selection of endpoints in oncology research studies.pptx

MD Pharmacology Resident

1. Selection of endpoints in Oncology Research Studies Dr. Laxmi Hotkar JR-2 1

2. Outline Definition of Endpoints in Oncology Research Importance of selecting appropriate endpoints Types of Endpoints Challenges in Endpoint Selection Case Studies Emerging Trends Summary 2

3. Definition Endpoints in oncology research refers to specific measurements or events used to evaluate the effectiveness, safety, and overall outcomes of treatments or interventions in cancer patients. 3 Center for Drug Evaluation and Research. Helping to understand oncology clinical trial endpoints. FDA; [cited 2024 Apr 23].

4. Importance of Selecting Appropriate Endpoints in Oncology Research Measurement of Treatment Efficacy Clinical Relevance Regulatory Approval Resource Optimization Interpretation of Study Results Comparison Across Studies Ethical Considerations Data Analysis Plan S ample size calculation 4

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6. P rimary endpoints - E fficacy measures that address the main research question. Examples: Overall Survival (OS) Progression-Free S urvival (PFS) Disease-Free S urvival (DFS) Duration of C linical B enefit ( DoCB ) 6 US Department of Health and Human Services F . 2017. Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER): Multiple Endpoints for Clincial Trials: Guidance for Industry.

7. Overall Survival (OS) OS measures the time from randomization until death from any cause. (1) R ecognized as the gold standard for clinical benefit in oncology clinical trials. (2) 7 2. Zhuang SH, Xiu L, Elsayed YA. Overall survival: a gold standard in search of a surrogate: the value of progression-free survival and time to progression as end points of drug efficacy. Cancer J. 2009 Sep-Oct;15(5):395-400. 1.Cheema PK, Burkes RL. Overall survival should be the primary endpoint in clinical trials for advanced non-small-cell lung cancer. Curr Oncol. 2013 Apr;20(2):e150-60 Merits : easily measured, unambiguous, objective, unaffected by the timing of assessment Demerits : requires large studies, long periods of follow-up, confounded by effective crossover, subsequent therapies, and noncancer death. Example: A clinical trial comparing two chemotherapy regimens for advanced lung cancer may use OS as the primary endpoint to determine which treatment provides better overall survival rates.

8. Progression-Free Survival (PFS) PFS measures the time from randomization until disease progression or death, whichever occurs first. (1) R eflects the duration during which the disease does not worsen. 8 Example: A study evaluating a targeted therapy for metastatic breast cancer might use PFS as the primary endpoint to determine if the treatment delays disease progression compared to standard therapy. (2) Merits: events occur more quickly & frequently Data available is earlier F ew patients required to obtain data expediting the approval process Demerits: inherent degree of subjectivity measurement error Difficult to establish if clinical benefit is meaningful 1. Cheema PK, Burkes RL. Overall survival should be the primary endpoint in clinical trials for advanced non-small-cell lung cancer.  Curr Oncol.  2013;20:e150–160. 2. Kaklamani VG. Clinical Implications of the Progression-Free Survival Endpoint for Treatment of Hormone Receptor-Positive Advanced Breast Cancer. Oncologist. 2016 Aug;21(8):922-30.

9. Disease Free Survival (DFS) D efined as the time from randomization until evidence of disease recurrence.  R elated to duration of response (DOR): the length of time a tumor will respond to treatment without growing or metastasizing. U sed as a clinical endpoint for adjuvant treatments after definitive surgery or radiotherapy. It is considered an event-based endpoint, with events defined as: Disease Recurrence, Disease Progression, Death: Death from any cause is often considered a competing event in DFS analysis. 9

10. Duration of Clinical Benefit ( DoCB ) I s defined as the time from randomization to disease progression or death in patients who achieve complete response, partial response, or stable disease for 24 weeks or longer. used in clinical trials in which disease stabilization in order to prolong survival is the primary goal. 10 Garnett SA, Martin M, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Lindemann JP, Di Leo A. Comparing duration of response and duration of clinical benefit between fulvestrant treatment groups in the CONFIRM trial: application of new methodology.  Breast Cancer Res Treat.  2013;138:149–155

11. Secondary endpoints A dditional outcomes measured in a clinical trial to provide supplementary information on treatment effects, safety, or other aspects of interest. Examples: Objective R esponse Rate (ORR), Health-Related Q uality of L ife ( HRQoL ) , Time To Progression (TTP), T umor -Related E ndpoints, 11

12. Objective response rate (ORR) D efined as the proportion of patients that respond either partially or fully to therapy.  Is a good measure of anti- tumor activity. ORR was primarily assessed by WHO Criteria which included tumor size and total tumor load as found via different anatomic imaging modalities (1,) R eplaced by the Response Evaluation Criteria in Solid Tumors (RECIST),  RECIST selects target lesions by size and defines them as representative lesions of all involved organs (2), These criteria define specific thresholds for tumor size reduction and the appearance of new lesions to determine response categories. High ORR may indicate potential effectiveness of a treatment. 12 1. Choi JH, Ahn MJ, Rhim HC, Kim JW, Lee GH, Lee YY, Kim IS. Comparison of WHO and RECIST criteria for response in metastatic colorectal carcinoma.  Cancer Res Treat.  2005;37:290–293. 2. Villaruz LC, Socinski MA. The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement.  Clin Cancer Res.  2013;19:2629–2636. 

