Issue Analysis Summary

Date: 2007-09-05

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

---

Contact Policy Bureau Enquiries

---

Regulatory Experiences in Adjuvant Therapy of Hormone Responsive Early Breast Cancer ― No Overall Survival Benefit Demonstrated Following Approval Based on Disease-Free Survival

Therapeutic Products Directorate,
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
Oncology Division
September 5, 2007

Table of Contents

1. Issue
2. Purpose/objective
3. Background
4. Consultation
5. Issue analysis
6. Recommendations
7. References

1. Issue:

As indicated in the Scientific Advisory Committee on Oncology Therapies (SAC-OT) Meeting Record held on 15 January 2004 on the regulatory issues for adjuvant therapy of hormone responsive early breast cancer (EBC), Health Canada was advised that "DFS (Disease Free Survival) is a surrogate for OS (Overall Survival), although there are couple of examples in oncology literature, when significant benefit on DFS was not followed by benefit on OS". Based on this advice, several hormonal therapies for the adjuvant treatment of EBC have been approved based on positive results for DFS benefit with the requirement of submission of survival data at a later time when the survival data would be sufficiently mature to allow analysis. In several cases, positive results for DFS have not yet translated to a survival benefit.

2. Purpose/Objective

To present the following questions to the SAC-OT to obtain their advice:

1. If the observation is made that DFS does not result in a survival benefit, what is the most likely explanation for this:

1. OS are not yet sufficiently mature;
2. DFS is not a good surrogate for OS:
   1. Lack of efficacy of the drug in the long term due to more aggressive disease at recurrence;
   2. Patients receive effective therapies upon recurrence of disease;
   3. Long term adverse effects (cardiovascular effects, bone effects, etc);
   4. Dilutional effects due to inclusion of patients either at low risk or those who may not benefit from treatment (e.g. node negative patients or hormone-receptor negative patients);
3. Other?

2. If DFS is not a surrogate for OS (or cannot be demonstrated to be such), should DFS be considered an endpoint reflecting a real benefit (being disease-free for longer) and thus a basis for full nonconditional approval? 

3. Are there better endpoints available that reflect a direct clinical benefit? Would distant disease free survival be more reasonable given that the intent of therapy has changed at the point of distant recurrence?

3. Background

Therapeutic Products Directorate (TPD) has received four submissions for three aromatase inhibitors for an indication involving the treatment of early breast cancer. Each has received conditional approval based upon a demonstrated DFS improvement. A brief description of each of the studies and a table with a summary of the primary and updated (if available) results of these studies are provided below.

Arimidex (anastrozole)
ATAC Study
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial is a double-blind randomized trial which compared five years of anastrozole alone with tamoxifen alone, or the combination, as adjuvant therapy in postmenopausal patients with operable breast cancer. The primary endpoint was disease-free survival, defined as time to earliest occurrence of local or distant recurrence, new primary breast cancer, or death from any cause. Primary analysis was planned when there were 1056 (352 per treatment arm) events; it occurred with a data cut-off in June 2001 when 1079 events had occurred and median follow-up was 33.3 months. One interim analysis had been done with a nominal p-value of 0.005 when about 528 events had been reported. The major survival analysis was planned when there were 352 events per treatment arm; it occurred with a data cut-off in March 2004 when 831 deaths had occurred in the two treatment groups and median follow-up was 68 months. As well, an efficacy update was published in 2003 with a data cut-off in June 2002, when median follow-up was 47 months and 1373 DFS had occurred. Patients are to be followed to 10 years post-randomization. Between July 1996 and March 2000, a total of 9366 women were enrolled in the study; 3125 were randomized to receive anastrozole 1 mg daily, 3116 to tamoxifen 20 mg daily, and 3125 to a combination of the two treatments for five years or until recurrence of the disease. Approximately 84% of these women had EBC that was hormone-receptor-positive. However, at the time of the primary analysis, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen, and this treatment arm was subsequently discontinued from the study. 

Femara (letrozole)
BIG 1-98
The Breast International Group (BIG) 1-98 study is a randomized, double-blind, four-arm trial in postmenopausal women with hormone-receptor-positive EBC that compared five years of treatment with various adjuvant endocrine therapy regimens: monotherapy with letrozole for five years, letrozole for two years followed by tamoxifen for three years, monotherapy with tamoxifen for five years, and tamoxifen for two years followed by letrozole for three years. The protocol-specified primary core analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched. The primary endpoint was DFS, defined as time to recurrence at local, regional, or distant sites, a new invasive contralateral breast cancer, any second non-breast cancer, and death without a prior cancer event. Secondary endpoints included OS, survival free of systemic disease (which excluded local and contralateral breast events). The primary analysis was planned after the occurrence of 647 events; two interim analyses were planned after the occurrence of 261 and 433 events. Between March 1998 and May 2003, a total of 8028 women were enrolled, with 8010 women with data that could be assessed: 4003 in the letrozole groups and 4007 in the tamoxifen group. The primary analysis was conducted with a data cut-off in Nov 2004 when 779 events had occurred and median follow-up was 25.8 months. Of note, a pre-planned subset analysis revealed that DFS advantage over tamoxifen was demonstrated in those patients with node positive disease (HR 0.71; 95% CI 0.59-0.85, p=0.0002), and was not observed in patients with node negative disease (HR 0.98; 95% CI 0.77-1.25), with a significant treatment by nodal status interaction.

