1. 1 David R. Gandara, MD University of California, Davis Comprehensive Cancer Center Evaluating Well-designed vs Poorly- designed Randomized Trials

2. Evaluating Good vs Poorly Designed Randomized Clinical Trials The Good, The Bad and the Ugly

3. Why do you want to do the study? Who do you want to study? How are you going to study them? What is the study design & primary study endpoint? Where are you going to conduct the study? When do you want to look at interim results, if at all? Who, What, Where, Why, When and more Randomized Clinical Trials: The Basics

4. Why do you want to do the study? – What is the hypothesis? – Will the results change SOC or lead to definitive trials? Who do you want to study? – What patient population? – “All comer” or Selected/Enriched? – What stratifications (for prognostic groups)? How are you going to study them? – Comparison of different treatments? (or against BSC) QOL or Comparative Effectiveness? Randomized Clinical Trials: The Basics (cont’d)

5. What is the study design & primary study endpoint? – Randomized Phase II, Phase II/III or Phase III? How big a patient sample size needed to address the hypothesis? – If Phase II, new treatment vs SOC or “pick the winner” – Primary Endpoint: Response, PFS, OS or Other (QOL)) Where are you going to conduct the study? – Single institution, multi-site in your country or Global If Global: Will there be issues of population-related pharmacogenomics? When do you want to look at interim results, if at all? – Planned interim analysis? – Is the study a Phase II/III with “go-no go” decision? Randomized Clinical Trials: The Basics (cont’d)

6. Example: QUARTZ Trial of Whole Brain Radiotherapy vs Optimal Supportive Care for NSCLC patients with brain metastases (ASCO 2015) Good, Bad or UGLY?

7. Whole brain radiotherapy for brain metastases from non-small cell lung cancer: Quality of life and overall survival results from the UK MRC QUARTZ trial PM Mulvenna, MG Nankivell, R Barton, C Faivre-Finn, P Wilson, B Moore, E McColl, I Brisbane, D Ardron, B Sydes, C Pugh, T Holt, N Bayman, S Morgan, C Lee, K Waite, RJ Stephens, MKB Parmar, RE Langley

8. Brain Metastases and NSCLC After radical treatment of primary Non Small Cell Lung Cancer (NSCLC), the brain remains a frequent and early site of distant relapse, affecting up to 40% of patients Patients with NSCLC and brain metastases fare poorly even if irradiated Median survival remains poor – RTOG RPA prognostic classes – RPA I7.1 months – RPA II 4.2 months all patients received WBRT; 57% NSCLC – RPA III 2.3 months In the face of modest prognosis, how do we ensure optimal quality of life? In spite of lack of randomised, controlled data, whole brain radiotherapy (WBRT) plus steroids standard care

9. R R QUARTZ Trial Randomised Controlled Non-Inferiority Design Histologically proven NSCLC with brain metastases – non-resectable and unsuitable for stereotactic radiosurgery Control Arm: Optimal Supportive Care Dexamethasone + Whole Brain Radiotherapy 20Gy in 5 daily # Investigational Arm: Optimal Supportive Care Dexamethasone Primary outcome quality adjusted life years (QALYS) Secondary outcomes overall survival symptom scores March 2007- August 2014

10. Main Inclusion Criteria Pragmatism, Inclusivity Histologically proven primary Non Small Cell Lung Cancer CT/MRI confirming brain metastases – considered inoperable or ineligible for SRS by lung/neuro-oncology Multi-Disciplinary Teams (Tumour Boards) Previous systemic treatment allowed, at least 4 weeks prior to randomisation Subsequent/simultaneous (extra cranial) palliative RT permitted Subsequent systemic treatment permitted at clinician’s discretion Adapted to changing landscape

11. Statistical Design Non-inferiority design Aiming to exclude >1 week reduction in QALYs with omission of WBRT 80% power Sample size re-assessed in 2009 following poor recruitment Recalculated independently of results from interim analyses PatientsWBRT QALYHROne- sided α Original (2006)10366 weeks1.22.5% Revised (2009)5345 weeks1.255%

12. Challenges “Treatment vs No Treatment” Patient / Clinician Preferences Interim Data Release Oct 2010

13. 538 Patients: Baseline characteristics 69 UK and 3 Australian centresOSC + WBRT (N=269) OSC Alone (N=269) AgeMedian (range)66 (38 – 84)67 (45 – 85) SexMale58% Karnofsky Performance Status ≥7062% <7038% Histology Adenocarcinoma55%51% Squamous20%25% Large cell3%2% NSCLC NOS23%22% Solitary brain metastasis Yes30%

14. RPA Class RTOG (N=1176 ) QUART Z (N=400) RPA I KPS >70 Controlled Primary Site Age <65 years No extra cranial metastases 20%5% RPA II Neither RPA I nor RPA III 65%61% RPA III KPS < 7015%34% RTOG Prognostic classes (RPA) Gaspar et al IJROBP 1997; 37:745-51

15. Baseline symptoms OSC + WBRT (N=269) OSC Alone (N=269) % Tiredness 40%44% Insomnia 28%35% Weakness 25%30% Drowsiness 24%27% Mood 21%17% Sight 19%17% Any moderate or severe symptom 72%78% Symptoms shown are those affecting at least 15% of patients

16. Steroid use Requiring steroids during… OSC + WBRT (N=269) OSC Alone (N=269) % First 4 weeksNo 9%5% Yes 91%95% First 8 weeksNo 15%10% Yes 85%90% At randomisation - all patients were receiving steroids (dexamethasone) Median dose 8mg/day

