Surrogate Endpoint For Overall Survival Research Articles

Potential Utility of Event-Free Survival (EFS) As Surrogate Endpoint for Overall Survival (OS) in Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) after Autologous Stem Cell Transplantation (ASCT): A Subgroup Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Randomized Phase III Trial

Background: EFS at 24 months (EFS24) in newly diagnosed patients with DLBCL following first line rituximab containing anthracycline-based chemotherapy has been shown to be a surrogate marker for long-term OS. In patients achieving EFS24, subsequent OS is nearly equivalent to that of the general population, suggesting that these patients will have a near normal life expectancy if they have not experienced disease relapse by this time point. (Maurer et al. JCO 2014, Jakobsen et al. JCO 2017). In this study, we aim to determine the value of EFS as a surrogate endpoint for OS among patients with relapsed and refractory de novo or transformed DLBCL undergoing ASCT.Methods: Patients with de novo or transformed DLBCL undergoing ASCT in the CCTG LY.12 trial (Crump et al. JCO 2014) were included in the analysis. This multi-center study enrolled patients from August 2003 to November 2011. Analyses were conducted on the updated locked database of June 30th, 2017. Data for an age and sex-matched control group were taken from the Statistics Canada (http://www.statcan.gc.ca) life tables, which provide the survival rate of the general Canadian population. EFS was defined as time from ASCT until relapse, progression, initiation of new lymphoma therapy, or death from any cause. Standardized mortality ratio (SMR) was calculated for each subgroup of patients achieving EFS0 (date of ASCT) to EFS72, with increments of 12 months. All statistical calculations were performed using the SAS version 9.2 and R version 3.3.2.Results: A total of 267 patients were included. The mean age at study entry was 54 years (range 24 to 70); 68% were age <60 years; 61% male; relapse IPI 0-1: 43.8%, 2: 31.5 %, >3: 24.7%; de novo DLBCL 82.8%. Sixty-seven percent of patients received prior rituximab; 70% received rituximab as part of salvage chemotherapy (gemcitabine, cisplatin, dexamethasone or dexamethasone, cytarabine, cisplatin). At a median follow-up of 8.5 years, the total recorded number of deaths was 124; 59 occurred within the first year of follow up, 21 occurred among patients achieving EFS 24, and 6 occurred in patients achieving EFS60. The SMR decreased with each year of follow up, at EFS0 it was 12.55 (95% CI 10.44-14.96), 3.27 (95% CI 2.03-5.00) at EFS24, and 1.92 (95% CI 0.70-4.18) at EFS 60 (Table and Figure). The incidence of disease progression also decreased with each year of follow up, with 88 occurring within the first year of follow up, 21 within year 2, and only 3 after 5 years. More deaths were caused by non-lymphoma conditions, including second malignancy, for patients achieving EFS24 or greater. The 5-year OS was 59.4% for patients at EFS0, 87.1% at EFS24, and 94.3% at EFS60. A multivariate analysis including age at ASCT, IPI, de novo vs transformed DLBCL, and response to prior therapy did not reveal any predictors of survival once patients had achieved EFS24 or EFS60.Conclusion: This study demonstrates that the SMR decreases over time among patients with relapsed DLBCL undergoing ASCT, and remains significant until these patients have achieved EFS60. Thus, earlier EFS cannot be used as a surrogate marker of OS in this clinical context. A larger sample size and a validation study are needed to establish the predictive value of EFS60 for OS following ASCT. [Display omitted] DisclosuresHay:Celgene: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Kite: Research Funding; Abbvie: Research Funding; Roche: Research Funding. Crump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Baetz:Merck: Honoraria; Novartis: Honoraria; Roche: Honoraria. Robinson:Abbvie: Honoraria; Lundbeck: Honoraria; Janssen: Honoraria; Roche: Honoraria; Gilead: Honoraria. Assouline:Bristol Myer Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis Canada Inc.: Honoraria; Paladin: Speakers Bureau; Janssen: Honoraria.

