Transcript Perspectives on the Use of Abraxane in Node-positive Breast Cancer

CP-1
Perspectives on the Use of Abraxane in
Node-positive Breast Cancer
Clifford A. Hudis, MD
Chief, Breast Cancer Medicine Service
Memorial Sloan-Kettering Cancer Center
CP-2
Reasons that an Efficacy Adjuvant Trial
Should not be Required for Approval of Abraxane
Abraxane is Cremophor-free
Formulation of Paclitaxel
Removing Cremophor Allows
Safe Delivery of Higher Doses
of Paclitaxel
In Metastatic Breast Cancer
Abraxane has Greater
Anti-tumor Activity
than Taxol
Paclitaxel is Approved for
Adjuvant Use (Taxol)
The Abraxane Dose of
Paclitaxel is Safe and Higher
than that Already Proven
Effective in the Adjuvant
Setting
Based Upon The Data, There
Is No Scientific Basis To
Hypothesize That Abraxane
Will Be Less Effective As
Adjuvant Therapy Since
Abraxane
• Safely delivers a higher
dose of paclitaxel than
already proven to be
effective in adjuvant
setting
and
• Is proven to be superior in
metastatic breast cancer
CP-3
Benefit of Paclitaxel in Node-positive Breast
Cancer CALGB 9344 / Intergroup 0148 (N = 3121)
RR: Recurrence ↓17%
C: 600 mg/m2
Paclitaxel:
175 mg/m2
x 4 cycles
None
A: 60 = 75 = 90 mg/m2
RR: Death ↓18%
Planned (Maximum)
Paclitaxel Dose 700 mg/m2
92% Patients Received
all 4 Cycles of Taxol
Henderson et al. JCO 2003
A Dose of Abraxane Higher Than the Approved Dose
of Taxol in the Adjuvant Setting can be Safely Delivered
over 4 Cycles
CP-4
Abraxane
260 mg/m2
Taxol
175 mg/m2
n = 179/229
n = 163/225
Number (%) of Patients Receiving
All 4 Cycles
164/179
(92%)
152/163
(93%)
Mean Cumulative Paclitaxel Dose
Over 4 Cycles
987 mg/m2
673 mg/m2
Number of Non-progressing
Patients
NOTE: In CALGB 9344, 92% of Patients Received All 4 Cycles of Taxol
(Planned Dose 700 mg/m2)
What are the Issues to Consider
in Approving Abraxane in the Node-positive Setting
without an Efficacy Adjuvant Trial?
What are the Risks of
Approving Abraxane without an
Efficacy Adjuvant Trial?
What are the Challenges in
Requiring an Efficacy Trial ?
What are the Benefits of not
Requiring an Efficacy Trial?
CP-5
What are the Issues to Consider
to Approve Abraxane in the Node-positive Adjuvant
Setting without an Efficacy Adjuvant Trial?
What are the Risks of
Approving Abraxane without an
Efficacy Adjuvant Trial?
 Could Abraxane have less antitumor activity than
Taxol?
 Could more/different toxicities be reported for
Abraxane compared to other approved taxanes?
 Could the higher dose of Abraxane compromise the
ability to give full dose of paclitaxel therapy already
known to be effective in the adjuvant setting?
CP-6
What are the Risks to Consider
to Approve Abraxane in the Node-positive Adjuvant
Setting without an Efficacy Adjuvant Trial?
 Could Abraxane have less antitumor activity than Taxol?
– Unlikely given the data in metastatic breast cancer
• Replacing Cremophor with albumin allowed for a higher
dose and more effective paclitaxel with comparable
tolerability
• This was the basis for the approval of Abraxane in
metastatic breast cancer with superior efficacy
 Could more/different toxicities be reported for Abraxane
compared to other approved taxanes?
– There is extensive clinical experience with paclitaxel
– Safety profile well-established from a randomized trial in
metastatic breast cancer and other clinical trials
– Solvents are more toxic than albumin
 Could the higher dose of Abraxane compromise the ability to
give full dose of paclitaxel therapy already known to be effective
in the adjuvant setting?
– No evidence from the randomized trial in stage IV MBC
CP-7
What are the Issues to Consider
to Approve Abraxane in the Node-positive Adjuvant
Setting without an Efficacy Adjuvant Trial?
What are the Risks of
Approving Abraxane without an
Efficacy Adjuvant Trial?
What are the Challenges in
Requiring an Efficacy Trial ?
What are the Benefits of not
Requiring an Efficacy Trial?
CP-8
What are the Issues to Consider
to Approve Abraxane in the Node-positive Adjuvant
Setting without an Efficacy Adjuvant Trial?
What are the Challenges in
Requiring an Efficacy Trial?
