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Concluding Remarks and Risk/Benefit Summary

Mace L. Rothenberg, MD

Professor of Medicine

Vanderbilt Ingram Cancer Center

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Historical Context: Therapeutic Advances in Advanced Pancreatic Cancer

1995: Gemcitabine presented to ODAC

–Small but significant improvement in survival

–Low objective response rate

–Higher rates of Grade 3-4 myelosuppression, LFTs, nausea and vomiting

1996: Gemcitabine approved by FDA for advanced pancreatic cancer

CR-3

Historical Context: Therapeutic Advances in Advanced Pancreatic Cancer

1996 – 2005

– 2 Phase III trials of new drug vs gemcitabine

None demonstrated a survival benefit

– 8 Phase III trials of new drug + gemcitabine vs gemcitabine alone or with placebo

None demonstrated a survival benefit

Clearly, improving outcomes in advanced pancreatic cancer has been more difficult than anticipated

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Tarceva and Advanced Cancers

Pancreatic cancer is a fatal disease

– Overall survival is the shortest of any solid tumor In other Phase III trials, the addition of a second agent to

gemcitabine has added toxicity without an improvement in survival

Tarceva was approved by the FDA in 2004 after demonstrating improvement in overall survival in patients with recurrent NSCLC

Clinical experience and safety profile for Tarceva in greater than 18,000 patients

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The application under consideration today is a supplemental NDA, a mechanism created by the FDA to encourage sponsors to submit significant clinical trial data and thereby promote concordance between labeled indications and emerging clinical use of the drug.

FDA Guidance for Industry: “If a product already has been shown to be safe and effective in the treatment of patients with a given type of cancer, a single, adequate and well-controlled, multicenter study demonstrating acceptable safety and effectiveness in another form of cancer that is known to have a generally similar pattern of responsiveness to chemotherapy may support labeling for that additional form of cancer.”†

† FDA Guidance For Industry: FDA Approval of New Cancer Treatment Uses for Marketed Drug and Biological Products (December 1998)

What is Under Consideration: sNDA

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NCIC CTG PA.3 is a Well-Designed, High-Quality Study

Randomized, double-blind, placebo-controlledPhase III trial

Conducted independently by a North American Cooperative Group with support from OSI

Primary endpoint, improvement in overallsurvival achieved

Therapeutic benefit conferred that is both statistically significant and clinically meaningful– 23% increase in overall survival – 30% increase in progression-free survival

A point estimate, such as median survival, does not accurately capture this benefit

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NCIC CTG PA.3 is a Well-Designed, High-Quality Study

Benefit associated with modest or infrequent toxicities

– Primarily rash and diarrhea

– Rare episodes of ILD-like events

– No worsening of global quality of life

Magnitude of toxicity is substantially less than what has been observed when other cytotoxic agents have been added to gemcitabine

Tarceva is an oral, self-administered drug that does not place a burden on outpatient resource utilization or inconvenience the patient

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Implications of Study PA.3 for Patients with Advanced Pancreatic CancerPA.3: the first trial in 10 years to demonstrate significant

improvement in survival in patients with advanced pancreatic cancer

The type and magnitude of benefits far outweigh the risk of toxicities

Tarceva and gemcitabine: an important treatment option for patients and physicians who want a more aggressive, more effective treatment for advanced pancreatic cancer

They should have that choice!