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Abstract Background The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials. Methods We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival. Results Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75). Conclusions One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.

Flexible parametric survival models with cure and milestone survival complement the Cox model, and help clinicians and regulators evaluate the benefit-risk ratios of new therapeutics. The flexible parametric survival model with cure facilitates patients' understanding of risk information. The Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments. The current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials. Individual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS. Each trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB. For each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75–1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period. Although ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion. Although immune checkpoint inhibitor treatments show substantial shifts toward long-term benefits in terms of progression-free survival, a more rigorous attempt to quantify this shift, rather than simply using a Kaplan-Meier estimate or comparing progression-free survival curves using the classic Cox model, is warranted. Our results suggest that advanced renal cell carcinoma patients who had not received a previous treatment are functionally cured by nivolumab and ipilimumab, which is not the case for second-line urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Background: The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials. Methods: We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival. Results: Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75). Conclusions: One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials. [ABSTRACT FROM AUTHOR]

The dynamic effects of immune checkpoint inhibitors (ICIs) are a challenge when designing and analysing data in non-proportional hazards (PH) scenarios. Herein, we present the risk of making type II errors, affecting pharmacotherapeutic development when methods that assume constant effects are applied. Individual patient data from six clinical trials (KEYNOTE-062/061, IMvigor211, CA184-143 y CheckMate-057/037) were extracted. The most relevant time-varying effects were examined using the Royston-Parmar spline model (RPSM), time-driven analyses and weighted log-rank and Renyi tests. The RPSM yields an appropriate fit in non-PH contexts, enabling dynamic descriptions of the hazard rate, and time-varying differences of overall survival (OS)/progression-free survival. In the KEYNOTE-061, CheckMate-057 and 037 trials, 12-, 18-, and 24-month OS rates were higher with immunotherapy (differences of some 10%) (P-value <0.05). In KEYNOTE-062, CA184-043 and IMvigor-211 trials, OS rate differences were significant for past 20 months. Flemming-Harrington and Renyi tests with late weighting (e.g. with ρ-value = 0 and γ-value = 1) captured the existence of significant differences on all curves. The Cox models and log-rank tests were inefficient at detecting the effect. This analysis highlights the risk of declaring studies with ICIs negative, despite associating substantial OS benefits. Effort and consensus are needed with respect to methodology to design and evaluate trials with ICIs in non-PH settings. • Some phase III trials with ICIs may be declared negative despite apparent benefit • The log-rank test and Cox model are unable to capture the time-varying effect of ICIs • Flexible parametrical models may be able to capture late effects of immunotherapy • Methods for analysing the dynamic mechanism of immunotherapy need to be established [ABSTRACT FROM AUTHOR]

The advent of immunotherapy leads to greater availability of effective subsequent treatments and extended survival in previously treated advanced non‐small cell lung cancer (NSCLC), complicating the evaluation of overall survival (OS) in second‐line NSCLC trials. Here, we aimed to assess the surrogacy of progression‐free survival (PFS) and milestone survival for OS in second‐line NSCLC trials investigating chemotherapy, targeted therapy and immunotherapy, respectively. We systemically searched for active‐controlled, second‐line NSCLC trials. The milestone time point was set at one‐year based on pre‐analysis. A two‐stage meta‐analytic validation model was adopted to assess associations between surrogate endpoint (SE) and OS and associations between treatment effects on SE and OS. Treatment effects on SE and OS were expressed as PFS hazard ratios (HRPFS), 1 yr‐milestone ratio (Ratio1y‐SUR) and HROS. Subgroup analyses stratified by treatment types and trial publication years evaluated the surrogacy in different clinical contexts. The study included 50 trials with 22,804 patients. One‐year survival strongly correlated with OS (R2[95% confidence interval]: one‐year survival ‐median OS = 0.707 [0.704–0.708]; Ratio1y‐SUR‐HROS = 0.829 [0.828–0.831]). No correlation was established between PFS and OS (median PFS‐median OS = 0.100 [0.098–0.101]; HRPFS‐HROS = 0.064 [0.059–0.069]), except in immunotherapy subgroup (HRPFS‐HROS = 0.835 [0.791–0.918]). In subgroup analyses, surrogacy of one‐year survival persisted in different clinical contexts, and the disassociation between PFS and OS persisted in recent trials. One‐year milestone survival showed strong surrogacy for OS in second‐line NSCLC trials. Although no association was identified between PFS and OS, the strong HRPFS‐HROS correlation in immunotherapy trials indicates the potential of PFS as a SE in NSCLC trials involving immunotherapies. What's new? The advent of immunotherapy has provided previously‐treated advanced non‐small cell lung cancer (NSCLC) patients with more subsequent treatment options. The evaluation of overall survival (OS) in second‐line NSCLC trials has however become more complicated and time‐consuming due to potential confounding effects, calling for the identification of surrogate endpoints. This literature‐based study of 50 trials identified strong correlations between one‐year survival and OS, supporting the use of milestone survival as a surrogate endpoint in future NSCLC trials. No correlation between progression‐free survival (PFS) and OS was established. However, the strong HRPFS‐HROS correlation in the immunotherapy subgroup suggested its potential utility in immunotherapy trials. [ABSTRACT FROM AUTHOR]