# Presentation: 195617

## 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**

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

**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**

**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  **

## Benefit of Paclitaxel in Node-positive Breast Cancer CALGB 9344 / Intergroup 0148 (N = 3121)

- None

- A: 60 = 75 = 90 mg/m2

- Paclitaxel:
- 175 mg/m2
- x 4 cycles

**RR: Recurrence ↓17%**

**RR: Death ↓18%**

**Henderson et al. JCO 2003**

- C: 600 mg/m2

**92%**** Patients Received all 4 Cycles of Taxol**

**Planned (Maximum) Paclitaxel Dose 700 mg/m****2**

## A Dose of Abraxane Higher Than the Approved Dose of Taxol in the Adjuvant Setting can be Safely Delivered over 4 Cycles

|  | Abraxane260 mg/m2 | Taxol175 mg/m2 |
| --- | --- | --- |
| Number of Non-progressing Patients
 | n = 179/229 | n = 163/225 |
| Number (%) of Patients Receiving All 4 Cycles | 164/179 (92%) | 152/163 (93%) |

**NOTE:**** **** In CALGB 9344, ****92%**** of Patients Received All 4 Cycles of Taxol ****(Planned Dose 700 mg/m****2****)**

**Mean Cumulative Paclitaxel Dose****Over 4 Cycles****	****                             ****987 mg/m****2****	****          ****673 mg/m****2**

## 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 Benefits of not Requiring an Efficacy Trial?**

**What are the Challenges in  Requiring an Efficacy Trial ?**

## What are the Issues to Considerto Approve Abraxane in the Node-positive Adjuvant Setting 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?**

**What are the Risks of Approving Abraxane without an Efficacy Adjuvant Trial?**

## 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**

## 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 Benefits of not Requiring an Efficacy Trial?**

**What are the Challenges in  Requiring an Efficacy Trial ?**

## 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**

## An Efficacy Adjuvant Trial Comparing Two Forms of the Same Drug (Paclitaxel) is Unlikely to Show a Difference

- 175

- 80

- 35

- 100

- mg/m2

**Paclitaxel**

**Docetaxel**

**A**
**C**

**Source:  Sparano et al:  SABCS, 2005**

- ECOG 1199

**An Efficacy Adjuvant Trial Comparing Two Forms of the Same Drug (Paclitaxel) is Unlikely to Show a Difference**

## 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**

## 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**

## Altering the Trial Design Assumptions Results in Scientifically Unacceptable Clinical Implications

| Assumption | Sample Size |  | Clinical Implication |
| --- | --- | --- | --- |
|  | Non-inferiority | 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 |

## 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 Benefits of not Requiring an Efficacy Trial?**

**What are the Challenges in  Requiring an Efficacy Trial ?**

## 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)**

## 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

**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**

**What are the Benefits of Not ****Requiring an Adjuvant Efficacy Trial? **

## Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

**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**

**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  **

## Abraxane®for the adjuvant treatment of node-positive breast cancer

**Oncologic Drugs Advisory Committee Meeting**
**September 7, 2006**