# Presentation: 762765

## Actions  Ongoing Clinical Development 

**Judith S. Ochs, MD**

## Immediate Actions Agreed With FDA

**Communicate rapidly and extensively**
**Enable informed physician decision making **
**Reduce the numbers of patients receiving IRESSA****®**** for the first time**
**Provide FDA with prescription data q 2 wk**
**Maintain IRESSA****®**** availability  **
**Rapidly provide full data to FDA for review   **

## Communications—December 17, 2004

**AstraZeneca actions**
**Press release **
**~ 141,000 Dear Doctor Letters (DDL)**
**Sales force distribution of DDL**
**DDL posted to Web sites**
**Patient advocate groups notified **
**Clinical trial investigators, NCI notified **
**Promotional activity suspended**
**External actions**
**ASCO e-mail from FDA  **
**Information posted on FDA Web site**

## Further Communications 

**Presentation at ODAC **
**Communications to healthcare professionals**
**Journal placement of DDL**
**AACR, WCLC abstracts**
**Manuscript in preparation**

## CR-<number>

**CR-**

## Feb/March Journal Placement

**American Journal Oncology Reviews**
**Clinical Lung Cancer**
**Clinical Advances in Hematology & Oncology**
**Hematology/Oncology Today**
**JAMA Oncology Subscriber**
**Journal of Clinical Oncology**
**New England Journal Oncology Subscriber**
**Oncology**
**Oncology Times**
**The Oncologist**

## Impact on IRESSA® Usage

**Total and new prescriptions for IRESSA****®**** have significantly decreased **
**Total prescriptions are 49% lower **
**New prescriptions are 58% lower **
**Market research**
**78% clinical oncologists aware of DDL content**
**86% modifying treatment practice**

## Clinical Implications andNext Steps

## Pertinent Questions to Ask

**Why did this result occur?**
**How does this result compare to other data on IRESSA****®**** in NSCLC?**
**The play of chance?**
**Dose selection strategy?**
**Trial population and geography?**
**What biologic data may be available to better understand the outcomes?**
**What other relevant clinical data are expected?**

## Consistency of Outcome Between Trial 709 and  Phase II Data (1)

**Adenocarcinoma**

**All patients**

**Female**

**PS 0,1**

**1 prior chemo**

**Refractory**

**Never smoked**

**Non-adenocarcinoma**

**Ever smoked**

**Intolerant**

**2 prior chemos**

**PS 2,3**

**Male**

**Hazard ratio and 95% CI**

**Favors IRESSA****®**

**Favors placebo**

**11.4**

**7.7**

**14.0**

**8.3**

**7.4**

**7.8**

**17.2**

**4.6**

**5.2**

**7.2**

**8.0**

**6.6**

**4.9**

**Response rate, %**
**Trial 709****	****Phase II**

**Survival**

**Consistency of Outcome Between Trial 709 and  Phase II Data (1)**

**13.8**

**10.2**

**20.7**

**10.4**

**26.8**

**5.3**

**7.1**

**10.5**

**9.8**

**4.4**

**NA**

**NA**

**9.3**

## Consistency of Outcome Between Trial 709 and  Phase II Data (2)

**Prior docetaxel**

**All patients**

**Asian ethnicity**

**Time since Dx: >12 mo**

**Time since Dx: <6 mo**

**<65 yr**

**No prior docetaxel**

**≥****65 yr**

**Time since Dx: 6-12 mo**

**Non-Asian ethnicity**

**Hazard ratio and 95% CI**

**Favors IRESSA****®**

**Favors placebo**

**Prior chemo response: PD/NE**

**Prior chemo response: CR/PR**

**Prior chemo response: SD**

**10.3**

**7.7**

**12.0**

**9.3**

**6.8**

**7.1**

**6.7**

**8.7**

**6.9**

**6.5**

**7.0**

**8.9**

**8.0**

**Survival**

**Consistency of Outcome Between Trial 709 and  Phase II Data (2)**

**11.1**

**10.2**

**27.5**

**12.4**

**10.0**

**10.7**

**6.0**

**10.4**

**NA**

**5.3**

**NA**

**Response rate, %**
**Trial 709****	****Phase II**

**8.0**

**NA**

## The Play of Chance?

**The Play of Chance?**

**Is the overall outcome in Trial 709 inconsistent with that seen in erlotinib study (BR21)?  **

**BR21**

**Trial 709**

**Survival**

**Response rate, %**

**Favors active agent****	****Favors placebo**

**9**

**8**

## Dose Selection Strategy

**Doses up to 1000 mg explored in extensive ****Phase I program**
**250 mg and 500 mg compared in randomized Phase II trials in 416 patients**
**No difference in survival **
**Increased toxicity at 500 mg**
**No data to suggest doses above 500 mg would achieve better outcomes but cannot be ruled out completely**

