation and Reasons.
The safety data for capecitabine/oxaliplatin regimens and 5-FU/oxaliplatin regimens
were comparable in terms of the incidence of adverse events, serious adverse events,
discontinuations due to adverse events and treatment related deaths. There were no
important differences in the safety data for capecitabine/oxaliplatin regimens compared
with 5 FU/oxaliplatin regimens other than the known differences between the safety
profiles of capecitabine and 5-FU monotherapy. The haematological toxicity observed
with 5 FU/oxaliplatin was less pronounced with capecitabine/oxaliplatin, while the
incidence of gastrointestinal disorders, diarrhoea and palmar-plantar erythrodysaesthesia
was greater.
9. Clinical Claim
The submission described the combination of capecitabine with
oxaliplatin as non-inferior in terms of comparative effectiveness
and non-inferior in terms of comparative safety over bolus and/or
infusional 5-FU plus folinic acid combined with oxaliplatin in both
first-line and second-line treatment of metastatic CRC.
The interpretation of the clinical evidence in non-inferiority
trials is highly dependent on the non-inferiority margin that is
applied. The PBAC noted the non-inferiority margins specified for
the randomised trials and the meta-analyses seemed unreasonably
large and were not based on the minimal clinically important
differences for these outcomes.
10. Economic Analysis
The submission presented cost minimisation analyses for the first-
and second-line settings. In the first-line setting, the
equi-effective doses were estimated as capecitabine 2,000mg twice
daily for two weeks over 7.47 cycles of therapy, as part of the
XELOX combination chemotherapy regimen, and 5-fluorouracil to a
total of 2,800 mg/m2 (bolus plus infusion) plus folinic acid 50mg,
each cycle, over 9.09 cycles of therapy, as part of the modified
FOLFOX-6 combination chemotherapy regimen. In the second-line
setting, the per-cycle equi-effective doses are the same as in the
first-line, but the number of cycles of therapy given for
equi-effect are considered to be: 5.1 cycles of XELOX and 7.5 for
the modified FOLFOX-6 regimen. In addition, the dose of oxaliplatin
given per cycle is different in each regimen.
The results of the cost-minimisation analysis, with revisions made
during the evaluation, showed a higher incremental cost for XELOX
compared to modified FOLFOX6.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year
using capecitabine to be less than 10,000 in Year 1. The overall
net cost to the PBS was estimated to be less than $10 million in
Year 1.
12. Recommendation and Reasons
The PBAC recommended a change to the listing for oxaliplatin to
allow use with capecitabine in advanced or metastatic colorectal
cancer on a cost-minimisation basis compared with the modified
FOLFOX6 regimen, noting that based on the proposed drug prices the
cost of treatment with XELOX was higher than with modified FOLFOX6
in the first- and second line settings and that the cost of the
drugs in the XELOX regimen will need to be reduced to eliminate
this differential.
The PBAC noted that the submission requested a change to the
wording of the oxaliplatin listing and not the capecitabine
listing, to allow the use of oxaliplatin with capecitabine.
However, the TGA approved product information for oxaliplatin does
not currently allow use in combination with capecitabine, although
an application seeking approval of this change is currently under
evaluation, and the change will not be made unless and until it is
approved. The PBAC also noted that one of the five manufacturers of
oxaliplatin had acknowledged and given approval for this
submission.
The Committee considered that the appropriate comparator in this
submission was fluorouracil in combination with oxaliplatin in the
regimen FOLFOX6, as this was the therapy most likely to be replaced
in clinical practice. The Committee noted that much of the clinical
evidence came from trials using the FOLFOX4 rather than FOLFOX6
regimens, but that the two regimens could be considered
non-inferior in clinical terms. However, the PBAC noted that the
cost-offsets of FOLFOX4 are higher than for FOLFOX6, and considered
that the submission’s inclusion of these higher offsets was
not reasonable.
The PBAC noted that capecitabine in combination with oxaliplatin
(XELOX or CAPOX) was intended to be a first- or second-line
treatment option for metastatic colorectal cancer, and hence the
submission presented five randomised trials comparing combination
capecitabine plus oxaliplatin chemotherapeutic regimens with
5-fluorouracil plus oxaliplatin regimens for first-line treatment
in patients with metastatic colorectal cancer (mCRC), and one
randomised trial comparing combination capecitabine plus
oxaliplatin chemotherapeutic regimens with 5-fluorouracil plus
oxaliplatin regimens for second-line treatment in patients with
metastatic colorectal cancer.
