# Presentation: 776392

## Trial 709The ISEL Study (IRESSA® Survival Evaluation in Lung Cancer)

** **

**Summary of Data ****as of December 16, 2004**
**Kevin Carroll,  MSc **

## Trial 709–Clinical Trial Design

**Randomization**** **

**IRESSA****®**** (250 mg) + BSC**

**Placebo + BSC**

**Primary endpoint:**
**SURVIVAL**

**2:1 ratio **

**1692 ****patients in 210 centers across 28 countries**
**Stratified for histology, gender, intolerant/refractory****and smoking history**

## Key Eligibility Criteria

**Histologically or cytologically confirmed****non-small cell lung cancer**
**Locally advanced or metastatic disease**
**1 or 2 prior chemotherapy regimens**
**Intolerant to most recent chemotherapy regimen or have progressed on or within****90 days of their last chemotherapy cycle**

## Endpoints and Methods

**Primary endpoint: overall survival**
**Stratified log-rank test**
**Cox regression supportive**
**Overall and adenocarcinoma populations co-primary**
**At least 900 deaths for 90% power**
**Secondary endpoints: time to treatment failure, objective response, QoL, symptoms, and safety**
**Several pre-planned subgroup analyses**
**Outcomes in relation to clinical and biologic factors**

## Data Presented Today 

**Patient data accruing up to October 29, 2004**
**Preliminary data available for analysis****mid-December 2004**** **
**Median (range) follow up: 7 mo (3 to 15 mo)**
**969 (57%) deaths in the database**

## Regional Recruitment

## Baseline Characteristics

**Median age 62 yr**
**67% Male **
**67% PS 0-1**
**22% Never smoked **
**20% Asian ethnicity**
**48% Adenocarcinoma**
**49% One prior chemotherapy**
**90% Refractory to most recent chemotherapy**
**Treatment groups well balanced**

## Overall Population–Survival

**Overall Population–Survival**

**	****Month:****	****0****	****2****	****4****	****6****	****8****	****10****	****12****	****14**
**	****At risk:****	****1692****	****1348****	****876****	****484****	****252****	****103****	****31**

** ****Patients surviving (%)**

|  | IRESSA® | Placebo |
| --- | --- | --- |
| Median (mo) | 5.6 | 5.1 |
| 1 yr survival | 27% | 22% |
| HR = 0.89 (0.78, 1.03), P = .11
N = 1692, deaths = 969
Cox analysis, P = .042 |  |  |

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

**——****	****IRESSA****®**
**------****	****Placebo**

## Adenocarcinoma Population–Survival

**	****Month:****	****0****	****2****	****4****	****6****	****8****	****10****	****12****	****14**
**	****At risk:****	****813****	****670****	****447****	****262****	****145****	****65****	****18**

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

|  | IRESSA® | Placebo |
| --- | --- | --- |
| Median (mo) | 6.3 | 5.4 |
| 1 yr survival | 31% | 17% |
| HR = 0.83 (0.67, 1.02), P = .07
N = 813, deaths = 449
Cox analysis, P = .030 |  |  |

**——****	****IRESSA****®**
**------****	****Placebo**

** ****Patients surviving (%)**

## Significant Improvement In Objective Response Rate

|  | Patients, % (n/N) |  | Odds ratio(95% CI) |  |
| --- | --- | --- | --- | --- |
|  | IRESSA® | Placebo |  | P value |
| Objective response rate | 7.7%(74/961) | 1.2%(6/483) | 7.03(3.0, 16.4) | < .0001 |

## Significant Improvement In Time to Treatment Failure

**Significant Improvement In ****Time to Treatment Failure**

**HR = 0.82 (0.74, 0.91), *****P *****= .0005**
**Median IRESSA****®**** = 3.0 mo****Median placebo = 2.6 mo**

**Patients without treatment failure (%)**

**Time, mo**

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

**	****0****	****1****	****2****	****3****	****4****	****5****	****6****	****7****	****8****	****9****	****10****	****11****	****12****	****13****	****14****	****15**

**——****	****IRESSA****®**
**------****	****Placebo**

## Fewer Treatment Failures on IRESSA® 

**Patients (%)**

**	****IRESSA****®**
**	****Placebo**

**60**
**50**
**40**
**30**
**20**
**10**
**0**

|  | Objective disease progression | Symptomatic deterioration | Adverse event | Other |
| --- | --- | --- | --- | --- |

## Preliminary Quality-of-Life Data–Change in Mean Scores (FACT-L)

|  | Possible range of scores† | Mean score |  | P value |
| --- | --- | --- | --- | --- |
|  |  | IRESSA®(n = 858) | Placebo (n = 425) |  |
| Symptoms (lung cancer subscore) | 0 to 28 | 16.9 | 16.4 | .02 |
| Overall quality of life  | 0 to 144 | 83.8 | 82.3 | .07 |
| Trial outcome index | 0 to 84 | 47.5 | 46.5 | .11 |

