Table of Contents
A Case for Time to Tumor Progression as a Clinical Benefit Endpoint in the First-line Therapy of Metastatic Colorectal Cancer
Acknowledgements
Premise (1)
PPT Slide
An Increasing Number of Treatments Has Added Therapeutic Complexity
An Increasing Number of Therapies Has Prolonged Survival
Multiple Therapies
Subsequent Therapies Confound Relationship Between Early Tumor Control and Overall Survival
Subsequent Therapies Disconnect Early Tumor Control and Long-Term Survival
Prolonged Survival
Sample Size Requirements for a Study Increase
Sample Size Requirements for a Study Increase
Time to Accrue Sufficient Number of Patients Increases
Time to Acquisition of Mature Data is Prolonged
Cost to Conduct A Study Increases
Implications for Evaluation of Survival as the Primary Measure of Clinical Benefit
PPT Slide
Issues with Symptom Control
Baseline Symptoms in Patients with Untreated Metastatic Colorectal Cancer
Issues with Symptom Control
Subjective Measures of Quality of Life May Not Change Despite Objective Tumor Shrinkage
Issues with Symptom Control
Weight Loss Most Often Occurs after Tumor Progression
Declines in Functional Scores Most Often Occur After Tumor Progression
Declines in Symptom Scores Most Often Occur After Tumor Progression
Symptom Progression When Patient is Off Study and is Receiving Second-Line Therapy Confounds Interpretation of Results
Implications for Evaluation of Symptoms as the Primary Measure of Clinical Benefit
Premise (2)
PPT Slide
Time to Tumor Progression
Tumor Progression is the Most Common Cause of Treatment Failure in Patients with Metastatic Colorectal Cancer
By Incorporating the Value of Time, TTP Better Categorizes Tumor Control Than Response Rate
It’s Only Logical That Halting Tumor Progression is Clinically Beneficial
It’s Only Logical That Halting Tumor Progression is Clinically Beneficial
Time to Tumor Progression
Changes in Median Endpoint Values Suggest that TTP Appears to Correlate with Survival
Changes in Median Endpoint Values Suggest Hypothetical Equation Correlating TTP with Survival
Both Hypothetical and Actual Equation Correlate TTP with Survival
One-One TTP-Survival Relationship is Constant Independent of Treatment, Performance Status, or LDH
TTP Correlation with Survival
TTP is Highly Correlated with Survival in Cox Regression Analysis
Results Are Corroborated by a Publication Analysis of Correlation Between TTP and Survival*
Time to Tumor Progression
TTP Provides an Accurate and Direct Reflection of Drug Activity, Unaffected by Subsequent Therapies
Time to Tumor Progression
Sample Size Requirements for a Study
Sample Size Requirements for a Study
Time to Accrue Sufficient Number of Patients
Time to Acquisition of Mature Data
Cost to Conduct A Study
Time to Tumor Progression
Tumor Measurement Criteria Have Been Standardized
Tumor Measurements Can be Readily Described and Quantified
Primary Data Can be Collected, Stored and Saved for Later Audit
Central, Independent, Blinded Radiographic Review Can Enhance Confidence in Results
Time to Tumor Progression
Kaplan-Meier Plotting and Log-Rank Testing Allows Comprehensive Display and Analysis of All Available Data
Assessment of Time to Treatment Failure Allows Confirmatory Analysis of Treatment Effect and Any Censoring Issues
Cox Regression Analysis Permits Confirmatory Analysis of Treatment Effect in the Context of Important Prognostic Variables
PPT Slide
Time to Tumor Progression Measurement Considerations
Unequal Tumor Assessment Intervals Between Study Arms Can Bias TTP Assessment
Plan for Uniform Tumor Assessment Frequency Despite Discordant Cycle Lengths
Actual Investigator Performance in Maintaining Tumor Assessment Frequency
Time to Tumor Progression Measurement Considerations
Conservative Censoring Rules
Nonconservative Censoring Rule Includes 2nd-line Therapy and Potential Biases TTP
Conservative Censoring Rule Confines TTP Determination to 1st-line Study Period
PPT Slide
PPT Slide
TTP Satisfies Critical Requirements as A Regulatory Clinical Benefit Endpoint
Survival Superiority Study Offers Too Little, Too Late, For Too Much
Single Superiority Study Can Offer Highly Robust TTP Assessment (?=0.0025)
Conclusion
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