The PBAC accepted the non-inferiority claim for the second-line
therapy based on clinical trial study NO16967 (CI <1.30), as the
preset non-inferiority criteria were met. However, the PBAC
considered that the claim of non-inferiority in the first-line
setting is uncertain because all the point estimates of the hazard
ratio for progression free survival (PFS) suggest XELOX might be
inferior to FOLFOX. For the key randomised clinical trial for
first-line treatment of metastatic colorectal cancer (study
NO16966), the point estimate for the blinded Independent Review
Committee (IRC) assessment of PFS for the per protocol population
(PPP) did not meet the non-inferiority criterion, suggesting a
statistically significant inferiority of XELOX in comparison with
FOLFOX. However, the PBAC noted that the unblinded
investigator’s assessment of PFS demonstrated non-inferiority
but this was determined in the eligible patient population (EPP)
and based on a subjective measure and an inappropriate population
set.
The PBAC considered that even if it is accepted that XELOX is
statistically inferior to FOLFOX4 it can be argued that the
difference between the regimens is not clinically relevant and in
current clinical practice capecitabine is accepted as
interchangeable with 5-fluorouracil. The PBAC took into account the
sponsor’s pre-Sub-Committee and pre-PBAC responses concerning
non-inferiority and accepted the non-inferiority of XELOX in both
the first and second-line therapy.
The PBAC noted that based on drug cost alone, the XELOX based
regimen is more expensive than the FOLFOX regimen but that the
higher costs for XELOX are subsequently offset by the higher
preparation, administration and other non-drug costs associated
with the FOLFOX regimen. However, the PBAC considered that it was
still likely that XELOX is more expensive than the FOLFOX regimens,
even FOLFOX6 regimens which are associated with a decreased cost
because of less dose splitting (i.e. one 46 hour infusion versus
two 22 hour infusions of fluorouracil and also less bolus
regimens).
Recommendation
CAPECITABINE, tablet, 150 mg and 500 mg
Restriction: Authority Required
Advanced breast cancer after failure of prior therapy which
includes a taxane and an anthracycline;
Advanced breast cancer where therapy with a taxane and/or an
anthracycline is contraindicated;
Advanced breast cancer in combination with docetaxel after failure
of prior anthracycline-containing chemotherapy;
Treatment of advanced or metastatic colorectal cancer;
Adjuvant treatment of stage III (Dukes C) colon cancer, following
complete resection of the primary tumour.
NOTE:
In the adjuvant setting, the recommended treatment duration is 24
weeks.
Capecitabine is not PBS-subsidised for the treatment of patients
with stage II (Dukes B) colon cancer.
Capecitabine is not PBS-subsidised for the adjuvant treatment of
patients with rectal cancer.
Maximum quantity: 60 (150 mg)
120 (500 mg)
Number of repeats: 2 (both strengths)
OXALIPLATIN, solution concentrate for I.V. infusion, 50 mg in 10
mL, 100 mg in 20 mL and 200 mg in 40 mL, powder for I.V. infusion,
50 mg and 100 mg.
Restriction: Authority Required
Metastatic colorectal cancer in a patient with a WHO performance
status of 2 or less, to be used in combination with:
(a) capecitabine; or
(b) 5-fluorouracil and folinic acid;
Adjuvant treatment of stage III (Dukes C) colon cancer, in
combination with 5 fluorouracil and folinic acid, following
complete resection of the primary tumour.
NOTE:
Oxaliplatin is not PBS-subsidised for the treatment of patients
with stage II (Dukes B) colon cancer.
Oxaliplatin is not PBS-subsidised for the adjuvant treatment of
patients with rectal cancer.
NOTE:
The solution concentrate for I.V. infusion 50 mg and powder for
I.V. infusion 50 mg (after reconstitution) are bioequivalent.
NOTE:
The solution concentrate for I.V. infusion 100 mg and powder for
I.V. infusion 100 mg (after reconstitution) are
bioequivalent.
Maximum quantity: 1
Number of repeats: 2
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 further comment.
