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Background Overall survival is the optimal marker of treatment efficacy in randomized clinical trials (RCTs) but can take considerable time to mature. Progression-free survival (PFS) has served as an early surrogate of overall survival but is imperfect. Time to deterioration in quality of life (QOL) measures could be a surrogate for overall survival. Methods Phase 3 RCTs in solid malignancies that reported overall survival, PFS, and time to deterioration in QOL or physical function published between January 1, 2010, and June 30, 2022, were evaluated. Weighted regression analysis was used to assess the relationship between PFS, time to deterioration in QOL, and time to deterioration in physical function with overall survival. The coefficient of determination (R 2) was used to quantify surrogacy. Results In total, 138 phase 3 RCTs were included. Of these, 47 trials evaluated immune checkpoint inhibitors and 91 investigated non–immune checkpoint inhibitor agents. Time to deterioration in QOL (137 RCTs) and time to deterioration in physical function (75 RCTs) performed similarly to PFS as surrogates for overall survival (R 2 = 0.18 vs R 2 = 0.19 and R 2 = 0.10 vs R2 = 0.09, respectively). For immune checkpoint inhibitor studies, time to deterioration in physical function had a higher association with overall survival than with PFS (R 2 = 0.38 vs R2 = 0.19), and PFS and time to deterioration in physical function did not correlate with each other (R 2 = 0). When time to deterioration in physical function and PFS are used together, the coefficient of determination increased (R 2 = 0.57). Conclusions Time to deterioration in physical function appears to be an overall survival surrogate measure of particular importance for immune checkpoint inhibitor treatment efficacy. The combination of time to deterioration in physical function with PFS may enable better prediction of overall survival treatment benefit in RCTs of immune checkpoint inhibitors than either PFS or time to deterioration in physical function alone. [ABSTRACT FROM AUTHOR]

Overall survival (OS) results from randomized control trials (RCT) provide the strongest evidence for efficacy of anti-cancer treatments but can take a considerable amount of time to mature. Progression free survival (PFS) and objective response rate (ORR) are used as an early surrogate of OS treatment effect however their validity remains unclear. Our study aims to comprehensively evaluate ORR and PFS as surrogates for OS treatment effect across tumor groups and treatment types. Phase 3 RCTs in solid malignancies that reported OS/PFS and ORR published between 1st of January 2010 and 30th of June 2022 were evaluated. The relationship of surrogate endpoints and OS treatment effect was assessed via weighted linear regression. The coefficient of determination (R2) quantified the fit of the regression model. 675 phase 3 RCT comprising of 350 112 patients were analysed. ORR (R2 of 0.10) and PFS (R2 of 0.38) were poor surrogate markers of OS treatment effect. The strength of surrogacy differed within treatment and tumour groups. PFS had the highest R2 for chemotherapy (0.56) and lowest for targeted therapy (0.40). PFS had the highest level of surrogacy for melanoma (R2 = 0.72) and pancreatic cancer (R2 = 0.70) compared to other tumour groups. Importantly ORR and PFS were also poorly correlated to each other (R2 = 0.33). ORR and PFS were poor trial-level surrogate markers of OS. The surrogacy performance of ORR and PFS differed by treatment and malignancy sub-type. • ORR and PFS are not strong surrogates of OS treatment effect. • Surrogacy of ORR and PFS for OS differs based on treatment and tumor. • surrogacy of ORR and PFS for OS treatment effect was highest for chemotherapy. • PFS was a better surrogate of OS treatment for melanoma and pancreatic cancer. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives It is uncertain whether survival increases from melanoma recorded by some population registries include a treatment effect. The US Surveillance, Epidemiology and End Results ( SEER) programme has good data quality control, large numbers of cases enabling high statistical precision and summary stage plus thickness, which we consider to be a best-case population registry scenario to investigate potential for a treatment effect. We have investigated SEER data to indicate whether survivals increases are fully attributable to earlier diagnosis and other non-treatment factors. Methods Through relative survival regression, the effects of diagnostic period on 5-year excess mortality were investigated, adjusting for socio-demographic factors, lesion sub-site, histology, thickness and stage at diagnosis in 1990-2009 (n = 99 690 cases). Results The reduction in excess mortality (95% confidence interval) between 1990-1999 and 2000-2009 was 31 (20-41)% for localised melanoma, 18 (12-22)% for regional melanoma and 3 (-5-10)% for melanomas with distant spread. Younger age was predictive of a greater percentage reduction. Treatment benefits are inferred from the higher survivals in 2000-2009 but uncertainty remains due to incomplete data to adjust for non-treatment factors and a lack of treatment data. Conclusions Registries should use new information systems to collect more complete data on stage, other prognostic indicators, co-morbidities and treatment, to provide more definitive and detailed information on population effects of cancer control. [ABSTRACT FROM AUTHOR]