17. Whole Brain Radiotherapy (WBRT) administration OSC + WBRT (N=269) % Dose received0 Gy 12% <20 Gy 6% 20 GY 82% Time to starting WBRT ≤7 days 39% 8 – 14 days 40% >14 days 21%

18. Symptoms at 4 weeks WorsenedImproved OSC + WBRTOSC aloneOSC + WBRTOSC alone Tiredness33%30%13%19% Drowsiness29%22%9%14% Insomnia17%14%19%22% Mood11%15% 8% Weakness26%21%10%13% Hair Loss33%1%4%2%

19. Overall Survival Median survival (weeks) 522 deaths (260 OSC+WBRT vs 262 OSC). OSC+WB RT 9.3 weeks (7.4, 10.7) OSC alone 8.1 weeks (7.6, 9.0) HR1.05 (0.89, 1.26) P-value0.52 --------- OSC+WBRT ------- OSC Alone

20. Components of the Primary Outcome Measure EuroQoL EQ-5D Better Worse --------- OSC+WBRT ------- OSC Alone Overall SurvivalQuality of Life

21. - 9.1-7-206.6 OSC+WBRT better DAYS OSC alone better Primary Outcome Measure: Quality Adjusted Life Years Mean QALY (days) OSC+WBRT43.3 days OSC alone41.4 days Difference-1.9 days 90% CI (Bootstrap)(-9.1, 6.6) Non-inferiority boundary -7 days --------- OSC+WBRT ------- OSC Alone QUALY

22. Conclusions – QUARTZ Trial Only large randomized trial of WBRT vs no WBRT for brain metastases from NSCLC Detailed QoL data can be collected in poor prognostic group WBRT does not appear to be a steroid-sparing modality Similar overall survival (9.3 weeks vs 8.1 weeks) Similar QALYs (43.3 days vs 41.4 days) The estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients

23. Why did they want to do this study? – What is the hypothesis? – Will the results change SOC or lead to definitive trials? Who did they want to study? – What patient population? – “All comer” or Selected/Enriched? – Eligibility criteria? – What stratifications (for prognostic groups)? How did they study them? – Comparison of different treatments? (or against BSC) QOL or Comparative Effectiveness? Randomized Clinical Trials: The Basics

24. What was the study design & primary study endpoint? – Randomized Phase II, Phase II/III or Phase III? How big a patient sample size needed to address the hypothesis? – If Phase II, new treatment vs SOC or “pick the winner” – Primary Endpoint: Response, PFS, OS or Other (QOL)) Where was the study conducted? – Single institution, multi-site in your country or Global If Global: Will there be issues of population-related pharmacogenomics? When were interim results looked at, if at all? – Planned interim analysis? – Is the study a Phase II/III with “go-no go” decision? Randomized Clinical Trials: The Basics (cont’d)

25. Discussion of Abstract #8005: “Challenging Convention” Whole brain radiotherapy for brain metastases from NSCLC: Quality of life (QoL) & overall survival (OS) -UK MRC QUARTZ randomised clinical trial Convention: WBRT is a SOC for brain metastases in NSCLC Discussion points: 1.Do the data support the conclusions? 2.Do the results change standard of care or alter current practice?

26. Who were these QUARTZ patients? QUARTZ raises as many questions as it answers – Patients were deemed “inoperable” or “not suitable for SRS” (yet 30% had a single brain met) – Median OS was dismal in both arms: ~ 2 months Did the study population include many “pre-terminal” cases? KPS <70% in ~38%. – What was the minimum KPS for eligibility? RPA class III in 34%. – Is this a group appropriate for this QOL study? – Were they appropriate candidates for WBRT? QUARTZ Protocol Eligibility: How do we explain the results of the QUARTZ trial? (No minimum KPS for eligibility) (A very poor prognosis group)

27. RTOG Prognostic Classes (RPA) in QUARTZ Study Gaspar et al: IJROBP 1997

28. Comparison of Prognostic Indices for Brain Metastases Sperduto et al: IJROBP 2008

29. Was the QOL tool utilized appropriate for the study hypothesis & for study design & eligibility criteria? – EQ5D utilized (Would FACT-BR have provided a better measure?) Are there better options for therapy of brain metastasis in 2015 than that utilized in QUARTZ? (initiated in 2007) – WBRT with hippocampal sparing – SRS is an ever expanding option How do we explain the results of this trial?

30. Was the QOL tool utilized appropriate for the study hypothesis & for study design & eligibility criteria? Symptoms reported in the presentation

31. EQ5D is a “Generic Health-related QOL Measure” Has been employed to study Rheumatoid Arthritis, Parkinson’s Disease Multiple Sclerosis CVA Chronic Hepatitis Attention Deficit Disorder Not specific to cancer or to Brain Metastases

32. Conclusions – QUARTZ Trial Only large randomized trial of WBRT vs no WBRT for brain metastases from NSCLC Similar overall survival and QALYs (43.3 vs 41.4 days) Although the results include the pre-specified non-inferiority margin (-9.1 days vs -7 days), the estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients My Conclusions: 1.Agree, in this group of patients. But uninterpretable for original intent. 2.Eligibility criteria (~low KPS, high RPA) & selection process (deemed inappropriate for surgery or SBRT) invalidated hypothesis testing for QOL endpoint, & for OS. 3.Non-inferiority was not proven. 4.Due to the nature of the patient population, this study does not alter SOC or current practice.