1. Patient Reported Outcomes as Endpoints in Lung Cancer and Thoracic Malignancies Richard J. Gralla, MD New York Lung Cancer Alliance For the ASCO and FDA Working Group

2. PATIENT REPORTED OUTCOMES (“PROs”) - Clinical Benefit and Quality of Life - Quality of Life –Multidimensional –Includes areas not likely to be affected by chemo Clinical Benefit - Subjective or Palliative Control of Common Problems - Previously Defined to Include such considerations as: - Pain Control - Weight Loss - Performance Status

3. QUALITY OF LIFE AND PRO EVALUATION - Is there a Need in Studies of Anticancer Treatments? - Highly Symptomatic Disease – Survival and Response data reveal only part of the results that are important to patients, families, and health care professionals Treatments and Agents Vary in their Side- Effects and Risk Profiles – Balancing patient experienced benefit and risk is needed Meaningful Survival Differences are Uncommon

4. SYMPTOMS OF LUNG CANCER - By Patient Reports (N = 121) - Ref: Hollen et al. (1993). Eur J Cancer, 29A, S51-S58 84% 79% 71% 62% 59% 56% 57% 60% 48% 25%14% 54% (n = 69)(n = 52) NON-SMALL CELL SMALL CELL FATIGUE COUGH DYSPNEA ANOREXIA PAIN HEMOPTYSIS

5. NON-SMALL CELL LUNG CANCER - Number of Presenting Symptoms at Baseline - Percentage (N = 673 Stage III and IV Patients) 80% 12% 5% Three or more Two One None 3% 020406080100

6. NON-SMALL CELL LUNG CANCER - Survival: Supportive Care and Chemotherapy 1991- 2001 (N = 10,995 / 9361) - 718 pts 783 pts 509 pts 1103 pts 4648 pts 1600 pts Refs: Proc ASCO 2002: Raftopoulos, Bria, Gralla, Eid

7. PATIENT REPORTED OUTCOMES (“PROs”) - Rationale and Need in Testing Anticancer Agents - PROs can create an accurate picture of the disease course that is unavailable from the review of other endpoints Health care professionals are not accurate in evaluating subjective or palliative benefits associated with anti-cancer treatments, when compared with patient self-reports PROs are often reported by patients as improved with less than major responses to treatment - even with only stable disease…response rates underestimate patient reported benefit The balance between symptom improvement and toxicity, or the effects of delayed progression summarized in many PRO measures, cannot be consistently predicted by other biomedical endpoints

8. QUALITY OF LIFE AND PRO’s - Questions - 1) Can we DEFINE quality of life? 2) Can we MEASURE quality of life? 3) Can we agree on how to ANALYZE quality of life results? 4) Can we PRESENT quality of life findings in a clear and useful way?

9. QUALITY OF LIFE INSTRUMENTS - Dimensions - Physical Functional Psychological Social Spiritual

10. - Conceptual Model for Clinical Trials: THE “LCSS” - PHYSICAL DIMENSION* Symptoms Symptomatic Distress distress from FUNCTIONAL DIMENSION* Activity Status QUALITY OF LIFE FOR THE LUNG CANCER EXPERIENCE Quality of Life Global QUALITY OF LIFE AND PRO’S IN LUNG CANCER Global Global symptomatic lung cancer Dimensions Captured: Dimensions Captured: OVERALL Cognitive Physical Social (Role) Cognitive Psychological Spiritual All others Appetite Fatigue Cough Dyspnea Hemoptysis Pain Social * PRO Dimensions

11. QUALITY OF LIFE INSTRUMENTS - Instrument Focus - DISEASE-SPECIFIC: SITE-SPECIFIC: TREATMENT-SPECIFIC: GENERAL HEALTH: All Populations Cancer Diabetes Arthritis Lymphoma Lung Cancer Clinical Trials Post - Op Clinical Trials BMT

12. QUALITY OF LIFE INSTRUMENTS - Lung Cancer Specific - 1. Lung Cancer Symptom Scale (LCSS) - Patient (9 items) & Observer (6 items) Forms - Developed Specifically for Clinical Trials 2. EORTC - General and Lung Cancer Modules (30-40 items) - Developed for General Use 3. FACT-L - General and Lung Cancer Modules (30-40 items) - Developed for General Use

13. LUNG CANCER SPECIFIC INSTRUMENTS - Psychometrics (1) - PSYCHOMETRICSCHARACTERISTICS FEASIBILITY: Short administration time Low reading level required Easily understood Multi-center utility CONTENT VALIDITY: Oncology expert agreement Patient agreement RELIABILITY: Items internally consistent Intra / interrater agreement Patient reproducibility

14. QUALITY OF LIFE INSTRUMENTS - Good reliability features include: - Internal consistency = Cronbach’s alpha > 0.70 for new measures Stability = Reliability coefficient > 0.70 Equivalence = Kappa statistic > 0.61 Ref: Nunnally & Bernstein, 1994; Landis & Koch, 1977

15. QOL MEASURES FOR LUNG CANCER - Example: Reliability Coefficients - FACT-L Total core measure (alpha, 0.89) for 116 patients Lung cancer module (alpha 0.68) for 116 patients LCSS Total patient scale (alpha 0.82) for 207 patients Observer scale (alpha 0.75) for 21 observers Cronbach’s alpha of 0.70 for new measures

