EVALUATING NON-OS ENDPOINTS IN CHRONIC LYMPHOCYTIC LEUKEMIA TRIALS FOR HEALTH TECHNOLOGY ASSESSMENT
Author(s)
Fei-Yuan Sharon Hsiao, PhD1, Elise Chia Hui Tan, MHA, MS, PhD2, Lin-Chieh Meng, MS1, Hui-Min Chuang, PharmD1, Szu-Yu Chen, MS1, Bor-Sheng Ko, PhD, MD3.
1National Taiwan University, Taipei, Taiwan, 2China Medical University, Taiwan, Taichung, Taiwan, 3National Taiwan University Hospital, New Taipei City, Taiwan.
1National Taiwan University, Taipei, Taiwan, 2China Medical University, Taiwan, Taichung, Taiwan, 3National Taiwan University Hospital, New Taipei City, Taiwan.
OBJECTIVES: The introduction of targeted therapies has transformed the treatment paradigm of chronic lymphocytic leukemia (CLL), resulting in prolonged disease control while overall survival (OS) data often remain immature at the time of evaluation. This review characterizes the use of non-OS endpoints in contemporary CLL trials and evaluates their relevance for health technology assessment (HTA).
METHODS: A narrative review was conducted using PubMed/MEDLINE, ClinicalTrials.gov, leading oncology journals, and major conference proceedings (ASCO, ESMO, SABCS), covering January 2015 to November 2025. Eligible Phase II-III interventional trials in adults with CLL or small lymphocytic lymphoma receiving drug-based therapies were categorized by treatment setting, therapeutic class, and primary and secondary endpoints.
RESULTS: Twenty-five trials were identified, of which 96% were Phase III studies. Treatment settings were distributed between previously untreated (48%) and relapsed/refractory disease (44%), with maintenance settings accounting for 8%. Targeted therapies predominated, including Bruton tyrosine kinase inhibitors (BTKi; 40%), PI3K inhibitors (16%), BCL-2 inhibitors (12%), and BTKi/BCL-2 inhibitor combinations (8%). Progression-free survival (PFS) overwhelmingly dominated as the primary endpoint (92%), whereas OS was used as a co-primary endpoint in one study. OS remained the most frequently reported secondary endpoint (92%), followed by response rate-based outcomes (84%) and minimal residual disease (MRD) negativity (60%). Other secondary endpoints included duration of response and safety outcomes, time to next treatment, event-free survival, quality of life, and sustained hematologic improvement.
CONCLUSIONS: Non-OS endpoints, particularly PFS, have become the evidentiary standard in modern CLL trials. Given the prolonged natural history of CLL and the limitations of OS as a timely decision-making endpoint, HTA frameworks should consider clinically meaningful non-OS endpoints, together with supportive outcomes, to facilitate earlier and more context-appropriate reimbursement decisions.
METHODS: A narrative review was conducted using PubMed/MEDLINE, ClinicalTrials.gov, leading oncology journals, and major conference proceedings (ASCO, ESMO, SABCS), covering January 2015 to November 2025. Eligible Phase II-III interventional trials in adults with CLL or small lymphocytic lymphoma receiving drug-based therapies were categorized by treatment setting, therapeutic class, and primary and secondary endpoints.
RESULTS: Twenty-five trials were identified, of which 96% were Phase III studies. Treatment settings were distributed between previously untreated (48%) and relapsed/refractory disease (44%), with maintenance settings accounting for 8%. Targeted therapies predominated, including Bruton tyrosine kinase inhibitors (BTKi; 40%), PI3K inhibitors (16%), BCL-2 inhibitors (12%), and BTKi/BCL-2 inhibitor combinations (8%). Progression-free survival (PFS) overwhelmingly dominated as the primary endpoint (92%), whereas OS was used as a co-primary endpoint in one study. OS remained the most frequently reported secondary endpoint (92%), followed by response rate-based outcomes (84%) and minimal residual disease (MRD) negativity (60%). Other secondary endpoints included duration of response and safety outcomes, time to next treatment, event-free survival, quality of life, and sustained hematologic improvement.
CONCLUSIONS: Non-OS endpoints, particularly PFS, have become the evidentiary standard in modern CLL trials. Given the prolonged natural history of CLL and the limitations of OS as a timely decision-making endpoint, HTA frameworks should consider clinically meaningful non-OS endpoints, together with supportive outcomes, to facilitate earlier and more context-appropriate reimbursement decisions.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
HTA21
Topic
Health Technology Assessment
Topic Subcategory
Decision & Deliberative Processes, Value Frameworks & Dossier Format
Disease
Oncology