AI3 Disease-Free Survival (DFS) As a Surrogate Endpoint for Overall Survival (OS) in Adults with Resectable Esophageal or Gastroesophageal Junction Cancer: A Correlation Meta-Analysis

To evaluate the appropriateness of using DFS as a surrogate for OS in trials investigating adults with resectable esophageal or gastroesophageal junction cancer (EC/GEJ) receiving therapies in the (neo)adjuvant and perioperative settings. A systematic literature review was conducted to identify EC/GEJ trials that reported OS and DFS, or progression-free survival (PFS) compatible with the definition of DFS. The primary analysis was restricted to studies meeting the proportional hazards (PH) assumption which was assessed statistically after digitization of the reported KM curves. Secondary analysis was restricted to the adjuvant setting only. Sensitivity analyses consisted of removing studies with outlier characteristics and other potential biases, and estimating differences between restricted mean survival times to assess the impact of including studies with non-proportional hazards. The surrogacy relationship was assessed using bivariate random-effects meta-analysis and weighted linear regression. Surrogate threshold effect (STE), the minimum DFS/PFS benefit that would translate into OS benefit, was also estimated. The robustness of the models was tested via leave-one-out cross-validation (LOOCV). The primary analysis included 26 trials after removing 7 trials not meeting the PH assumption. The estimated correlation coefficient was 0.83 (95% CI: 0.70-0.90). The resulting surrogacy equation was log(HROS) = 0 + 0.80 × log(HRDFS/PFS) with a corresponding STE of 0.82. LOOCV verified the stability of the results with 95% alignment between observed and estimated HROS. Correlation estimates across secondary analyses and sensitivity scenarios were similar to those from the primary analysis. The results and their validation point out a correlation between DFS and OS in EC/GEJ. The estimated surrogacy equation and the corresponding STE can enable HRDFS/PFS as a surrogate predictor of HROS in EC/GEJ trials. These findings can be useful when evaluating the long-term efficacy of treatments where OS may not be immediately available.

The concept and use of the neoadjuvant rectal score as a composite endpoint in rectal cancer.

There is no universally accepted instrument to use as a validated surrogate endpoint for overall survival in phase 2 and phase 3 multimodal rectal cancer trials using chemoradiotherapy. Efforts are hampered by the inaccuracy of clinical TNM staging, the variability of indications for neoadjuvant treatment, and diverse definitions of tumour regression grade. Pathological complete response is commonly used, but fails to capture information from the majority of patients. The neoadjuvant rectal score categorises response and downstaging from the entire trial population to identify whether or not a novel treatment group in a chemoradiation trial is superior by predicting overall survival outcomes. Additionally, the neoadjuvant rectal score assesses the difference between initial clinical and pathological T stage and the presence or absence of nodal involvement after treatment. The neoadjuvant rectal score has been conceptually, but incompletely, statistically validated by two independent trial datasets. However, a fundamental weakness of the score is that no preoperative phase 3 trials in locally advanced rectal cancer in the past 20 years have provided a significant benefit in overall survival to statistically validate the neoadjuvant rectal score as a surrogate endpoint for overall survival. We review the robustness, practical value, applicability, generalisability, advantages, and disadvantages of the neoadjuvant rectal score as a surrogate endpoint for overall survival and recommend how this score could be improved and be acceptable as a standard endpoint in studies investigating neoadjuvant chemotherapy and chemoradiation in patients with rectal cancer.

Effect of Adding Bevacizumab to Chemotherapy on Pathologic Response to Preoperative Systemic Therapy for Resectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis

BackgroundLiver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM. MethodsWe systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. ResultsOf the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P < .001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P < .001), in the bevacizumab group. The analyses showed a low level of heterogeneity (I2 = 0% to 6%). Publication bias was not found. ConclusionsThis meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials. MicroAbstractThe benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.

Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer.

5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R2= 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.

The validity of progression-free survival (PFS) 2 as a surrogate endpoint for overall survival (OS) in randomized controlled trials (RCTs) of advanced solid tumors.

