Patient Reported Outcomes as Endpoints in Lung Cancer and Thoracic Malignancies

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

5. 0 20 40 60 80 100 NON-SMALL CELL LUNG CANCER - Number of Presenting Symptoms at Baseline - (N = 673 Stage III and IV Patients) 80% Three or more Two 12% One 5% 3% None Percentage

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

11. QUALITY OF LIFE INSTRUMENTS- Instrument Focus - GENERAL HEALTH: All Populations Diabetes Arthritis Cancer DISEASE-SPECIFIC: LungCancer Lymphoma SITE-SPECIFIC: TREATMENT-SPECIFIC: Clinical Trials Clinical Trials Post - Op 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) - PSYCHOMETRICS CHARACTERISTICS 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 LCSS Total patient scale (alpha 0.82) for 207 patients Observer scale (alpha 0.75) for 21 observers Total core measure (alpha, 0.89) for 116 patients Lung cancer module (alpha 0.68) for 116 patients • Cronbach’s alpha of 0.70 for new measures

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

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 - • Cumbersome instruments • Patient deterioration • Lack of investigator commitment

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

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

25. PATIENT REPORTED OUTCOMES IN CLINICAL TRIALS- Prospective Emphasis on PRO: A Recent Study *- • A brief training session for all investigative and data management personnel on the methods and role of PRO evaluation • Inclusion of baseline QoL data as part of eligibility for randomization • Continued emphasis during the trial for vigilance in assessing PRO endpoints • 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. ENDPOINTS AND TREATMENT Relationships and Role of Patient Reported Outcomes (“PROs”) Malignancy Survival Quality of Life Tumor Response & Side Effects Treatment

27. 100 80 60 PERCENT SURVIVING* 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 MONTHS LOWER QL HIGHER QL 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

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* - Improvement Change from baseline (mm) Note: y-axis error bars represent SE of the means N=92 N=41 N=77 N=37 N=87 N=94 Worsening * Greater benefit reported by patients in 8 of 8 PRO parameters (p <0.05), validated LCSS-meso (Model-based means.)

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