EVALUATION OF USE OF OVERALL SURVIVAL AS CO-PRIMARY OR SECONDARY ENDPOINT IN CROSSOVER TRIALS: A SYSTEMATIC LITERATURE REVIEW OF HEALTH TECHNOLOGY ASSESSMENT (HTA) SUBMISSIONS OF TREATMENTS FOR SELECT TUMORS IN ONCOLOGY
Author(s)
Anandaroop Dasgupta, PhD1, Ankita Kaushik, PhD1, Catherine Lai, PharmD1, Bart Van den Daele, MBA, PharmD, PhD1, Kevin Punie, MD2, Peeter Karihtala, PhD, MD3, Theodoros Foukakis, PhD, MD4, Marcus Vetter, PD Dr. Med5, Laura Mazilu, PhD, MD6, Sumeet Attri, MS7, Barinder Singh, RPh7.
1Gilead Sciences, Inc., Foster City, CA, USA, 2Department of Medical Oncology, Oncology Center Antwerp, Ziekenhuis Aan de Stroom, Antwerp, Belgium, 3Helsinki University Hospital, Comprehensive Cancer Center and University of Helsinki, Helsinki, Finland, 4Karolinska Institutet, Stockholm, Sweden, 5Cancer Center Baselland, Liestal, Switzerland & Medical Faculty University Basel, Basel, Switzerland, 6Head of Department, Oncology Clinic, Ovidius Clinical Hospital, Ovidius University of Constanta, Constanta, Romania, 7Pharmacoevidence, Mohali, India.
1Gilead Sciences, Inc., Foster City, CA, USA, 2Department of Medical Oncology, Oncology Center Antwerp, Ziekenhuis Aan de Stroom, Antwerp, Belgium, 3Helsinki University Hospital, Comprehensive Cancer Center and University of Helsinki, Helsinki, Finland, 4Karolinska Institutet, Stockholm, Sweden, 5Cancer Center Baselland, Liestal, Switzerland & Medical Faculty University Basel, Basel, Switzerland, 6Head of Department, Oncology Clinic, Ovidius Clinical Hospital, Ovidius University of Constanta, Constanta, Romania, 7Pharmacoevidence, Mohali, India.
OBJECTIVES: Crossover in oncology trials (defined as patients in control arm, upon meeting certain conditions, receiving all/part of the experimental treatment regimen in subsequent line of therapy) impedes understanding of an intervention’s benefit in prolonging overall survival (OS) and may impact health technology assessment (HTA) ratings. This systematic literature review contextualized use of OS as co-primary/secondary endpoint in oncology trials with crossovers.
METHODS: HTA reports (2013-2024) were retrieved from NICE-UK, CDA-Canada, HAS-France, G-BA/IQWiG-Germany, PBAC-Australia, AIFA-Italy, AEMPS-Spain, and ICER-USA. Searches were supplemented with clinical practice guidelines and regulatory product labels. Submissions were reviewed to extract OS in endpoint hierarchy, proportion of control-arm patients receiving (all/ part of) experimental therapy through protocol-defined crossover or off-study access, statistical significance of intention-to-treat (ITT) OS, crossover timing, and study design.
RESULTS: Fifty unique oncology trials were identified across 114 HTA submissions. No open-label trial reported crossover rate >40% with OS as co-primary endpoint. Four open-label trials with OS as co-primary endpoint reported crossover rates between 0.4%-36.4%, with three achieving statistically significant ITT OS (crossover rate: 0.4%-3.0%). Among first-line metastatic open-label trials (n=12), crossover rates ranged 1.5%-70.0%. Crossover was allowed before primary readout (showing progression-free survival, PFS results) in 67% trials (n=8/12), 58% had built-in crossover (n=7/12), and 67% had OS included as secondary endpoint (n=8/12). Among trials using OS as secondary endpoint, 47% had built-in crossover (n=15/32), and 50% (n=16/32) reported crossover >40%, of which 75% (n=12/16) showed non-significant OS. Only one trial with OS as co-primary endpoint demonstrated significant result with crossover >40% (comparator arm n=206; 2:1 randomization ratio).
CONCLUSIONS: High crossover was rarely observed in oncology trials designating OS as co-primary endpoint. Trials with substantial crossover more commonly positioned OS as secondary endpoint and frequently failed to show significant ITT OS. This may impact HTA decision-making and warrants evaluation of other endpoints (PFS, patient-reported outcomes).
METHODS: HTA reports (2013-2024) were retrieved from NICE-UK, CDA-Canada, HAS-France, G-BA/IQWiG-Germany, PBAC-Australia, AIFA-Italy, AEMPS-Spain, and ICER-USA. Searches were supplemented with clinical practice guidelines and regulatory product labels. Submissions were reviewed to extract OS in endpoint hierarchy, proportion of control-arm patients receiving (all/ part of) experimental therapy through protocol-defined crossover or off-study access, statistical significance of intention-to-treat (ITT) OS, crossover timing, and study design.
RESULTS: Fifty unique oncology trials were identified across 114 HTA submissions. No open-label trial reported crossover rate >40% with OS as co-primary endpoint. Four open-label trials with OS as co-primary endpoint reported crossover rates between 0.4%-36.4%, with three achieving statistically significant ITT OS (crossover rate: 0.4%-3.0%). Among first-line metastatic open-label trials (n=12), crossover rates ranged 1.5%-70.0%. Crossover was allowed before primary readout (showing progression-free survival, PFS results) in 67% trials (n=8/12), 58% had built-in crossover (n=7/12), and 67% had OS included as secondary endpoint (n=8/12). Among trials using OS as secondary endpoint, 47% had built-in crossover (n=15/32), and 50% (n=16/32) reported crossover >40%, of which 75% (n=12/16) showed non-significant OS. Only one trial with OS as co-primary endpoint demonstrated significant result with crossover >40% (comparator arm n=206; 2:1 randomization ratio).
CONCLUSIONS: High crossover was rarely observed in oncology trials designating OS as co-primary endpoint. Trials with substantial crossover more commonly positioned OS as secondary endpoint and frequently failed to show significant ITT OS. This may impact HTA decision-making and warrants evaluation of other endpoints (PFS, patient-reported outcomes).
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
SA6
Topic
Study Approaches
Disease
Oncology