1516 Background: OS is the gold-standard endpoint for treatment efficacy in oncology RCTs. However, prolonged follow-up is required to obtain mature data, which impedes regulatory approval of potentially beneficial therapies. Furthermore, increasing therapeutic options including cross over to investigational agents at disease progression often confound OS findings. PFS-2, defined as time from randomization to progression on second-line therapy, has been proposed as a potential surrogate endpoint for OS. Using a meta-analytic approach, we aimed to assess the association between OS and PFS-2, and its validity compared with other surrogate endpoints. Methods: We performed an electronic literature search to identify RCTs of systemic therapies that reported PFS-2 as a pre-specified endpoint with defined follow up protocols. Articles were screened for eligibility and outcome data were extracted. Correlations in the relative treatment difference between treatment arms for OS vs PFS-2, PFS-1, and objective response rate (ORR) were assessed as the comparison of hazard ratios (HR) and odds ratio (OR) respectively. Results: 38 eligible RCTs comprising of 44 analysis units, with 19,031 patients across 8 unique tumor types were identified. The majority received targeted therapies (72.2%), followed by immunotherapy (IO; 26.3%). The correlations of HR-OS/HR-PFS-2, HR-OS/HR-PFS-1 and HR-OS/OR-ORR were r = 0.67 (95% CI 0.08-0.69), r = 0.12 (95% CI 0.00-0.13) and r = 0.21 (95% CI 0.00-0.33) respectively. Correlations between OS with surrogates was assessed in different subgroups according to post-progression survival times (SPP), types of treatment agents and rate of subsequent therapy after progression (table). Conclusions: Across diverse tumors and therapies, treatment effect on PFS-2 has modest to strong correlation with OS, but poor correlations were observed between OS-PFS-1 and OS-ORR respectively. Across all subgroups, PFS-2 performs consistently better than traditional surrogates of PFS-1 and ORR, validating and providing support for use in future RCTs.[Table: see text]

A trial-level correlation analysis of progression-free survival as a surrogate for overall survival in the immunotherapy era.

e18580 Background: Progression-free survival (PFS) is accepted as a surrogate endpoint for cancer drugs approval by the Food and Drug Association. In the expanding immunotherapy era, there is no convincing data for reliable surrogacy of PFS. Methods: We systematically searched PubMed and included all phase III trials of ICIs. Besides, we manually included phase III trials of ICIs presented in congresses. Trials including non-metastatic patients and hematologic malignancies were excluded. The primary endpoint was the relationship between treatment effects (i.e., hazard ratio (HR) of PFS and overall survival (OS)). The secondary endpoint was the relationship between the median PFS (mPFS) and median OS (mOS). We also performed subgroup analyses by ICIs subtypes (i.e., anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1)), treatment lines (i.e., the first-line and subsequent treatments), ICI plus CT combination, and ICI monotherapy. To ensure parametric assumptions, we addressed logarithmic conversion to HRs by using log10. We used Pearson’s correlationand weighted linear regression for parametric variables and Spearman’s rank-order correlation for non-parametric variables. We assessed the relationship between variables by using correlation coefficient (r) and coefficient of determination (R2). Results: We included 57 phase III clinical trials with 39,525 patients. A total of 67 outcomes were compared. There was a good correlation between the logarithmic HR of PFS (log HRPFS) and OS (log HROS) (r=0.71, R2=0.50 p&lt;0.001). In subgroup analyses, there was a weak or moderate correlation between the log HRPFS and log HROS in anti-PD-L1, ICI plus CT, and the first-line treatment subgroups (r=0.61, R2=0.38 p=0.004 for anti-PD-L1; r=0.65, R2=0.43 p=0.008 for ICI plus CT; r=0.70, R2=0.49 p&lt;0.001 for the first-line treatment). Conversely, there was a good correlation between the log HRPFS and log HROS in the anti-PD-1, ICI monotherapy, and subsequent treatment line subgroups (r=0.81, R2=0.66 p&lt;0.001 for anti-PD-1; r=0.71, R2=0.51 p&lt;0.001 for ICI monotherapy; r=0.78, R2=0.62 p&lt;0.001 for subsequent treatment line). Correlations between the mPFS and mOS were good or strong in all subgroups. (Table). Conclusions: PFS might be considered a reliable surrogate endpoint for OS, particularly in anti-PD-1 ICIs, ICI monotherapy, and subsequent metastatic cancer treatment lines.[Table: see text]

