Joanne Edwards Medical Information Manager ASCO Tech Assessment Update Commercial Implications & Promotional Guidance

ASCO Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women With H ormone Receptor–Positive Breast Cancer: Status Report 2004 Data covered –ATAC (47 month update) –ITA –IES –MA-17 Although there are no recommendations specific to ‘Arimidex’, there are a number of ways we can use these guidelines to support establishing ‘Arimidex’ as the new ‘standard of care’

JCO ASCO Tech Assessment - Page 1 Adjuvant therapy should now include use of an AI to reduce the risk of recurrence 5 years’ tamoxifen alone is no longer the optimal treatment

JCO ASCO Tech Assessment - Page 1 Those with a contra- indication to tamoxifen should receive an AI For ALL other patients options include –5 years initial AI therapy –Switch from tamoxifen after 2-3/5 years NOT restricted to those who cannot tolerate tamoxifen aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, to 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor

The AIs are different and not interchangeable The Panel recommends using the AI with the most data, in the relevant clinical setting Evidenced-based medicine JCO ASCO Tech Assessment - Page 4

Neither MA-17 or IES address initial therapy Only ‘Arimidex’ applies as “best first” treatment option

JCO ASCO Tech Assessment - Page 4 The jury are still out on PgR status BUT no limitations recommended should be treated with an aromatase inhibitor. There is the suggestion, from a subgroup analysis within the ATAC trial, that women with ER, progesterone receptor negative tumors may derive relatively greater benefit from initial therapy with an aromatase inhibitor. Although this subset analysis was retrospective, the number of events considered was relatively large. Some Panel members felt the results should be factored into the decision-making process, while other Panel members did not favor using this information in clinical decisions.

JCO ASCO Tech Assessment - Page 4 No need to consider HER-2 status AI therapy need not be restricted to certain subgroups based on baseline prognostic factors positive tumors. Based on the available clinical evidence, the Panel would generally recommend that HER-2 status not be considered when making choices about adjuvant hormonal therapy. It must be noted, however, that some Panel members

JCO ASCO Tech Assessment - Page 5 Based on ITA data, you may consider a switch to ‘Arimidex’ The ITA trial data substantiate this clinical decision

JCO ASCO Tech Assessment - Page 7 AI-induced bone loss may represent a preventable and treatable condition This should not be a significant barrier to ‘Arimidex’ use

JCO ASCO Tech Assessment - Page 7 Arthralgia is a class effect of all the AIs Overall, these three large studies support the conclusion that there is a small but statistically significant increase in arthralgias and/or myalgias with aromatase inhibitors compared with either tamoxifen or placebo.

Side effects of tamoxifen recognized as life-threatening - ‘Arimidex’ is a safer treatment option Tamoxifen lowering cholesterol not linked to cardiovascular disease - this is not a reason to initiate treatment with tamoxifen JCO ASCO Tech Assessment - Page 8 Thus, incidence of three life-threatening side effects seen with tamoxifen—endometrial cancer, pulmonary emboli, and stroke—was significantly reduced with aromatase inhibitor use. Although tamoxifen lowers cholesterol levels, its influence on cardiovascular disease is not established.

So why are the ASCO Tech Committee still sitting on the fence?!

Important and Unresolved Issues: 1.Are the AIs most effective if used as initial therapy or after exposure to tamoxifen? 2.What are the long-term toxicities and risks associated with AI s? 3.Are there specific patient populations who derive differing degrees of benefit from an AI compared with tamoxifen? 4.Are there specific patient populations who are at greater risk of toxicity from an AI? 5.How long should an AI be continued? 6.Are aromatase inhibitors effective in premenopausal women? 7.Can the AIs be used interchangeably? Are there clinical differences in their toxicity profile (eg, bone health)?

Remember….. ! These guidelines were issued without consideration of the benefits of ‘Arimidex’ seen in the ATAC Completed Treatment Analysis or the ABCSG/ARNO combined analysis These new data will go a long way towards addressing many of these issues WE CAN LOOK FORWARD TO MORE SPECIFIC GUIDELINES IN THE FUTURE

Use of the Guidelines in Promotion Not all markets will be able to use these data: –Some local codes prohibit citing national or international guidelines in promotional material –Some markets may feel it inappropriate to cite US guidelines as an endorsement for local practice

Story Flow – ASCO Tech Assessment Tamoxifen is no longer the optimal adjuvant therapy Optimal adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer should now include an aromatase inhibitor – as initial therapy or after treatment with tamoxifen, in order to lower the risk of tumour recurrence Risk of recurrence in early breast cancer is highest during the first 5 years following diagnosis, irrespective of baseline prognostic factors; therefore, it is important to use the most effective drug first, following surgery Results from the ATAC Completed Treatment Analysis indicate that it may be more effective to start treatment with 'Arimidex' than start with tamoxifen with the intention of switching to an AI Specifically, higher rates of recurrence, adverse events, and treatment withdrawals associated with tamoxifen, and the substantial benefit of 'Arimidex' in the first 3 years following surgery, justify the approach of offering the most effective therapy at the earliest opportunity

Story Flow – ASCO Tech Assessment It not known if the AIs are interchangeable in clinical practice From evidenced-based medicine, the AI used should be the one with the most data in the relevant clinical setting Neither MA-17 nor the IES trial addressed use of an AI as initial therapy 'Arimidex' should be the AI of choice in this setting These new guidelines endorse the use of an AI, such as 'Arimidex', as the new standard of care for postmenopausal women with hormone receptor- positive early breast cancer 'Arimidex' is the only AI with conclusive evidence demonstrating superior efficacy and tolerability versus tamoxifen in both newly diagnosed patients (ATAC) and in those patients already receiving adjuvant tamoxifen (ABCSG8/ARNO and ITA)

Hot off the press ….. !

NCCN Guidelines The panel believes the 3 selective AIs have similar efficacy and toxicity profiles The AI(s) specified is that used in the clinical trial(s) that most closely approximates the clinical situation