An updated analysis of this study was published in February 2007. This protocol-specified analysis was limited to the 4933 women allocated to continuous therapy with either letrozole or tamoxifen, 4922 with data that could be assessed: 2448 in the letrozole monotherapy arm and 2447 in the tamoxifen monotherapy arm. The analysis was conducted when 770 DFS events had occurred and median follow-up time in the monotherapy arms was 51 months (the data cut-off date for this analysis was not reported). This median follow-up time was reported to be substantially longer than that of the primary core analysis because of the exclusion of patients on the sequential arms censored at therapy switch. Of note, a pre-planned subset analysis showed no significantly different relative efficacy by nodal status in this update (node positive subgroup: HR 0.77, 95% CI 0.64-0.92, p=0.004); node negative subgroup: HR 0.88, 95% CI 0.70-1.10, p=0.26).

Intergroup MA17 Trial
The Intergroup MA17 Trial is a randomized, double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with hormone-receptor-positive EBC who have completed five years of tamoxifen therapy.  The primary endpoint was DFS, defined as time to recurrence of the primary disease (in the breast, chest wall, or nodal or metastatic sites) or the development of a new contralateral breast cancer (secondary cancer and death without a recurrence or diagnosis of contralateral breast cancer were not included as events). Secondary endpoints included OS. The primary analysis was to be conducted after 515 events had occurred; two interim analyses were planned after 171 and 342 events had occurred. Between August 1998 and September 2002, 5187 women were enrolled in the study; 2593 were assigned to the letrozole group and 2594 to the placebo group. Thirty women who did not have investigation forms at baseline were excluded from the analyses. The required number of events (171) for the first analysis occurred by March 2003; the analysis was conducted with a data cut-off in Aug 2003 when 207 events had occurred and median follow-up time was 2.4 years. With this number of events, the O'Brien-Fleming boundary was 0.0008. Based on the results of this analysis, the IDMC recommended that the study be un-blinded and the results be made available expeditiously.

In addition, updated results were published in September 2005; these are reported to be the final efficacy and toxicity results, based on all events that occurred up to the un-blinding of the study participants in October 2003.

Aromasin (exemestane)
IES
The Intergroup Exemestane Study (IES) is a randomized, double-blind study in postmenopausal women with EBC who have remained free of disease after receiving adjuvant tamoxifen therapy for two to three years to test whether switching to exemestane is more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary endpoint was DFS, defined as time to recurrence of breast cancer at any site, diagnosis of a second primary breast cancer, or death from any cause. Secondary endpoints included OS. The primary analysis was to be carried out after 716 events had occurred. Three interim analyses were to be conducted, with the use of O'Brien Fleming stopping boundaries, after one quarter, one half, and three quarters of the planned total number of events. Between February 1998 and February 2003, a total of 4742 women were enrolled in the study; 2362 were randomly assigned to the exemestane group and 2380 to the tamoxifen group. Approximately 81% of these women had EBC that was estrogen-receptor-positive. The second interim analysis, triggered by the reporting of 358 events, occurred with a data cut-off of June 2003 when 449 events had occurred and median follow-up was 30.6 months. The IDMC recommended that these data be released because the O'Brien-Fleming stopping boundary (p=0.004) had been exceeded. An updated analysis was published in February 2007. After the early release of the results of this study; the trials IDMC and steering committee decided to undertake an updated analysis that would be triggered when 95% of patients had at least 3 years follow-up or had died during the corresponding period; this analysis was conducted with a data cut-off of Feb 2006 when median follow-up was 56 months and total number of DFS events was 809.

The study outcomes for these trials are summarized in the table below.

4. Consultations

5. Issue analysis

6. Tpd's recommendations:

7. References

Arimidex (anastrozole, 1 mg tablet) Product Monograph, AstraZeneca Canada Inc., December 11, 2006. 

ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98: 1802-10.

ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002; 359: 2131-39.

ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment of breast cancer. Lancet 2005; 365.

Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747-57.

Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007; 25: 486-92.

Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081-92.

Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369: 559-70.

Femara (letrozole, 2.5 mg Tablet) Product Monograph, Novatis Pharmaceuticals Canada Inc., October 5, 2006.