Exploration of modified progression-free survival as a novel surrogate endpoint for overall survival in immuno-oncology trials

BackgroundProgression-free survival (PFS) exhibits suboptimal performance as the surrogate endpoint for overall survival (OS) in trials studying immune checkpoint inhibitors (ICIs). Here we propose a novel surrogate endpoint, modified PFS...

Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis.

The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. Prostate Cancer Foundation and National Institutes of Health.

Progression-free survival is a robust surrogate endpoint of overall survival in immunotherapy trials of hepatocellular carcinoma

Progression-free survival is a robust surrogate endpoint of overall survival in immunotherapy trials of hepatocellular carcinoma

Impact of Advantage in Tumor Response on the Correlation Between Progression-Free Survival and Overall Survival: Meta-Analysis of Clinical Trials in Patients with Advanced Non-Small Cell Lung Cancer.

Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) in patients with advanced non-small cell lung cancer. This study aimed to investigate an impact of advantage in tumor response on the correlation between PFS and OS in advanced non-small cell lung cancer. Based on a literature search, we identified randomized controlled trials of first-line therapy for advanced non-small cell lung cancer. The impact of absolute difference in objective response rate between treatment arms on the correlation between hazard ratios (HRs) for PFS and OS was evaluated based on Spearman rank correlation coefficients. Sixty trials with a total of 29,134 patients were identified. The HR for PFS showed a relatively higher correlation with HR for OS (rs = 0.75) when the trials were limited to those that demonstrated a larger advantage in objective response rate, compared with the case for trials that demonstrated a smaller advantage (rs = 0.66). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (non-targeted, anti-angiogenic, and immunotherapy) except for the group of epidermal growth factor receptor-targeted agents. The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS-HR based on PFS-HR in clinical trials in patients with advanced non-small cell lung cancer.

Searching for potential surrogate endpoints of overall survival in clinical trials for patients with prostate cancer.

BackgroundThe purpose of this study was to investigate the correlation between overall survival (OS) and other clinical outcomes in patients with prostate cancer. Further, we conducted subgroup analysis in the correlation of OS.AimThis study intended to investigate potential surrogate endpoints of OS for prostate cancer by examining the correlation between OS and the other endpoints.MethodsWe performed a systematic review through a literature search by computer‐based searches of the Medline database (January 1965 and May 2014).ResultsThe contents of 115 studies with endpoint as OS were analyzed in our study. Our results showed that 47.8% (55/115) of the studies used progression‐free survival as an endpoint besides OS, followed by time to progression (43.5% [50/115]) and PSA response (40.9% [47/115]). Also, the relationship between OS and each surrogate endpoint was examined using the hazard ratio (HR) by a Bayesian hybrid model for random effect multivariate meta‐analysis. Our results showed that the endpoint that had the highest correlation with OS was progression‐free survival (PFS) with an estimated marginal correlation of 0.939 (95%CI: 0.900, 0.967). Furthermore, our stratified analysis identified PFS in castration‐resistant prostate cancer patients (0.937), in sensitive patients (0.932), in none of chemotherapy patients (0.929), in first line of the chemotherapy (0.948), in patients who received no Docetaxel previously (0.942), in both symptomatic and asymptomatic patients (0.950), in patients who received only chemotherapy (0.956), and in phase III (0.960), time to progression (TTP) in castration‐resistant prostate cancer (CRPC) patients (0.942), in metastasis patients (0.948), in both symptomatic and asymptomatic patients (0.953), in patients who received only chemotherapy (0.938), and in Phase III (0.927) as endpoints, which showed a lower limit for 95% CI of estimated marginal correlation ≥0.850 with overall survival.ConclusionsOur study suggests that PFS is a potential surrogate endpoint of OS in clinical trials for patients with prostate cancer. It also suggests potential surrogate endpoints for CRPC and locally advanced prostate cancer.

Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma.

Simple SummarySurrogate radiology-based endpoints such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in oncology. However, their surrogacy with overall survival (OS) has not been evaluated in immunotherapy trials for hepatocellular carcinoma (HCC). We found that the surrogacy of PFS with OS is highly variable depending on treatment class (immune-checkpoint inhibitors or multikinase inhibitors) and evaluation time-point. Early PFS is a robust surrogate endpoint for OS in immunotherapy trials, while the surrogacy relationship between ORR and OS is weak. Early assessment of PFS could be useful for allowing analyses with small sample sizes and short accrual times, enhancing the interpretability of immunotherapy trials in HCC.Background: Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods. Methods: A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.gov) for trials of systemic therapies for advanced HCC reporting both OS and PFS was performed. Individual patient data were extracted from PFS and OS Kaplan–Meier curves. Summary median PFS and OS data were obtained from random-effect model. The surrogate relationships of median PFS, first quartile (Q1), third quartile (Q3), and restricted mean survival time (RMST) for OS were evaluated by the coefficient of determination R2. Heterogeneity was explored by meta-regression. Results: We identified 49 trials, 11 assessing immune-checkpoint inhibitors (ICIs) and 38 multikinase inhibitors (MKIs). Overall, the correlation between median PFS and median OS was weak (R2 = 0.20. 95% Confidence Intervals [CI]-0.02;0.42). Surrogacy robustness varied between treatment classes and PFS endpoints. In ICI trials only, the correlations between Q1-PFS and Q1-OS and between 12-month PFS-RMST and 12-month OS-RMST were high (R2 = 0.89, 95%CI 0.78–0.98, and 0.80, 95% CI 0.63–0.96, respectively). Interaction p-values obtained by meta-regression confirmed the robustness of results. Conclusions: In trials of systemic therapies for advanced HCC, the surrogate relationship of PFS with OS is highly variable depending on treatment class (ICI or MKI) and evaluation time-point. In ICI trials, Q1-PFS and 12-month PFS-RMST are robust surrogate endpoints for OS.

Validation of International Working Group response criteria in higher-risk myelodysplastic syndromes: A report on behalf of the MDS Clinical Research Consortium.

The utility of the International Working Group (IWG) 2006 response criteria for myelodysplastic syndromes (MDS) as a surrogate endpoint for outcomes is unclear. We assessed the validity of the IWG 2006 response criteria in a large cohort of higher‐risk MDS patients (pts) treated at centers from the MDS Clinical Research Consortium. The best overall response rate (ORR) by IWG 2006 criteria to first‐line therapy among 597 evaluable pts was 38% and include complete response (CR) 16%, marrow CR (mCR) 2%, partial response (PR) 10%, hematological improvement (HI) 10%, stable disease (SD) 33%, and progressive disease (PD) 24%. CR was associated with a better overall survival (OS) compared to all other response groups (P < 0.001). Among 470 pts treated with hypomethylating agent (HMA) as first‐line therapy, the overall Response Rate, defined as HI or better was 39%. The median OS from time of best response was 21 mo, 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P < 0.001). We validated those results in a separate cohort of 539 higher‐risk MDS pts treated at Moffitt Cancer Center who received first‐line HMA therapy, particularly addressing the value of mCR and mCR+HI. mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI. In conclusion, CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher‐risk MDS pts. Any response associated with restoration of effective hematopoiesis is associated with better outcome.