13. Contd … Disadvantages of ORR : It fails to capture patients with a stable disease, it does not differentiate patients with complete response from those with partial response  13

14. Health-related quality of life ( HRQoL ) E valuation of a patient’s quality of life with respect to health status over time. Used in comparing treatments that have similar effects with differences in toxicity. A ssessed using a set of four core questions developed by the Centers for Disease Control and Prevention (CDC) : Four core questions : 1. O verall health 2. P hysical health 3. M ental health 4. Activities of daily living 14 Barile JP, Reeve BB, Smith AW, Zack MM, Mitchell SA, Kobau R, Cella DF, Luncheon C, Thompson WW. Monitoring population health for healthy people 2020: evaluation of the NIH PROMIS(R) global health, CDC healthy days, and satisfaction with life instruments.  Qual Life Res.  2013;22:1201–1211

15. Time to progression (TTP) Is defined as the time from randomization until first evidence of disease progression  V alue of TTP’s assessment has the potential to be adversely affected by disease characteristics unique to each patient, including inter- tumor variation and the tumor’s natural growth rate. R esearchers have proposed a patient-personalized “TTP ratio” as an additional parameter to measure the effectiveness of targeted therapy. V ariant of TTP compares tumor growth both on and off treatment, serving as an intra-patient control for natural tumor growth rate 15 Cirkel GA, Weeber F, Bins S, Gadellaa -van Hooijdonk CG, van Werkhoven E, Willems SM, van Stralen M, Veldhuis WB, Ubink I, Steeghs N, de Jonge MJ, Langenberg MH, Schellens JH, Sleijfer S, Lolkema MP, Voest EE. The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies.  Ann Oncol.  2016;27:1638–1643. 

16. S urrogate Endpoints Pathological complete response Used as a surrogate endpoint Assesses time from randomization to absence of residual invasive cancer upon evaluation of the resected breast tissue and regional lymph nodes Disease-specific, especially in breast cancer 16 Duration of response Used as a surrogate endpoint Assesses time from randomization to disease progression or death in patients who achieve complete or partial response Needs disease-specific validation Endpoint Applications Functions Drawbacks Milestone survival Used as a surrogate endpoint Assesses time from randomization to survival probability at a given time point Requires further validation

17. Exploratory Endpoints I nclude clinically important events that are expected to occur too infrequently to show a treatment effect, or Endpoints that for other reasons are thought to be less likely to show an effect but are included to explore new hypotheses. It p rovide preliminary insights into treatment effects or disease characteristics, which may inform future research or treatment strategies. 17

18. Challenges in Endpoint Selection Disease Heterogeneity Longitudinal Studies Time and Resource Intensive Loss to Follow-Up Changing Treatment Landscape Regulatory Approval Ethical Challenges 18

19. Case Study 1 Overall Survival (OS) as Primary Endpoint Background : Clinical Trial: Phase III trial comparing chemotherapy plus targeted therapy versus chemotherapy alone in metastatic colorectal cancer. Endpoint: Overall Survival (OS) defined as the time from randomization to death from any cause. Importance of Endpoint : Clinical Relevance: directly assess the impact of treatment on patients survival. Regulatory Acceptance: OS is a well-established endpoint accepted by regulatory agencies Outcome : Results showed a statistically significant improvement in median OS in the combination therapy arm compared to chemotherapy alone. Kanemitsu Y, Shitara K, Mizusawa J, Hamaguchi T, Shida D, Komori K, Ikeda S, Ojima H, Ike H, Shiomi A, Watanabe J, Takii Y, Yamaguchi T, Katsumata K, Ito M, Okuda J, Hyakudomi R, Shimada Y, Katayama H, Fukuda H; JCOG Colorectal Cancer Study Group. Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS ): A Randomized Clinical Trial. J Clin Oncol. 2021 Apr 1;39(10):1098-1107.  19

20. Case Study 2: Surrogate Endpoint in Breast Cancer Trials Background : Clinical Trial: Phase II trial testing a new targeted therapy in HER2-positive breast cancer. Endpoint: Pathologic Complete Response ( pCR ) defined as the absence of invasive cancer in the breast and lymph nodes after neoadjuvant treatment. Challenges : Surrogate Nature: While pCR is correlated with long-term outcomes, its validity as a surrogate endpoint is debated. Regulatory Approval: Uncertainty exists regarding the acceptance of pCR as a surrogate endpoint by regulatory agencies. Outcome : The trial showed a high pCR rate in the treatment arm, indicating potential efficacy. Long-term follow-up data is needed to confirm if pCR correlates with improved survival, which may impact regulatory decision-making. 20 Fazal F, Bashir MN, Adil ML, Tanveer U, Ahmed M, Chaudhry TZ, Ijaz AA, Haider M. Pathologic Complete Response Achieved in Early-Stage HER2-Positive Breast Cancer After Neoadjuvant Therapy With Trastuzumab and Chemotherapy vs. Trastuzumab, Chemotherapy, and Pertuzumab : A Systematic Review and Meta-Analysis of Clinical Trials. Cureus . 2023 May 31;15(5):e39780.