**FACT-L = Functional assessment of cancer treatment-lung.**
**†****Higher scores indicate more a favorable status.**

## Pre-Planned Subset Analyses

**Subset identified up front on basis of Phase II results and findings on other drugs in class**
**Rigorous statistical approach**
**Treatment by subset interactions  **
**Effects in subsets **
**Confidence that differences, if seen, are due to the drug and not the play of chance**

## Effects in Subsets (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%**

**Survival**

**Response rate**

**Effects in Subsets (1)**

- 0.4

- 0.6

- 0.8

-   1

- 1.5

## Effects in Subsets (2)

**Prior docetaxel**

**All patients**

**Asian ethnicity**

**Time since Dx: >12 mo**

**Time since Dx: <6 mo**

**<65 yrs**

**No prior docetaxel**

**≥****65 yrs**

**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**

**Response rate**

**Effects in Subsets (2)**

## Survival by Smoking History

**Survival by Smoking History**

**Ever smoked (n = 1318)****HR = 0.93 (0.80,1.07), *****P *****= .315**
**RR = 5.2%**

**Never smoked (n = 374)****HR = 0.67 (0.49,0.91), *****P *****= .011**
**RR = 17.2%**

**	****0****	****1****	****2****	****3****	****4****	****5****	****6****	****7****	****8****	****9****	****10****	****11****	****12****	****13****	****14****	****15**

**Patients surviving (%)**

**Time, mo**

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

**	****0****	****1****	****2****	****3****	****4****	****5****	****6****	****7****	****8****	****9****	****10****	****11****	****12****	****13****	****14****	****15**

**——****	****IRESSA****®**
**------****	****Placebo**

## Survival by Ethnic Origin

**Survival by Ethnic Origin**

**Asian (n = 342)****HR = 0.66  (0.48, 0.91), *****P *****= .011**
**RR = 12.0% **

**Non-Asian (n = 1350)****HR = 0.93  (0.81, 1.08), *****P *****= .364**
**RR = 6.5%**

**	****0****	****1****	****2****	****3****	****4****	****5****	****6****	****7****	****8****	****9****	****10****	****11****	****12****	****13****	****14****	****15**

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

**	****0****	****1****	****2****	****3****	****4****	****5****	****6****	****7****	****8****	****9****	****10****	****11****	****12****	****13****	****14****	****15**

**——****	****IRESSA****®**
**------****	****Placebo**

**Time, mo**

**Patients surviving (%)**

## Safety Data

**Adverse event profile consistent with established safety profile for IRESSA****®**
**Rash (35% vs. 9%) and ****diarrhea (27% vs. 9%) most common adverse events **
**No difference in serious adverse events**
**Few (5% vs. 4%) withdrawals due to adverse events**
**No difference in incidence of interstitial lung disease (ILD)-like events (1.1% vs. 0.9%)**

## Adverse Events Occurring in ≥5% of the Trial Population or Difference in Incidence of ≥3 (1) 

|  | IRESSA®
N = 1126 |  | Placebo
N = 562 |  |
| --- | --- | --- | --- | --- |
|  | All grades | Grade 3/4 | All grades | Grade 3/4 |
| Rash | 35% | 1.2% |   9% | 0.2% |
| Diarrhea | 27% | 3.0% |   9% | 1.0% |
| Nausea | 17% | 0.8% | 16% | 0.4% |
| Anorexia | 15% | 2.0% | 12% | 2.0% |
| Vomiting | 14% | 1.0% | 10% | 0.4% |
| Dry skin | 11% | 0 |   4% | 0 |

## Adverse Events Occurring in ≥5% of the Trial Population or Difference in Incidence of ≥3% (2)

|  | IRESSA®
N = 1126 |  | Placebo
N = 562 |  |
| --- | --- | --- | --- | --- |
|  | All grades | Grade 3/4 | All grades | Grade 3/4 |
| Constipation | 10% | 1.0% | 13% | 2.0% |
| Pruritus |   7% | 0.2% |   5% | 0.2% |
| Pyrexia |   7% | 0.6% |   5% | 0.4% |
| Asthenia |   7% | 2.0% |   6% | 1.0% |
| Cough |   7% | 0.2% |   8% | 0.7% |
| Dyspnea |   7% | 3.0% |   8% | 4.0% |
| Acne |   4% | 0.1% |   1% | 0 |

**Adverse Events Occurring in ≥5% of the Trial Population or Difference in Incidence of ≥3% (2)**

## Final, Validated Data Show No Change

**Preliminary data validated as of February 2, 2005**
**976 deaths on or before October 29, 2004**
**Findings based on preliminary data unchanged**
**Overall population HR = 0.89, *****P *****= .09**
**Adenocarcinoma subset HR = 0.84, *****P *****= .09**

## Further Follow-up Recommended by the Independent Data Monitoring Committee

**Median follow-up 10 months, 70% deaths**
**Data consistent with planned, protocoled****analysis **
**Overall HR = 0.89, *****P***** =.07**
**Adenocarcinoma HR = 0.84, *****P***** = .07**
**Continued variability despite increased crossover **

## Trial 709 Data as of December 16, 2004

**Trial 709 showed some improvement in survival; however, the difference did not reach statistical significance**
**Preliminary data highlights efficacy and variability in terms of survival outcome**