Exploring the relationship between Overall Survival (OS), Progression Free Survival (PFS) and Objective Response Rate (ORR) in patients with advanced melanoma

PurposeFrom 2011 to 2016, 13 randomized clinical trials with active controls were submitted to U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma. While regular approval is generally granted due to a substantial improvement in overall survival (OS), or a large, clinically meaningful improvement in progression-free survival (PFS), accelerated approval can be granted based on incremental change in a surrogate end point reasonably likely to predict clinical benefit, such as objective response (ORR) of large magnitude and long duration. However, the relationship between objective response rate and progression free survival or objective response rate and overall survival in advanced melanoma has not been established. Patients and MethodsWe conducted analyses to assess the correlation of objective response rate with progression free survival as well as overall survival by examining all advanced melanoma trials submitted to the FDA between 2011 and 2016. In order to examine these relationships, associations between trial-level hazard ratio (HR) of progression free survival, hazard ration of survival and odds ratio of objective response rate were analyzed using a weighted linear regression model. Patient-level responder analyses comparing progression free survival and overall survival between patients with and without an objective response were performed using pooled data from all studies. ResultsIn the trial-level analysis, the linear relationships between progression free survival and objective response rate, and overall survival and objective response rate were weak (R²adj = 0.019 and 0.093, respectively). The linear relationship between overall survival and progression free survival (R²adj = 0.075) was also weak. In the patient-level responder analyses, patients who achieved a response had better progression free survival and overall survival compared with non-responders in both the control drug treatment and the experimental drug treatment. ConclusionBased on this analysis, use of objective response rate as a surrogate endpoint for overall survival or progression free survival in this population appears not appropriate. However, due to the nature of heterogeneity, interpretation needs to be cautious.

EX3 Investigating Time to Next Treatment As a Surrogate Endpoint for Overall Survival in Previously Untreated Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma Patients: An Insight from the Phase III CheckMate-214

Time to next treatment (TNT) may be a patient-relevant endpoint by capturing durable response, post-progression benefit, and the time free of systemic anticancer therapy, which may be achieved with immune-checkpoint inhibitors (ICI). This study investigated TNT as a surrogate endpoint (SE) of overall survival (OS) in previously untreated intermediate- to poor-risk advanced renal cell carcinoma (aRCC) patients. Patient-level data from CheckMate-214 randomized clinical trial (RCT) (NCT02231749) with 42 months’ minimum follow-up were used. In this RCT, patients were randomly assigned to nivolumab combined with ipilimumab (NIVO+IPI) versus sunitinib. The SE one-step validation method based on a joint frailty model was used where the country of residence was applied to define synthetic clusters. Kendall’s τ and the coefficient of determination (R2trial) were estimated for measurement of the association at the individual and cluster levels, respectively. Surrogate threshold effect (STE), the maximum threshold hazard ratio (HR) for TNT that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was performed to evaluate model robustness and predictive accuracy. Twenty-two clusters were considered from 847 patients. The association between TNT and OS was deemed acceptable at the individual level (Kendall’s τ = 0.59; 95% confidence interval (CI) [0.56; 0.64]) and strong at the cluster level (R2trial close to 1; 95% CI [0.97; 1.03]). The estimated STE was 0.70 for NIVO+IPI versus sunitinib. Cross-validation results showed association measures were minimally influenced when the analyses were repeated with slightly smaller and balanced clusters. The predictive accuracy of the model was modest (45%), with optimistic OS HR predictions when TNT HR was below the STE. TNT may be a valuable SE in previously untreated aRCC patients treated with ICI. Further surrogacy analyses considering multiple RCTs of ICI-treated aRCC patients are warranted for confirming these findings and for improving the accuracy of the predictions.

PCN24 Disease-Free Survival (DFS) As a Surrogate Endpoint for Overall Survival (OS) in HER2 Negative (HER2–) Primary Breast Cancer (BC)

