Dario Pasalic1, Gwendolyn J McGinnis1, C David Fuller1, Aaron J Grossberg2, Vivek Verma3, Walker Mainwaring4, Austin B Miller5, Timothy A Lin6, Amit Jethanandani7, Andres F Espinoza4, Markus Diefenhardt8, Prajnan Das1, Vivek Subbiah1, Ishwaria M Subbiah1, Reshma Jagsi9, Adam S Garden1, Emmanouil Fokas10, Claus Rödel10, Charles R Thomas2, Bruce D Minsky1, Ethan B Ludmir11. 1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Oregon Health & Science University, Portland, OR, USA. 3. Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA. 4. Baylor College of Medicine, Houston, TX, USA. 5. The University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA. 6. The Johns Hopkins University School of Medicine, Baltimore, MD, USA. 7. The University of Tennessee Health Science Center, Memphis, TN, USA. 8. University of Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany. 9. University of Michigan, Ann Arbor, MI, USA. 10. University of Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany; German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Frankfurt, Germany. 11. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ebludmir@mdanderson.org.
Abstract
BACKGROUND: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS. METHODS: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes. RESULTS: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045). CONCLUSIONS: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval.
BACKGROUND: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS. METHODS: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes. RESULTS: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045). CONCLUSIONS: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval.
Authors: Timothy A Lin; Clifton David Fuller; Vivek Verma; Walker Mainwaring; Andres F Espinoza; Austin B Miller; Amit Jethanandani; Dario Pasalic; Prajnan Das; Bruce D Minsky; Charles R Thomas; David R Fogelman; Vivek Subbiah; Ishwaria M Subbiah; Ethan B Ludmir Journal: Cancers (Basel) Date: 2020-09-16 Impact factor: 6.639
Authors: Aya El Helali; Charlene H L Wong; Horace C W Choi; Wendy W L Chan; Naomi Dickson; Steven W K Siu; Karen K Chan; Hextan Y S Ngan; Roger K C Ngan; Richard D Kennedy Journal: Sci Rep Date: 2022-03-09 Impact factor: 4.379
Authors: Joseph Abi Jaoude; Ramez Kouzy; Ethan B Ludmir; Cullen M Taniguchi; Marc Ghabach; Roshal Patel; Dario Pasalic; Elie Ghossain; Austin B Miller; Timothy A Lin; Vivek Verma; C David Fuller; Vivek Subbiah; Bruce D Minsky Journal: BMC Cancer Date: 2021-06-12 Impact factor: 4.430