New Safety Alert
12-01-2007

 

 

Amgen released a summary of an interim analysis of a German clinical study of 733 breast cancer patients given preoperative chemotherapy with or without AranespÒ treatment on November 30, 2007.

 

Editorial commentary:  This summary adds to concern about the safety of ESA products used during cancer treatment. 

 

Questions:

 

Does this interim analysis suggest that the risk of ESA use during cancer treatment exceeds its potential benefit?

 

·        Patients were able to maintain adequate hemoglobin levels without use of   Aranesp

·         Longer-term follow up shows numerically more deaths and tumor progression events in the group of patients treated with AranespÒ  than in the group that did not receive ESA treatment, despite  no significant differences reported in tumor response to chemotherapy as assessed at the time of surgery.

·        14% of ESA treated patients died, versus 9.8% of untreated patients, and 24.7% of ESA treated patients suffered tumor progression versus 18.6% of untreated patients.

·        According to materials released by FDA, this trial was not designed to adequately evaluate tumor progression, and did not evaluate thrombotic or cardiovascular events.  Even with those limitations, the number of patients who had tumor progression was greater in the Aranesp arm.

 

When in 2009 will the full statistical analysis be available to the public?

 

When will the FDA receive the primary data from this study?

 

Key Question:  Does the interim analysis alone justify a further modification of the FDA approved label for ESA use during cancer treatment?

 

Interim Results:

 

Arm

Number

Number of deaths

Number of tumor progression events

Mean hemoglobin at entry

Mean hemoglobin at end of chemo

Control

377

37 (9.8%)

70 (18.6%)

13.6 g/dL

12.6 g/dL**

Aranesp

356

50 (14%)

88 (24.7%)

13.6 g/dL

13.6 g/dL

 

**12.6 g/dL, naturally maintained by patients without ESA treatment, is higher than the FDA-recommended target limit of 12 g/dL for ESA administration.

 

Amgen’s press release here: http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1083091

 

Trial design as described in the FDA briefing document can be found here: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf

 

 

 

 

 

FDA concerns raised in briefing document (page 47):

(note: bolding is ours)

 

Limitations of assessment of impact on RFS, OS, and TVE:

 

·   This study has a mutifactorial design to study the effects of two neoadjuvant chemotherapy regimen on relapse-free survival and overall survival as co-primary endpoints.  Assessment of the impact of Aranesp co-administration on relapse-free or overall survival is one of multiple secondary endpoints.  There are insufficient details in the protocol to determine the adequacy of the analytic approach, including adjustment for multiplicity.

 

·   The dosing regimen and dose modifications rules for Aranesp employed in this study are not consistent with either of the approved regimens, (2.25 ug/kg QW or 500 ug Q3W).

 

·   The design of the study was not adequate to assess tumor proliferation.  In this protocol, subjects with breast cancer were to be given 12 weeks of neoadjuvant chemotherapy, followed by surgery, radiation and hormonal therapy.  The structure of this study would allow the determination of possible effects of darbepoetin alfa on tumor growth during the chemotherapy phase.  However, since all subjects would undergo surgery, further tumor size determination would not be possible.

 

·   Follow-up monitoring was inadequate.  Routine scans or blood chemistries were not mandated as part of follow-up monitoring for disease recurrence, no imaging of the contralateral breast was mandated, and it was not stated when follow-up monitoring ended.

 

·   This study did not address specific monitoring for possible thrombotic / cardiovascular events, as outlined in the ODAC recommendations on May 4, 2004.