16. LUNG CANCER SPECIFIC INSTRUMENTS - Psychometrics (2) - PSYCHOMETRICS CHARACTERISTICS Based on conceptual model Valid for LC patients with different extents of disease Compares well to "gold standards" 673 LC patients from two North American cancer trials (30 centers) CONSTRUCT VALIDITY: CRITERION-RELATED (CONCURRENT) VALIDITY: NORMATIVE DATA: CLINICAL SIGNIFICANCE: KPS and LCSS Observer scales used as anchors

17. QUALITY OF LIFE AND PRO EVALUATION - Additional Information - Clinically “meaningful” difference – Often subject to “risk-benefit” considerations – Not clearly defined for survival or response endpoints too Normative data for subgroups Ref: Mayo Proceedings, 2002

18. NON-SMALL CELL LUNG CANCER - Clinical Benefit and Quality of Life – Assessment in Patients In Phase II Trials

19. RANDOMIZED PHASE II TRIAL OF GEFITINIB AT TWO DOSE LEVELS – “IDEAL 2” Quality of Life / Clinical Benefit: ASCO 2002 Abstract #1167 A subscale of the FACT-L instrument was used (the LCS) Palliation was noted rapidly when it occurred: generally within 7 to 10 days Responding patients had greater symptom relief than those with stable disease or progressive NSCLC –43% with symptom improvement –34% with quality of life improvement

20. QUALITY OF LIFE AND PRO EVALUATION - Difficulties with Analysis: Phase II Trials - Analysis Problem – as with Surivial Analysis – relates to the lack of a Control Group for Judging Context Appropriate Standard Palliation Confounds Analysis: –Complicates benefit assessment when there is no control group –Leads to overestimate of benefit with study agent when patients are receiving standard approaches as well Response and Palliation: –Major response underestimates benefit: Lesser responses may give symptom relief –Benefit in patients with stable disease may be due to either the study agent or to standard palliation: can lead to overestimation

21. NON-SMALL CELL LUNG CANCER - Clinical Benefit and Quality of Life – Assessment in Patients In Phase III Trials

22. PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS - Problems in Evaluation and Analysis - 1) Cumbersome instruments 2) Patient deterioration 3) Lack of investigator commitment

23. PROSPECTIVE CLINICAL TRIAL IN NSCLC - Causes of Patient Attrition - Causes for attrition Death Disease progression Unknown Patients entered Remaining on study after 3 cycles 673 97 131 14 431 14% 19% 2% 64% 100%

24. QUALITY OF LIFE AND PRO EVALUATION - Baseline Values for Age and LCSS - 79 72 76 60 (p = 0.0001) (p = 0.0002) Percent of Patients 60 62 Age Average Symptom Burden QL Item (p = NS) Patients remaining on study (n=431); attrition group (n=242) (N = 673 Patients with NSCLC) 0 10 20 30 40 50 60 70 80 90 On Study Attrition Group

25. PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS - Prospective Emphasis on PRO: A Recent Study * - 1)A brief training session for all investigative and data management personnel on the methods and role of PRO evaluation 2)Inclusion of baseline QoL data as part of eligibility for randomization 3)Continued emphasis during the trial for vigilance in assessing PRO endpoints 4)As a result, more than 90% of the planned weekly assessments occurred over the initial 6 cycles of the trial * Vogelzang et al, J Clin Oncol 2003; ** Gralla et al, Proc ASCO 2003.

26. Quality of Life Survival Tumor Response & Side Effects Treatment Malignancy ENDPOINTS AND TREATMENT Relationships and Role of Patient Reported Outcomes (“PROs”)

27. NON-SMALL CELL LUNG CANCER - Quality of Life at Baseline: Influence on Survival - - Prospective Analysis of 673 Patients at 30 Centers - * p = 0.0001, using the LCSS quality of life instrument 0 20 40 60 80 100 024681012141618202224 MONTHS PERCENT SURVIVING* LOWER QLHIGHER QL

28. QUALITY OF LIFE EVALUATION IN CLINICAL TRIALS - Difficulties with Results Analysis: Phase III Trials -  Standards for statistical approaches remain controversial: –Simply evaluating averages of scores at subsequent time points is problematic: In Single Arm evaluation: Overestimates QoL and Clinical Benefit In Comparison trials: Underestimates QoL differences between study arms IF survival differences also are found  Survival differences complicate QoL analysis –Patient attrition (due to death or progression) is not random The most symptomatic patients drop out of the analysis first Patients with the poorer prognostic factors drop out first Thus, a regimen with poorer survival loses more lower QoL patients earlier and paradoxically - but incorrectly - appears to gain in QoL  Results from ALL patients on trial need to be Analyzed

29. Response and PRO Outcomes in a Random Assignment Trial: Added Value from Patient Determined Data - Using Pain Scores within Major Response as an Example* - N=92 N=77 N=94 N=41 N=87 N=37 Change from baseline (mm) Improvement Worsening Note: y-axis error bars represent SE of the means * Greater benefit reported by patients in 8 of 8 PRO parameters (p <0.05), validated LCSS-meso ( Model-based means.)

30. Survival and PRO Outcomes in a Random Assignment Trial: Added Value from Patient Determined Outcome Data Week 12 Week 18 Pem+cis Cis % Surviving * Quality of Life ** Symptom Distress ** 92% 82% 86% AUC 47%43%45%38% 53%50%51%44% p = 0.167 p = 0.162 p = 0.012 p = 0.009 p = 0.797 p = 0.247 *Vogelzang et al, J Clin Oncol 2003; ** Gralla et al, Proc ASCO 2003.