Robert Pirker, MD

Clinical Trial Endpoint Selection in Oncology: What Can Make a Difference?

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

LUX-Lung 1: OSMiller VA et al. Lancet Oncol 2012, 13, 528

LUX-Lung 1: PFSMiller VA et al. Lancet Oncol 2012, 13, 528

Wishes/Hopes of Patients With Advanced NSCLC

To live long(er) and without suffering

or at least

To live without suffering

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

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.

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

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

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 1 LUX-Lung 3 LUX-Lung 6

HR 0.38 vs 0.37 HR 0.58 vs 0.49 HR 0.28 vs 0.26

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

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;26:463Mandrekar SJ et al. J Thorac Oncol 2010;5:3

Overall Survival Challenges

• Magnitude of the benefit–Hazard ratio of 0.7-0.8–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 ?

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.

Lung CancerPrevention

WHO Tobacco Free Initiative

• WHO Framework Convention on Tobacco Control www.fctc.org

• MPOWER

www.who.int/tobacco/mpower/en/

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)

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

http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/incidence

Benefits of stopping smoking: United Kingdom Million Women Study

Jha P & Peto R. NEJM 2014, 370, 60

The National Lung Screening Trial Team N Engl J Med 2011, 365, 395

53.454 persons at high risk (08/2002-04/2004); 3 annual screens CT (26.277 persons) X-ray (26.732 pers.)Lung cancer cases 645 572Lung cancer deaths 247 309Relative risk reduction in lung cancer mortality of 20% with CT