Capecitabine, tablet, 150 mg and 500 mg, Xeloda® - March 2011

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Public Summary Document

Product: Capecitabine, tablet, 150 mg and 500 mg, Xeloda®
Sponsor: Roche Products Pty Limited
Date of PBAC Consideration: March 2011

1. Purpose of Application

The submission sought the PBS listing of capecitabine to include use in combination with oxaliplatin for the adjuvant treatment of stage III (Dukes C) colon cancer.

2. Background

Capecitabine has been listed on the PBS since 1 November 1999.

In November 2005, the PBAC recommended extending the listing for capecitabine to include the adjuvant treatment of patients with Dukes C colon cancer on a cost-minimisation basis with the Mayo Clinic regimen for 5-FU plus leucovorin. Listing was effective from 1 April 2006.

Oxaliplatin had not previously been considered by the PBAC for the adjuvant treatment of colorectal cancer in combination with capecitabine but is currently listed for the adjuvant treatment of stage III colorectal cancer in combination with 5-fluorouracil and folinic acid. Listing was effective 1 December 2005.

3. Registration Status

Oxaliplatin

As at 2 February 2011, oxaliplatin TGA registered indications were extended to include:

  • adjuvant treatment of stage III (Duke's C) colon cancer, in combination with a fluoropyrimidine agent.

Capecitabine

As at 2 February 2011, capecitabine TGA registered indications were amended as follows:
Colon Cancer

  • the adjuvant treatment of patients with Dukes stage C and high-risk stage B colon cancer, either as monotherapy or in combination with oxaliplatin.

4. Listing Requested and PBAC’s View

CAPECITABINE
No amendments to the current listing:

Authority required

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.

Alternatively, it was proposed that the following PBS restriction be amended as follows highlighted by italics:

Authority required

Adjuvant treatment of stage III (Dukes C) colon cancer, either as monotherapy or in combination with oxaliplatin, following complete resection of the primary tumour.

NOTE:

In the adjuvant setting, the recommended treatment duration is 24 weeks.

OXALIPLATIN

Authority required

Adjuvant treatment of stage III (Dukes C) colon cancer, in combination with a fluoropyrimidine agent.

NOTE: In the adjuvant setting, the recommended treatment duration is 24 weeks.

For PBAC’s view, see Recommendation and Reasons.

5. Clinical Place for the Proposed Therapy

Colorectal cancer accounts for approximately 14% of all cancer registrations and is the second most common cancer in Australia.

Adjuvant chemotherapy has become the standard of care for stage III colon cancer patients (includes tumours with metastases in regional lymph nodes but no distant metastases) as it can reduce the likelihood of recurrence and improve overall survival in these patients.

The submission proposed that the place in therapy of combination oral capecitabine and intravenous oxaliplatin is as an alternative to intravenous combination chemotherapy regimens containing oxaliplatin, 5-fluorouracil and folinic acid in patients with good performance status who are able to tolerate oxaliplatin-based chemotherapy for the adjuvant treatment of colon cancer.

6. Comparator

The submission nominated oxaliplatin with 5-fluorouracil and leucovorin (described as FOLFOX and FLOX regimens) as the main comparator, which was considered appropriate by the PBAC.

7. Clinical Trials

The basis of the submission was an indirect comparison of XELOX vs. FOLFOX/FLOX for the adjuvant treatment of colon cancer using 5-FU/LV as the common comparator.

The submission included one trial of XELOX vs. 5-FU/LV (NO16968), one trial of FOLFOX-4 vs. 5-FU/LV (MOSAIC) and one trial of FLOX vs. 5-FU/LV (NSABP C-07).

The trials published at the time of submission are presented in the following table:

Trial ID/First author Protocol title/ Publication title Publication citation
XELOX vs. 5-FU/LV
NO16968
Schmoll HJ et al Phase III trial of capecitabine plus oxaliplatin as adjuvant treatment for Stage III colon cancer: a planned safety analysis in 1,864 patients. Journal of Clinical Oncology, 2007, 25(1): 102-109
Schmoll HJ et al Final safety findings from a randomised phase III trial of capecitabine + oxaliplatin (XELOX) vs bolus 5-FU/LV as adjuvant therapy for patients (I) with Stage III colon cancer. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings (Post-Meeting Edition), 2006, 24(18S): June 20 Supplement: 3569
FOLFOX vs. 5-FU/LV
MOSAIC
Andre T et al Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in Stage II or III colon cancer in the MOSAIC trial. Journal of Clinical Oncology, 2009, 27(19): 3109-3116
Andre T et al Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. New England Journal of Medicine, 2004, 350(23): 2343-2351
De Gramont A et al Oxaliplatin/5FU/LV in the adjuvant treatment of Stage II and Stage III colon cancer: efficacy results with a median follow-up of 4 years. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2005, 23(16S): 3501
ASCO lectures. Available on website. Accessed May 24 2010
FLOX vs. 5-FU/LV
NSABP C-07 Kuebler JP et al Severe enteropathy among patients with stage II/III colon cancer treated on a randomised trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin. Cancer, 2007, 110(9): 1945-1950
Kuebler JP et al Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. Journal of Clinical Oncology, 2007, 25(16): 2198-2204
Land SR A brief review of results from NSABP protocol C-07: Neurotoxicity with oxaliplatin combined with 5-fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer. American Journal of Hematology/Oncology, 2007, 6(11): 634-637
Land SR et al Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for Stage II and III colon cancer: NSABP C-07. Journal of Clinical Oncology, 2007, 25(16): 2202-2211
Land SR et al Patient-reported neurotoxicity with FULV versus FLOX in patients with Stage II or III carcinoma of the colon: Results of NSABP protocol C-07. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2006, 24(18S): 3564
Yothers G et al Neurotoxicity (NT) in colon cancer (CC) survivors from NSABP protocol C-07 comparing 5-FU + leucovorin (FULV) with the same regimen + oxaliplatin (FLOX): Preliminary results from NSABP protocol LTS-01 Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2008, 26(15S): 9575
Wolmark N et al A phase III trial comparing FULV to FULV + oxaliplatin in Stage II or III carcinoma of the colon: Survival results of NSABP protocol C-07 Journal of Clinical Oncology, ASCO Annual Meeting Proceedings, 2008, 26: LBA4005

The 5-FU/LV treatment arm was the common comparator used in each of the included studies. However, the dose regimen used in the 5-FU/LV treatment arms varied between trials. The submission claimed that all dosing regimens of 5-FU/LV had been shown to have comparable efficacy in the adjuvant setting (based on published studies by Andre et al 2003, Andre et al 2005; Carrato et al 2006; Chau et al 2005; Poplin et al 2005; Saini et al 2003 and Wils et al 2001). The PBAC considered this claim was reasonable, see Recommendation and Reasons.

8. Results of Trials

The primary outcome of all trials was disease-free survival at 3 years which was the primary outcome used in the submission.

The survival measures used in the trials were defined as follows:

  • Disease-free survival: Time from randomisation to the time of the first event (recurrence of the original colon cancer, development of a new colon or rectal cancer, or death due to any cause)
  • Overall survival: Time from randomisation to death from any cause
  • Relapse-free survival: Time from randomisation to the time of the first event (recurrence of the original colon cancer, development of a new colon or rectal cancer or deaths due to treatment, tumour recurrence or new colorectal cancer)

Results of the indirect comparison – 3-year disease-free survival

All oxaliplatin chemotherapy regimens (XELOX, FOLFOX-4 and FLOX) improved disease-free survival compared to 5-FU/LV alone. The relative treatment benefit of oxaliplatin regimens appeared to be maintained over time. The improvement in disease-free survival was only statistically significant in the overall/Stage III patient populations. No treatment had demonstrated a statistically significant benefit in Stage II disease.

The indirect analysis did not identify any statistically significant difference in disease-free survival with XELOX vs. FOLFOX-4 (HR 1.05; 95% CI 0.82, 1.35) or with XELOX vs. FOLFOX/FLOX (HR 1.01; 95% CI 0.84, 1.22). Based on the data presented in the submission it appeared that disease-free survival is comparable between the various oxaliplatin treatment regimens.

Results of the indirect comparison – 3-year overall survival

FOLFOX-4 is the only oxaliplatin regimen that has demonstrated a statistically significant improvement in overall survival compared to 5-FU/LV. However, statistical significance was only reached after 6 years of patient follow-up. Subgroup analyses of the MOSAIC trial suggest that the overall survival improvement associated with FOLFOX-4 treatment is limited to Stage III patients only.

Although not statistically significant, the overall survival results favour XELOX compared to 5-FU/LV.

The indirect analysis did not identify any statistically significant difference in overall survival with XELOX vs. FOLFOX-4 (HR 1.01; 95% CI 0.73, 1.39). Overall survival appeared to be comparable between treatments. However, at 3 years (the only time point available for the indirect analysis), neither treatment had demonstrated a statistically significant difference in overall survival compared to 5-FU/LV.

Results of the indirect comparison – recurrence-free survival

Both XELOX and FLOX demonstrated a statistically significant improvement in recurrence-free survival compared to 5-FU/LV.