OS is an endpoint for measuring lifetime clinical benefit of oncology therapies; however, studies in the adjuvant setting may not detect OS benefit owing to the time required to observe sufficient events. DFS is commonly measured in primary (neo)adjuvant BC trials when OS may be prolonged. We used linear regression analysis to assess DFS as a surrogate for OS in HER2– primary BC. MEDLINE, Embase, CENTRAL, CDSR, DARE, major oncology congresses and clinical trial databases were searched in August 2019 to identify studies reporting OS and DFS in a HER2– primary BC population. Studies were included if they were conducted in North America and/or Europe, if hazard ratios (HRs) were reported for both outcomes, and if patients had completed local treatment and (neo)adjuvant chemotherapy. Spearman’s rank correlation and linear regression analyses were performed to evaluate the correlation between HRs for OS and DFS. Among 2,596 records reviewed, eight studies (six RCTs, two comparative retrospective studies) were included. Studies comprised triple-negative BC populations (n=2), hormone receptor positive HER2– BC populations (n=2), and overall HER2– BC populations (n=4). The Spearman’s rank correlation coefficient between OS and DFS was 0.756 (p=0.030), which when weighted by study sample size was 0.803 (p=0.016). The regression coefficient on natural logarithm (ln) HROS versus ln HRDFS was 1.75 (95% confidence interval: 1.49–2.02; R2 = 0.972), suggesting a 10% relative risk reduction (RRR) for DFS was associated with an additional 7% RRR for OS. A nominally significant positive correlation was found between OS and DFS in HER2– primary BC, indicating that DFS can be used as a valid surrogate for OS, enabling earlier assessment of clinical benefit. Limitations include the number of studies. Validation of this correlation including future studies is required.

PCN29 Time to Next Treatment As a Candidate Surrogate Endpoint for Overall Survival in Previously Untreated Advanced Melanoma Patients Treated with Immune-Checkpoint Inhibitors

Time to next treatment (TNT) may be a patient-relevant endpoint by capturing durable response, post-progression benefit, and the time free of systemic anticancer therapy, which may be achieved with immune-checkpoint inhibitors (ICI). This study investigated TNT as a surrogate endpoint (SE) of overall survival (OS) in previously untreated advanced melanoma patients. Patient-level data from the 60-month results of the CheckMate-067 randomized clinical trial (RCT) (NCT01844505) were used. Analyses were performed for nivolumab monotherapy (NIVO) or nivolumab with ipilimumab (NIVO+IPI) versus ipilimumab monotherapy (IPI). The SE one-step validation method based on a joint frailty model was used where the country of residence was applied to define synthetic clusters. Kendall’s τ and the coefficient of determination (R2trial) were estimated for respective measurements of association at the individual and cluster levels. Surrogate threshold effect (STE), the maximum threshold hazard ratio (HR) for TNT that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was performed to evaluate model robustness and predictive accuracy. Fifteen clusters were considered from 945 patients. For both nivolumab-containing arms, the association between TNT and OS was deemed acceptable at the individual level (Kendall’s τ >0.60) and strong at the cluster level, with R2trial fairly close to 1, and narrow confidence intervals. The estimated STEs were 0.58 for NIVO versus IPI and 0.39 for NIVO+IPI versus IPI. Cross-validation results showed minimum variation of the correlation measures and modest predictive accuracy for the model. The observed and predicted HRs of OS were closer to each other in the comparison of NIVO+IPI versus IPI than with NIVO versus IPI. Results suggest that TNT may be a valuable SE in previously untreated advanced melanoma patients treated with ICI. Surrogacy analyses considering multiple RCTs of ICI-treated melanoma patients are warranted for confirming these findings and for improving the accuracy of the predictions.

Comprehensive Analysis of Candidate Surrogate Endpoints in Localized Prostate Cancer: Analysis of 59 Randomized Trials