21. Emerging Trends in Endpoint Selection Patient-Reported Outcomes (PROs) : as endpoints to capture patients perspectives on treatment impact and quality of life. - Integration of electronic PRO platforms for real-time data collection and monitoring. 2. Immunotherapy Biomarkers : Development of multiplex biomarker assays for comprehensive immune profiling. 3. Adaptive Trial Designs : allowing for real-time adjustments of endpoints and treatment arms based on accumulating data. Mercieca-Bebber R, King MT, Calvert MJ, Stockler MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018 Nov 1;9:353-367. 21

22. Summary Endpoint selection in oncology research is critical for determining treatment efficacy and guiding clinical decision-making. Well-defined endpoints such as Overall Survival (OS) and Progression-Free Survival (PFS) remain gold standards, but emerging trends are expanding endpoint options. Thoughtful endpoint selection ensures that clinical trials are relevant, efficient, and ethically sound. Appropriate endpoints facilitate accurate assessment of treatment benefits and support regulatory approval. Selection of endpoints that align with patient needs and preferences enhances the relevance of research outcomes. Incorporation of biomarkers and precision oncology approaches offer personalized endpoints and treatment strategies 22

23. References Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021 Apr 15;11(4):1121-1131. PMID: 33948349; PMCID: PMC8085844. McLeod C, Norman R, Litton E, Saville BR, Webb S, Snelling TL. Choosing primary endpoints for clinical trials of health care interventions. Contemp Clin Trials Commun . 2019 Nov 12;16:100486 Augustus S. Drug development in oncology: a regulatory perspective. Am J Ther . 2011 Jul;18(4):323-31. doi : 10.1097/MJT.0b013e3181d1d833. PMID: 20335790. Fazal F, Bashir MN, Adil ML, Tanveer U, Ahmed M, Chaudhry TZ, Ijaz AA, Haider M. Pathologic Complete Response Achieved in Early-Stage HER2-Positive Breast Cancer After Neoadjuvant Therapy With Trastuzumab and Chemotherapy vs. Trastuzumab, Chemotherapy, and Pertuzumab : A Systematic Review and Meta-Analysis of Clinical Trials. Cureus . 2023 May 31;15(5):e39780. Mercieca-Bebber R, King MT, Calvert MJ, Stockler MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018 Nov 1;9:353-367.  Purna Singh A, Shahapur PR, Vadakedath S, Bharadwaj VG, Kumar DP, Pinnelli VB, Godishala V, Kandi V. Research Question, Objectives, and Endpoints in Clinical and Oncological Research: A Comprehensive Review. Cureus . 2022 Sep 25;14(9):e29575. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012 Nov 10;31(25):2973-84. Kilickap S, Demirci U, Karadurmus N, Dogan M, Akinci B, Sendur MAN. Endpoints in oncology clinical trials.  J BUON.  2018;23:1–6 Wilson MK, Karakasis K, Oza AM. Outcomes and endpoints in trials of cancer treatment: the past, present, and future.  Lancet Oncol.  2015;16:e32–42   Gyawali B, Hey SP, Kesselheim AS. Evaluating the evidence behind the surrogate measures included in the FDA’s table of surrogate endpoints as supporting approval of cancer drugs.  EClinicalMedicine .  2020;21:100332 23

24. References 24 12. Kanemitsu Y, Shitara K, Mizusawa J, Hamaguchi T, Shida D, Komori K, Ikeda S, Ojima H, Ike H, Shiomi A, Watanabe J, Takii Y, Yamaguchi T, Katsumata K, Ito M, Okuda J, Hyakudomi R, Shimada Y, Katayama H, Fukuda H; JCOG Colorectal Cancer Study Group. Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS ): A Randomized Clinical Trial. J Clin Oncol. 2021 Apr 1;39(10):1098-1107.  13. Cheema PK, Burkes RL. Overall survival should be the primary endpoint in clinical trials for advanced non-small-cell lung cancer. Curr Oncol. 2013 Apr;20(2):e150-60 14. Zhuang SH, Xiu L, Elsayed YA. Overall survival: a gold standard in search of a surrogate: the value of progression-free survival and time to progression as end points of drug efficacy. Cancer J. 2009 Sep-Oct;15(5):395-400.

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