 A trial comparing 2 formulations of paclitaxel
would consume considerable resources
 ECOG 1199 is informative
– There is a high chance of finding no
difference
– There is a very low chance of demonstrating
less activity for Abraxane
CP-9
CP-10
An Efficacy Adjuvant Trial Comparing Two Forms of the
Same Drug (Paclitaxel) is Unlikely to Show a Difference
ECOG 1199
80
Paclitaxel
175
A
C
mg/m2
35
Docetaxel
100
Source: Sparano et al: SABCS, 2005
CP-11
An Efficacy Adjuvant Trial Comparing Two Forms of the
Same Drug (Paclitaxel) is Unlikely to Show a Difference
 N = 5,052
 Median F/U ~ 4 years
 Fewer events than planned
 No difference in DFS for:
– Taxol and Taxotere
(HR = 0.985)
– Q3w vs. weekly
(HR = 1.043)
Event rates will continue to be low for breast cancer adjuvant
studies because:
–HER2+ tumors treated with Trastuzumab
–ER+ tumors treated with prolonged hormonal therapy
CP-12
Assumptions in Calculating Sample Size
 Abraxane/Taxol HR = 0.97
– 2 x the Taxol/Taxotere treatment difference (E1199)
 Lower bound 95% CI = 0.89
– Maintains 50% of Taxol treatment effect (Taxol PI)
 Event rate 18%
– Event rate on E1199 = 17% at 4 years
 α = 0.05, 80% power
– Standard statistical criteria
Based on these assumptions, sample sizes for:
Non-inferiority = 8,644
Superiority = 190,622
CP-13
Altering the Trial Design Assumptions Results in
Scientifically Unacceptable Clinical Implications
Sample Size
Noninferiority
Superiority
Wider confidence
interval?
The upper bound of
HR 95% CI = 1.28
(ie 1/0.78)
2560
N/A
Fails to exclude no benefit over AC
alone
(Taxol Package Insert)
Larger effect size?
True HR of
Abraxane/Taxol is
0.85
2558
7124
Unreasonable to assume treatment
difference is 10 x that of
Taxol/Taxotere (E1199)
Higher event rate?
Event rate = 36%
Twice the event rate
of E1199
4272
95,156
Accrual would be limited to extremely
poor prognosis patients
Prolonged accrual
Larger type I error?
α = 0.10
6778
150,154
Allows a large false positive error rate
Assumption
Clinical Implication
What are the Issues to Consider
to Approve Abraxane in the Node-positive Adjuvant
Setting without an Adjuvant Efficacy Trial?
What are the Risks of
Approving Abraxane without an
Efficacy Adjuvant Trial?
What are the Challenges in
Requiring an Efficacy Trial ?
What are the Benefits of not
Requiring an Efficacy Trial?
CP-14
CP-15
FDA Position Regarding 505(b)(2)
 “FDA’s longstanding interpretation of section
505(b)(2) ……… the Agency’s approach is to use
the 505(b)(2) drug approval pathway to avoid
requiring drug sponsors to conduct and submit
studies that are not scientifically necessary.”
 “The conduct and review of duplicative studies
would …. slow the process for drug approval with
no corresponding benefit to the public health.”
Source: Woodcock 2003 Response to Citizen’s Petition regarding 505(b)(2)
CP-16
What are the Benefits of Not
Requiring an Adjuvant Efficacy Trial?
 Preservation of resources for other research
 Immediate availability of a Cremophor-free
paclitaxel alternative
– While rare, patients occasionally die from
Cremophor induced HSRs
– Steroid premedication would be reduced (not
required for Abraxane)
– These considerations are important for patients
who may already be cured of their disease
CP-17
Reasons that an Efficacy Adjuvant Trial
Should not be Required for Approval of Abraxane
Abraxane is Cremophor-free
Formulation of Paclitaxel
Removing Cremophor Allows
Safe Delivery of Higher Doses
of Paclitaxel
In Metastatic Breast Cancer
Abraxane has Greater
Anti-tumor Activity
than Taxol
Paclitaxel is Approved for
Adjuvant Use (Taxol)
The Abraxane Dose of
Paclitaxel is Safe and Higher
than that Already Proven
Effective in the Adjuvant
Setting
Based Upon The Data, There
Is No Scientific Basis To
Hypothesize That Abraxane
Will Be Less Effective As
Adjuvant Therapy Since
Abraxane
• Safely delivers a higher
dose of paclitaxel than
already proven to be
effective in adjuvant
setting
and
• Is proven to be superior in
metastatic breast cancer
CP-18
Abraxane®
for the adjuvant treatment of
node-positive breast cancer
Oncologic Drugs Advisory Committee
Meeting
September 7, 2006