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

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

2. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane Abraxane is Cremophor-free Formulation of Paclitaxel Based Upon The Data, There Is No Scientific Basis To Hypothesize That Abraxane Will Be Less Effective As Adjuvant Therapy Since Abraxane Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel In Metastatic Breast Cancer Abraxane has Greater Anti-tumor Activitythan Taxol • Safely delivers a higher dose of paclitaxel than already proven to be effective in adjuvant settingand • Is proven to be superior in metastatic breast cancer Paclitaxel is Approved forAdjuvant Use (Taxol) The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting

3. Benefit of Paclitaxel in Node-positive Breast CancerCALGB 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

4. A Dose of Abraxane Higher Than the Approved Dose of Taxol in the Adjuvant Setting can be Safely Delivered over 4 Cycles Mean Cumulative Paclitaxel DoseOver 4 Cycles 987 mg/m2 673 mg/m2 NOTE: In CALGB 9344, 92% of Patients Received All 4 Cycles of Taxol (Planned Dose 700 mg/m2)

5. What are the Issues to Considerin 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?

6. What are the Issues to Considerto 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?

7. What are the Risks to Considerto 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

8. What are the Issues to Considerto 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?

9. What are the Issues to Considerto 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

10. An Efficacy Adjuvant Trial Comparing Two Forms of the Same Drug (Paclitaxel) is Unlikely to Show a Difference ECOG 1199 80 Paclitaxel 175 mg/m2 A C 35 Docetaxel 100 Source: Sparano et al: SABCS, 2005

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

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 = 8,644Superiority = 190,622

13. Altering the Trial Design Assumptions Results in Scientifically Unacceptable Clinical Implications

14. 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?

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 pathwayto 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)

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

17. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane Abraxane is Cremophor-free Formulation of Paclitaxel Based Upon The Data, There Is No Scientific Basis To Hypothesize That Abraxane Will Be Less Effective As Adjuvant Therapy Since Abraxane Removing Cremophor Allows Safe Delivery of Higher Doses of Paclitaxel In Metastatic Breast Cancer Abraxane has Greater Anti-tumor Activitythan Taxol • Safely delivers a higher dose of paclitaxel than already proven to be effective in adjuvant settingand • Is proven to be superior in metastatic breast cancer Paclitaxel is Approved forAdjuvant Use (Taxol) The Abraxane Dose of Paclitaxel is Safe and Higher than that Already Proven Effective in the Adjuvant Setting

18. Abraxane®for the adjuvant treatment of node-positive breast cancer Oncologic Drugs Advisory Committee Meeting September 7, 2006