# Presentation: 808858

## Ethyol® Non-Small Cell Lung Cancer IndicationODAC Meeting March 12, 2003 MedImmune Oncology

## Outline of Presentation

- Amifostine
- Accelerated approval in NSCLC
- Outcome of Phase III study in NSCLC
- Continuing post-accelerated approval obligation

## Amifostine: Mechanism of Action

***Capizzi RL. Oncology. 1999;13:47-59***

- Amifostine: *Mechanism of Action*

**WR-1065**

**NH****2****-(CH****2****)****3****-NH-(CH****2****)****2****-S-PO****3****H****2**

**Amifostine (WR-2721)**

**Free radicals****produced by****radiation and****chemotherapy**

**NH****2****-(CH****2****)****3****-NH-(CH****2****)****2****-SH**

## AmifostineSelective Uptake: Normal vs Tumor Tissues

**Time Post-injection (minutes)**

- Yuhas JM et al. *Cancer Res.* 1980;40:1519-1524.

## Ethyol Indications

- Prevention of xerostomia from radiation therapy in post-operative patients with Head and Neck cancer
- Reduction of cumulative renal toxicity associated with cisplatin in advanced ovarian cancer

## Ethyol Accelerated Approval 

- Prevention of cisplatin nephrotoxicity in NSCLC (1996)
- Phase II (n=25)
- Phase III trial required for full approval
- Demonstration of nephroprotection
- Lack of tumor protection

## Post-Approval Study (WR-0053)

- Phase III randomized controlled trial
- Stage IIIB or IV NSCLC (n=366)
- Cisplatin and Vinblastine ± Amifostine
- Endpoint:
- No reduction in anti-tumor efficacy with a reduction in cisplatin-related nephrotoxicity

## WR-0053 Nephroprotection

- Confirmed nephroprotection in cisplatin-treated patients

## WR-0053 Results

- No difference observed in Response Rate and Progression Free Survival in Amifostine patients

## WR-0053 Results

- Months

- % Survival

- Control

- Amifostine

| Median Survival Events |  |
| --- | --- |
| Amifostine | 8.75 mo |
| Control | 9.93 mo |

| Log-Rank | P=0.097 |
| --- | --- |
| Wilcoxon | P=0.288 |

## WR-0053 Results

|  | ECOG PS=0 | ECOG PS=1 |
| --- | --- | --- |
| Control | 17.2 mos | 8.0 mos |
| Amifostine | 9.8 mos | 7.3 mos |
| Historical Control* | 9 – 10.8 mos | 6.6 – 7.1 mos |

** Schiller, et al.  *_*N Engl J Med*_*.  346:92, 2002, Ruckdeschel, et al. *_*J Clin Oncol*_*.  4:14, 1986*

- Covariate analysis on survival
- Interaction between treatment and PS (P<0.10)

## Phase III Trials: Survival

## Post-approval Study Conclusion

- Nephroprotection confirmed
- Anti-tumor efficacy endpoint
- No difference in Response Rate
- No difference in Progression Free Survival
- Median survival
- Amifostine	=	8.75 months
- Control	=	9.93 months

## Continuing Obligation

- Completion of a new cisplatin-based study in NSCLC
- Co-primary endpoints
- Nephroprotection
- Non-inferiority of survival or survival surrogate

## Sample Size: Non-Inferiority

- Assumptions
- One-sided 97.5% CI
- Retention of at least 50% of treatment effect from literature

|  | Response Rate | Survival
(in Hazard Ratio) |
| --- | --- | --- |
| Treatment effect* | 16% | 0.225 |
| 50% retention rate | 8% | 0.1125 |
| Lower Bound | -8% | 0.8875 |
| Statistical Power | 85% | 85% |
| N (# of patients) | 1,150 | 2,600 |

**Le Chevalier T, et al.  *_*The Oncologist.*_*  6(suppl 1):8-11,** **2001.*

## Challenge

- Accrual
- Changing pattern of cisplatin utilization
- Decreased use of high-dose cisplatin regimens
- Competing higher priority protocols
- Trial length  6.5 years
- Patient pool	=	700 per year
- Accrual	=	240 patients per year
- Follow-up	=	2 years

## Summary

- Amifostine nephroprotection established
- Lack of tumor protection not established
- Additional definitive trial of tumor protection in cisplatin-treated NSCLC required