Capecitabine, tablets, 150 mg and 500 mg, Xeloda®, July 2009
Public summary document for Capecitabine, tablets, 150 mg and 500 mg, Xeloda®, July 2009
Page last updated: 13 November 2009
Public Summary Document
Product: Capecitabine, tablets, 150 mg and 500 mg,
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request an extension to the Section 85 Authority required
listing for capecitabine to include the treatment in combination
with a platinum-based regimen of previously untreated advanced
Capecitabine had not previously been considered for this indication
by the PBAC.
3. Registration Status
Capecitabine was registered by the TGA in February 2009 for first
line treatment of patients with advanced oesophagogastric cancer in
combination with a platinum-based regimen.
4. Listing Requested and PBAC’s View
Treatment, in combination with a platinum-based regimen, of a patient with previously untreated advanced oesophago-gastric cancer with a WHO performance status of 2 or less.
The PBAC considered that any future restriction proposed by the sponsor should include use of capecitabine with cisplatin only rather than platinum-based therapies.
5. Clinical Place for the Proposed Therapy
Capecitabine would provide an oral alternative to 5-fluorouracil
(5-FU) in the above treatment algorithms, which the submission
claimed may be more convenient for patients and less resource
intensive than continuous infusions of 5-FU.
5-fluorouracil (5-FU). 5-FU is a pharmacological analogue of
7. Clinical Trials
The submission presented one randomised open-label triplet
chemotherapy trial (REAL-2). It compared capecitabine plus
epirubicin (either with oxaliplatin or cisplatin) with 5-FU plus
epirubicin (either with oxaliplatin or cisplatin) in patients with
advanced oesophagogastric cancer (OGC). One randomised open-label
doublet chemotherapy trial (ML17032) was also presented which
compared capecitabine plus cisplatin with 5-FU plus cisplatin in
patients with advanced gastric cancer. The submission also
presented a meta-analysis of survival data from the REAL-2 and
Details of the trials and associated reports used in the submission are summarised in the following table:
|Trial ID||Protocol title/ Publication title||Publication citation|
|Direct randomised trials|
|REAL-2/ Cunningham D, 2008||Capecitabine and oxaliplatin for advanced oesophagogastric cancer.||The New England Journal of Medicine 2008; 358(1): 36-46.|
|ML17032/Kang Y, 2006||Randomised phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5 FU/cisplatin (FP) as first line therapy in patients (pts) with advanced gastric cancer (AGC): efficacy and safety results.||Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I, Vol 24, No. 18S (June 20 Supplement) 2006: LBA4018|
8. Results of Trials
In the triplet chemotherapy trial (REAL-2), the primary efficacy
endpoint was the assessment of overall survival (OS) in the
per-protocol (PP) population. The median and one-year survival
rates for the pooled capecitabine regimens compared with the 5-FU
regimens (both oxaliplatin-based and cisplatin-based therapy) were
10.9 months versus 9.6 months and 44.6 % (95 % CI: 40.1 %, 49.0 %)
versus 39.4 % (95 % CI: 35.0 %, 44.0 %), respectively. The
unadjusted hazard ratio for death for the non-inferiority
comparison of capecitabine versus 5-FU was 0.86 (95 % CI: 0.80,
0.99). The adjusted (for performance status, extent of disease and
age) hazard ratio for death in the pooled capecitabine group, as
compared with the pooled 5-FU group, was 0.89 (95 % CI: 0.77,
1.02). The REAL-2 study met the pre-specified non-inferiority
criteria for overall survival, as the upper limits of the
confidence intervals of both the adjusted and non-adjusted hazard
ratios were below the pre-specified margin of 1.23.
The secondary analyses from the REAL-2 trial of OS and progression-free survival (PFS) in the ITT population showed that there was no statistically significant difference in OS between the epirubicin and cisplatin plus capecitabine (ECX) and epirubicin and cisplatin plus 5-FU (ECF) treatment arms [HR = 0.92 (95 % CI: 0.76, 1.11)]. The results were similar for PFS [HR = 0.98 (95 % CI: 0.82, 1.17)].
In the doublet chemotherapy trial (ML17032), the primary efficacy endpoint was the assessment of PFS in the PP population. In two-sided tests, non-inferiority was concluded for a non-inferiority margin of 1.40 (p=0.003) and, subsequently, for a non-inferiority margin of 1.25 (p=0.005). The unadjusted hazards ratio, using a two-sided test in terms of PFS in the PP population for capecitabine + cisplatin was found to be non-inferior to that of 5-FU + cisplatin [HR: 0.81 (95 % CI: 0.63, 1.04)] using a non-inferiority margin of 1.25. Results were consistent for the ITT population.
The results from the meta-analyses of survival data from the REAL-2 and ML17032 were consistent with the results from the individual trials.
The key safety issues from the key REAL-2 trial are summarised as follows:
- The most frequent treatment-related adverse events were anaemia, neutropenia, diarrhoea, stomatitis, nausea/vomiting, lethargy and alopecia. Hand and foot syndrome, lethargy and thrombocytopenia were more frequent (differences were statistically significant) in the capecitabine groups compared to the 5-FU groups. All grades of stomatitis were more frequent (also statistically significant) in the 5-FU groups compared to the capecitabine groups;
- There were less chills, infections and thromboembolic events but more peripheral arterial ischemia and abnormal neutrophil/granulocyte values in the ECX treatment arm compared to the ECF treatment arm.
9. Clinical Claim
The submission described capecitabine as non-inferior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over 5-FU.
For PBAC’s views see Recommendation and Reasons
10. Economic Analysis
The submission presented a cost minimisation analysis with the
estimates based directly on the mean drug use in the clinical
The key cost differences between treatments were:
- the cost of administration (either on an inpatient or outpatient basis), and;
- the drug acquisition cost of capecitabine vs 5-FU.
For PBAC’s views see Recommendation and Reasons
11. Estimated PBS Usage and Financial Implications
The likely financial cost per year to the PBS was less than $10
million in Year 1.
12. Recommendation and Reasons
The PBAC accepted that 5-fluorouracil (5-FU) was the appropriate
comparator. The PBAC noted that the submission presented one
randomised open-label triplet chemotherapy trial (REAL-2) which
compared capecitabine plus epirubicin (either with oxaliplatin or
cisplatin) with 5-FU plus epirubicin (either with oxaliplatin or
cisplatin) in patients with advanced oesophago-gastric cancer
(OGC). The PBAC also noted that oxaliplatin was not PBS listed for
use in OGC and was much more expensive than cisplatin. Therefore,
the PBAC considered that any future restriction proposed by the
sponsor should include use of capecitabine with cisplatin only
rather than platinum-based therapies.
One randomised open-label doublet chemotherapy trial (ML17032) was also presented which compared capecitabine plus cisplatin with 5-FU plus cisplatin in patients with advanced gastric cancer. However, the PBAC noted that three-drug regimens were now considered standard in the treatment of advanced gastric cancer, and the combination of capecitabine with cisplatin (and capecitabine monotherapy) was rejected for registration by the TGA Delegate on the grounds of inadequate evidence of efficacy, due to the lack of comparative data with a triple-drug regimen.
The PBAC accepted that capecitabine was non-inferior in terms of comparative effectiveness and safety over 5-FU.
The main matter of concern to the PBAC was the use of resources to offset the higher drug cost requested for the capecitabine tablet.
The PBAC deferred this submission so that the issues regarding the cost of the diagnostic related groups (DRGs) and the magnitude of the cost-offsets can be resolved.
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.