## Methodologic: Areas to Explore

**Highly refractory population?**
**Cultural or environmental differences ****between regions?**
**Smoking exposure**

## What Does This Mean?

**IRESSA****®**** is an active and well-tolerated agent**
**Data consistent with Phase II and large clinical experience**
**Variability in outcome, with significant survival increase in**
**Never smokers**
**Asian patients**
**Biomarker studies from Trial 709 may help in further interpretation of results**

## Biomarkers of Interest in NSCLC

**EGFR expression**
**Exploratory analyses from Phase II IDEAL studies**
**Relationship with survival shown for erlotinib**
**EGFR activating mutations**
**Described in dramatic responders to IRESSA****®**
**Other exploratory biomarkers**
**EGFR gene copy number**
**HER-family dimerization patterns**

## Relationship Between EGFR Expression and Survival for Erlotinib BR21

**A positive EGFR expression status was defined as having at least 10% of cells staining for EGFR in contrast to the 1% cut-off specified in the DAKO EGFR pharmDxTM kit instructions. The use of the pharmDx kit has not been validated for use in Non-Small Cell Lung Cancer.**
**TARCEVA prolonged survival in the EGFR positive subgroup (N = 127; HR = 0.65; 95% CI = 0.43 - 0.97) (figure 3) and the subgroup whose EGFR status was unmeasured (N = 493; HR = 0.76; 95% CI = 0.61 - 0.93) (figure 5), but did not appear to have an effect on survival in the EGFR negative subgroup (N = 111; HR = 1.01; 95% CI = 0.65 - 1.57) (figure 4). However, the confidence intervals for the EGFR positive, negative and unmeasured subgroups are wide and overlap, so that a survival benefit due to TARCEVA in the EGFR negative subgroup cannot be excluded.**

**CR-**

## Mutation of the EGFR Tyrosine Kinase in Human Non-Small Cell Lung Carcinoma 

**Mutation of the EGFR Tyrosine Kinase in Human Non-Small Cell Lung Carcinoma **

**Mutation appears almost exclusively in NSCLC**
**Mutation is activating, in****ATP-binding site**
**Mutation more frequent in**
**Females**
**Adenocarcinomas**
**Never smokers**
**Frequency of mutation approx. 12% in Caucasian, 26% in Asian population**
**Incomplete association of mutation with response in IDEAL studies (6/14 PR in mutation+)**

**Paez J, Janne, PA, Lee JC, et al. *****Science*****. April 29 2004;****Lynch TJ, Bell DW, Sordella et al. *****N Engl J Med.***** April 30 2004.**

## Biologic CorrelationsSummary of Currently Available Data

**EGFR expression appears to be associated with increased survival in BR21**
**EGFR mutations appear to explain some, but not all, of the responses to IRESSA****®**
**Outcomes in trial 709 comparing IRESSA****®**** to placebo will be explored in terms of EGFR expression, activating mutation and other biomarkers**
**Data available in June 2005 **
**Results may provide further insight into clinical outcomes**
**Prospective studies needed**

## Prospective Studies to Investigate Predictive Markers and Outcome in NSCLC

**IRESSA****®**** vs. doublet chemotherapy**
**Mandatory tissue collection to evaluate further utility of defined biomarkers**
**Targeted study population**
**Mutation+**
**Never smokers**
**Specific studies in Asian population(s)**

## Further Studies in Advanced NSCLC

**Trial 721—IRESSA****®**** vs. docetaxel**
**Post-approval commitment (n = 1440)**
**Interim analysis: ~ May-June with 380 deaths**
**IRESSA****®**** vs. docetaxel**
**Japan post-approval commitment (n = 484)**
**Phase II Trial 503: IRESSA****®**** vs. docetaxel**
**Supportive of Trial 721 and dose **

## Trial 503—IRESSA® 250 mg Daily vs. Docetaxel 75 mg/m2

**Trial 503—IRESSA****®**** 250 mg Daily vs. Docetaxel 75 mg/m****2**

|  | IRESSA® | Docetaxel |
| --- | --- | --- |
| Median (mo) | 7.5 | 7.1 |
| HR = 0.96 (0.61, 1.52), P = .87
N = 141, 55% mortality |  |  |

**Time, mo**

**	****0****	****2****	****4****	****6****	****8****	****10****	****12****	****14**

**——****	****IRESSA****®**
**------****	****Docetaxel**

**Patients surviving (%)**

**1.0**
**0.9**
**0.8**
**0.7**
**0.6**
**0.5**
**0.4**
**0.3**
**0.2**
**0.1**
**0.0**

## Clinical Summary

**Well-tolerated agents like IRESSA****®**** are an accepted addition to the therapeutic armamentarium**
**Clinical and translational data are pointing the way to most appropriate use**
**AstraZeneca remains committed to IRESSA****®**** and other biologically targeted agents**