1. Clinical Trial Endpoint Selection in Oncology: What Can Make a Difference?
Robert Pirker, MD

2. Advanced NSCLC: Why Overall Survival?
OS as primary end point (or powered for survival)
Adjuvant chemotherapy trials, e.g. IALT
Chemoradiotherapy in NSCLC stage III
Most phase lll trials in advanced NSCLC
Pemetrexed
Bevacizumab (ECOG); Cetuximab (FLEX), Necitumumab (SQUIRE)
Maintenance trials (pemetrexed, erlotinib, gefitinib)
Nintedanib
Ramucirumab
PFS as primary end point
Tyrosine kinase inhibitor trials in selected patients
Prolonged PFS

3. LUX-Lung 1: OS Miller VA et al. Lancet Oncol 2012, 13, 528

4. LUX-Lung 1: PFS Miller VA et al. Lancet Oncol 2012, 13, 528

5. Wishes/Hopes of Patients With Advanced NSCLC
To live long(er) and without suffering or at least To live without suffering

6. End Points in Phase III Trials
Statistically significant
Clinically meaningful Ocana A, Tannock I. J Clin Oncol 2011;103:16
Should reflect patient benefit
Survival
Progression-free survival (PFS) plus some measure of symptom relief or quality of life (QoL)
Symptom relief
QoL

7. Overall Survival
“Overall survival is accepted as the gold standard for efficacy evaluation in clinical trials of oncology agents.” Soria JC, Massard C, Le Chevalier T. Ann Oncol 2010;21:2324
OS should be the primary end point in phase III trials.
If OS is a secondary end point, trials should be powered for assessing survival.

8. Advanced NSCLC: Why Overall Survival?
Most relevant to patient
Most objective end point
Clear and accurate end point
Usually easy to get this information
Relevant for other reasons
It is easier to decide upon a treatment when its impact on survival is known
Reimbursement issues
Assessment in earlier disease stages
Impact on drug development in general
PFS is a problematic end point
Continuation of targeted therapies beyond progression

9. Advanced NSCLC: Progression-Free Survival
Based on tumour size
Factors other than tumour size are also important
Nonmeasurable lesions might be an issue
Difficult to assess (subjectivity and risk of errors)
Which and how many lesions?
Large interobserver and intraobserver variability Erasmus JJ et al. J Clin Oncol 2003;21:2574
Blinded independent central review might not be of help Dodd LE et al. J Clin Oncol 2008;26:3791
Assessment schedule matters Panageas KS et al. J Natl Cancer Inst 2007;99:428
Evaluation time bias (experimental vs control arm)
Adverse events might delay treatment and reassessments
No treatment might result in earlier assessments

10. Is independent review a waste of resources ?
Blinded independent central review might not be of help Dodd LE et al. JCO 2008, 26, 3791
LUX-Lung LUX-Lung LUX-Lung 6
HR 0.38 vs 0.37 HR 0.58 vs HR 0.28 vs 0.26

11. Advanced NSCLC: Progression-Free Survival
Placebo-controlled, double-blind studies are required but sometimes impossible (eg, in cases of rash)
Other challenges
Progression without radiologic documentation
Clinical deterioration without radiologic progression
Missing data
Sensitivity analyses are required to assess whether the results are robust Bhattacharya S et al. J Clin Oncol 2009;27:5958
Problems are more pronounced when PFS is short

12. Advanced NSCLC: Progression-Free Survival
Relevant for patient ?
Only if associated with improved QoL (symptom relief) and absence of relevant toxicity
Magnitude of improvement in QoL becomes an issue
Overall PFS is a soft end point
Reliable surrogate marker for survival ? Lara BN et al. J Clin Oncol 2008;26:463 Mandrekar SJ et al. J Thorac Oncol 2010;5:3

13. Overall Survival Challenges
Magnitude of the benefit
Hazard ratio of
Median benefit of 2-3 months
Should be realistic and achievable
Impact of further treatment (poststudy therapy)
Cannot be excluded
Treatment lines beyond first line have fewer benefits
No major imbalances in subsequent treatments among the arms in large phase lll trials
Role of crossover
Is it really unethical to avoid crossover ?

14. Overall Survival in Advanced NSCLC: Summary
Overall survival remains the most relevant end point for phase lll trials in patients with advanced NSCLC.
Easy to assess, accurate, and reliable
Assessment of PFS is challenging.
Consistency in outcome of the various end points is also important. RR
PFS OS
QoL (symptom relief)
Phase lll trials in patients with advanced NSCLC have been properly designed and well conducted.

15. Lung Cancer Prevention
WHO Tobacco Free Initiative
WHO Framework Convention on Tobacco Control
MPOWER

16. WHO Framework Convention on Tobacco Control www.fctc.org
The object is to protect present & future generations from the devastating health, social, environmental & economic consequences tobacco consumption
Effective measures
Increase price of cigarettes, taxes
Protection from exposure (working place, public)
Regulation of the contents of tobacco products
Packaging & labeling must not promote tobacco product
Health warnings
Education, communication, training, public awareness
Global ban on advertising and sponsoring
International cooperation (laws, research)

17. WHO MPOWER http://www.who.int/tobacco/mpower/en/
Monitor tobacco use
Protect people from tobacco smoke
Offer help to quit tobacco use
Warn about the dangers of tobacco
Enforce bans on tobacco advertising, promotion
Raise taxes on tobacco products

18. http://www. cancerresearchuk

19. Benefits of stopping smoking: United Kingdom Million Women Study
Jha P & Peto R. NEJM 2014, 370, 60

20. The National Lung Screening Trial Team N Engl J Med 2011, 365, 395
persons at high risk (08/ /2004); 3 annual screens
CT ( persons) X-ray ( pers.)
Lung cancer cases
Lung cancer deaths
Relative risk reduction in lung cancer mortality of 20% with CT