The international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group established metastasis-free survival (MFS) as a surrogate endpoint for overall survival (OS) for men with localized prostate cancer (PCa). ICECaP required individual patient data which limited their analyses to <25% of all eligible randomized controlled trials (RCTs). Since surrogate endpoints are both disease stage and treatment specific, the performance of MFS and other intermediate clinical endpoints (ICEs) across the landscape of localized PCa patients and treatments is unclear. Herein, we comprehensively assess all commonly reported ICEs in localized PCa. A systematic search utilizing Medline to identify RCTs in localized PCa was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Hazard ratios for OS and the ICEs were collected. ICEs included local failure (LF), biochemical failure (BF), distant metastases (DM), BF-free survival (BFS; includes BF, DM, or death), progression-free survival (PFS; LF, DM, or death), and MFS (DM or death) with OS. Candidacy for surrogacy was evaluated using the second condition of the two-stage meta-analytic approach testing whether the treatment effect on the ICE and OS are correlated using R2, weighted by the inverse variance of the log of the ICE hazard ratio. Of 4,217 RCTs screened, 59 trials including 42,272 patients were eligible for analysis. Overall, LF (R2 0.036), BF (R2 0.176), BFS (R2 0.238), and DM (R2 0.364) had poor correlation to the treatment effect on OS. PFS (R2 0.655) had moderate correlation, and MFS (R2 0.781) had the strongest correlation. These trends held true in trials that included or were exclusively in high risk disease. Radiotherapy (RT) RCTs (n = 50, 36,872 patients) showed similar trends with low correlation of LF (R2 0.073), BF (R2 0.334), and BFS (R2 0.229). MFS had stronger correlation to OS (R2 0.777). In RCTs testing use/duration of hormone therapy (n = 26 trials, 24,071 patients), MFS had very strong correlation to OS (R2 0.957). By contrast, in trials evaluating RT dose escalation or fraction size, MFS had lower correlation (R2 0.691). MFS also had strong a correlation to OS (R2 0.947) in patients treated with radical prostatectomy which to date has not been demonstrated. This novel approach corroborates the findings of ICECaP in a substantially larger sampling of RCTs in localized PCa, and supports MFS as the most robust surrogate endpoint for OS across disease stage and treatment type. Importantly, LR and BF have almost no correlation to the treatment effect observed for OS, even in high risk trials, and these ICEs should not be used as surrogate endpoints for phase 3 randomized trials.

Metastasis-Free Survival, but Not Biochemical Failure, is a Strong Surrogate Endpoint for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601

The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival (MFS) as a valid surrogate for overall survival (OS) in men treated for localized prostate cancer. Only 8% of men in the ICECaP MFS analysis were treated with prostatectomy and no salvage radiotherapy (SRT) trials were included. Surrogate endpoints are treatment and disease state specific, thus the performance of intermediate clinical endpoints (ICEs) to function as surrogate endpoints in the SRT setting are unknown. Leveraging NRG/RTOG 9601, we aimed to determine the performance of ICEs as surrogate endpoints for OS in men receiving SRT. Endpoints assessed for surrogacy were biochemical failure (BF), as defined in NRG/RTOG 9601(PSA nadir + 0.3-0.5 ng/mL, or initiation of salvage hormone therapy) and NRG/RTOG 0534 (PSA nadir + 2 ng/mL), distant metastasis (DM), and MFS (DM or all-cause death). Surrogacy was assessed by the Prentice criteria, however given its well-established limitations, the preferred methodology used in ICECaP of a two-stage meta-analytic approach was also utilized. The meta-analytic approach requires two conditions: (1) that the ICE be correlated with OS and (2) that the treatment effect on the ICE and OS be correlated. Condition one was assessed at the patient level with Kendall’s τ and condition two was assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the R2 between treatment hazard ratios for ICE and OS. BF defined in NRG/RTOG 9601 and by nadir + 2 ng/mL, DM, and MFS all satisfied each of the four Prentice criteria for surrogacy for OS. However, with the two-condition approach for assessment of surrogacy, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF (τ = 0.25) or PSA nadir + 2 ng/mL (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (R2 = 0.67), but this was not true for BF and OS (R2 = 0.09), PSA nadir + 2 ng/mL and OS (R2 = 0.12), or DM and OS (R2 = 0.18). We demonstrate that MFS is a strong surrogate for OS in men receiving SRT for recurrent prostate cancer after prostatectomy, consistent with data in the intact primary treatment setting. While BF and PSA nadir + 2 ng/mL both are prognostic, these PSA based ICEs were weakly correlated with OS at the patient level. Similarly, the treatment effect of antiandrogen therapy on these endpoints was only weakly correlated with treatment effect on OS. Thus, caution should be used when inferring clinical benefit from effects on BF as a surrogate for OS.