Choice of appropriate endpoints in clinical trials. Fortunato Ciardiello Second University of Naples

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1 Choice of appropriate endpoints in clinical trials Fortunato Ciardiello Second University of Naples

2 Main primary endpoints used in advanced or metastatic various types of cancers Kiba, J Cancer Sci Ther 2011, 3:7

3 Regular approval is based on end points that demonstrate that the drug provides a longer life, a better life, or a favorable effect on an established surrogate for a longer life or a better life. Johnson JR, Williams G, Pazdur R Endpoints and US FDA approval of oncology drugs J Clin Oncol 21: , 2003

4 Guidance for industry Clinical trials endpoints for the approval of cancer drugs FDA, May 2007 Overall survival is considered the most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint.?

5 Why OS is not the only endpoint for drug approval and we need PFS? May involve larger trials May require lengthy follow-up May be affected by sequential treatments May be affected by crossover Other endpoints can have intrinsic value Di Maio M ESMO 2011

6 PFS.. why an issue? Progression-Free Survival: Meaningful or Simply Measurable? Some trials showing improvement in PFS, without a corresponding increase in OS, have led to approval of new drugs and/or changes in standard of care. This suggests that delaying progression in metastatic disease is a worthy goal, even if OS is not improved.

7 Open Questions Progression-Free Survival: Meaningful or Simply Measurable? But is a new treatment that improves PFS really an advance for patients? Or is it only lowering the bar to declare active some of new molecular targeted therapies?

8 Progression-Free Survival: Meaningful or Simply Measurable? ISSUES: Defining Disease Progression Use of PFS in the Contemporary Era What does PFS mean for patients? Why do treatments that increase PFS fail to improve survival? Post-progression therapy debate

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11 Guidance for industry Clinical trials endpoints for the approval of cancer drugs FDA, May 2007 Endpoints Advantages Disadvantages Overall survival Clinical benefit for regular approval Universally accepted direct measure of benefit Easily measured Precisely measured Blinding not essential May involve larger studies May be affected by crossover or sequential therapy

12 Guidance for industry Clinical trials endpoints for the approval of cancer drugs FDA, May 2007 Endpoints Advantages Disadvantages Progression-free survival Surrogate for accelerated approval or regular approval* Smaller sample size and shorter follow-up Not affected by crossover or subsequent therapies Not precisely measured; subject to assessment bias, particularly in open label studies Frequent radiological or other assessments, balanced among treatment arms Blinding preferred Blinded review recommended *Adequacy as a surrogate endpoint is highly dependent upon other factors such as effect size, effect duration, and benefits of other available therapy.

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14 FDA guidelines OS is the gold standard endpoint in metastatic breast cancer since it is both a safety and efficacy parameter. PFS may be an acceptable endpoint if measured properly and is of sufficient magnitude. Survival also should be measured to ensure that any new therapy does not lead to a decrement. Discussion of the appropriate setting to use PFS is encouraged by the FDA during trial design.

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19 Definition of valid surrogate endpoints Strong correlation between the surrogate and definitive endpoints Surrogate endpoint should predict net effect (complex regression analyses) No intermediate endpoint is a universal surrogate for OS across different disease sites

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23 For clinical trials with a PFS benefit, lack of statistical significance in OS does not imply lack of improvement in OS, especially for diseases with long survival post-progression (SPP) OS is a reasonable endpoint when SPP is short but is too high a bar when median SPP is long Broglio KR, Berry DA. J Natl Cancer Inst 2009; 101:

24 PPS represents nearly two thirds of patient survival after on-trial disease progression

25 ..Other surrogate endpoints Depth of Response (DpR) Early tumor shrinkage (ETS) DpR was defined as the maximal tumor shrinkage observed in a patient. ETS was defined as a reduction in tumor diameter of more than 20% at first-tumor assessment after baseline

26 Evaluation of Depth of Response (DpR*) FIRE-3 trial

27 Association of ETS* and survival FIRE-3 trial

28 FIRE-3 trial: rational for OS difference Deepness of respnse correla con l OS Draft 1 Stintzing Oral presentation ESMO 2014

29 The real limitation of PFS as an endpoint the real limitation is that we are focusing on a single line of treatment, and we consider all that happens beyond progression no more than a confounding factor

30 Conclusions We need accelerated approval on the basis of rapid trials - Unless small and with weak endpoints Approval might be based upon validated and reproducible surrogate endpoints - With clinical relevance (not only statistical) from a magnitude and patients perspective - QoL, symptoms control should be concurrently considered OS should always be considered