The indirect analysis did not identify any statistically significant difference in recurrence-free survival with XELOX vs. FLOX (HR 0.98; 95% CI 0.77, 1.23). Despite the limitations of this analysis (different patient populations and follow-up times between trials), the results of the indirect comparison suggested that recurrence-free survival is comparable between treatments.

All oxaliplatin regimens (XELOX, FOLFOX-4 and FLOX) appeared to be more toxic than 5-FU/LV treatment and there were differences in the toxicity profiles of the various oxaliplatin regimens.

Based on an indirect analysis of adverse events, XELOX is associated with a lower incidence of diarrhoea, nausea/vomiting, stomatitis, neutropenia and febrile neutropenia compared to FOLFOX-4 but is associated with an increased risk of hand-foot syndrome.

9. Clinical Claim

The submission described XELOX as no worse than FOLFOX/FLOX in terms of comparative effectiveness and safety in the treatment of patients with Stage III adjuvant colon cancer, which the PBAC considered reasonable.

For PBAC’s view, see Recommendation and Reasons.

10. Economic Analysis

The submission presented a cost analysis model of XELOX vs. mFOLFOX-6 with the intention to demonstrate cost-minimisation. The submission claimed that mFOLFOX-6 is the appropriate economic comparator as it is the most commonly used chemotherapy regimen for the adjuvant treatment of colon cancer in Australia.

XELOX was associated with a cost saving per patient compared to mFOLFOX-6 based on the cost analysis model presented in the submission.

For PBAC’s view, see Recommendation and Reasons.

11. Estimated PBS Usage and Financial Implications

The submission estimated the likely number of patients/year to be less than 10,000 in Year 5.

The submission estimated the financial cost/year to the PBS to be less than $10 million in Year 5 with overall annual cost savings to the health care budget, both State and Commonwealth, over the first five years of listing.

12. Recommendation and Reasons

The PBAC recommended the listing of capecitabine in combination with oxaliplatin (XELOX) on the PBS for the adjuvant treatment of stage III (Dukes C) colon cancer on a cost-minimisation basis compared with modified FOLFOX-6. The PBAC considered that the equi-effective doses are XELOX (capecitabine 1000 mg/m2 twice daily days 1-14 and oxaliplatin 130 mg/m2 day 1 given every 21 days) and m-FOLFOX-6.

The PBAC recommended that the restriction for capecitabine be amended to include “monotherapy or in combination with oxaliplatin for the adjuvant treatment of colon cancer”, consistent with the ACPM recommended wording and that the restriction for oxaliplatin be amended to include “in combination with capecitabine or 5-fluorouracil and folinic acid” rather than “in combination with a fluoropyrimidine agent” to reflect more appropriately the drug combinations used in the clinical trials.

The PBAC considered that the main comparator, oxaliplatin with 5-fluorouracil and folinic acid (described as FOLFOX and FLOX regimens) was appropriate.

The PBAC noted that the submission presented an indirect comparison of XELOX, FOLFOX-4 and FLOX. However, the included trials enrolled different patient populations (Stage II/Stage III disease) and used different 5-FU/LV (leucovorin (folinic acid)) treatment regimens in the common comparator arm. The PBAC considered that the submission had adequately addressed these differences.

The PBAC considered the clinical claim in the submission that XELOX is no worse than FOLFOX/FLOX in terms of comparative effectiveness and safety in the treatment of patients with Stage III adjuvant colon cancer was reasonable as the indirect analysis suggests that disease-free, recurrence-free and overall survival are similar between oxaliplatin regimens (XELOX, FOLFOX-4 and FLOX). The PBAC agreed that whilst the statistical evidence does not, on its own, demonstrate non-inferiority, the conversion of capecitabine to 5FU and the point estimates of the hazard ratios being close to 1 suggests non-inferiority.

The PBAC noted that a breakdown of drug administration costs (conducted during the evaluation) showed that the difference in drug administration costs is primarily driven by the cost of removing the 5-FU delivery device in the mFOLFOX-6 treatment arm. The PBAC noted that the sensitivity analysis presented in the Pre-Sub-Committee Response removed the disconnection cost of the 5-FU device for mFOLFOX-6 but that this still resulted in a cost saving per patient.

The PBAC also acknowledged the option of an oral treatment for patients in this treatment setting was valuable.

Recommendation:
CAPECITABINE, tablet, 150 mg and 500 mg

Amend the current restriction for use in adjuvant treatment of stage III (Dukes C) colon cancer to read as follows:

Authority required

Adjuvant treatment of stage III (Dukes C) colon cancer following complete resection of the primary tumour either as

(a)monotherapy; or

(b) in combination with oxaliplatin,

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.

 

Max qty: 120 (500 mg), 60 (150 mg)
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 had no further comment.