E Lesaffre1,2, M J Edelman3, N H Hanna4, K Park5, N Thatcher6, S Willemsen2, B Gaschler-Markefski7, R Kaiser7,8, C Manegold9. 1. L-Biostat, KU Leuven, Leuven, Belgium. 2. Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. 3. University of Maryland Greenebaum Cancer Center, Baltimore. 4. Indiana University, Melvin and Bren Simon Cancer Center, Indianapolis, USA. 5. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 6. The Christie NHS Foundation Trust, Manchester, UK. 7. Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach. 8. Institute of Clinical Pharmacology, University Göttingen, Göttingen. 9. Department of Surgery, Interdisciplinary Thoracic Oncology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
Abstract
BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.
BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.
Authors: Brian T Fisher; Theoklis Zaoutis; Christopher C Dvorak; Michael Nieder; Danielle Zerr; John R Wingard; Colleen Callahan; Doojduen Villaluna; Lu Chen; Ha Dang; Adam J Esbenshade; Sarah Alexander; Joseph M Wiley; Lillian Sung Journal: JAMA Date: 2019-11-05 Impact factor: 56.272
Authors: Nick R Parsons; Nigel Stallard; Helen Parsons; Aminul Haque; Martin Underwood; James Mason; Iftekhar Khan; Matthew L Costa; Damian R Griffin; James Griffin; David J Beard; Jonathan A Cook; Loretta Davies; Jemma Hudson; Andrew Metcalfe Journal: BMC Med Res Methodol Date: 2022-10-01 Impact factor: 4.612