Surrogate Endpoint For Overall Survival Research Articles

Abstract PO1-03-03: STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival

Abstract Background: Standardized definitions of efficacy endpoints are needed to improve clinical trial designs, data reporting and interpretation of results, and to allow cross-trial comparisons. STEEP (Standardized Definitions for Efficacy Endpoints) criteria were proposed in 2007 by an expert panel from the National Cancer Institute (NCI) to provide common definitions for clinical trials in early breast cancer (BC). Invasive disease-free survival (IDFS) was selected as a candidate surrogate endpoint for overall survival (OS) in adjuvant trials and has been widely used in the last 15 years. Advances in BC systemic treatment led to review these criteria (STEEP v2.0), with the definition of a new modified endpoint: invasive BC-free survival (IBCFS). IBCFS excludes second primary non-breast invasive cancers from IDFS which may better detect efficacy effects when the toxicity profile of the intervention is well-known and the risk of second primary cancer is small. Methods: We proposed a multi-trial analysis of 8 adjuvant chemotherapy (CT) trials from GEICAM and TRIO to evaluate the different surrogate endpoints defined in the STEEP v2.0. Trial-level surrogacy was assessed through correlation between the ln hazard ratio (HR) of OS and the ln HR of the different studied endpoints across trials. The correlation was estimated by the weighted, by trial size, least squares regression (WLS) line and evaluated comparing the R2 values between OS and the corresponding endpoint tested. Primary analyses evaluated the correlation of OS with IDFS/IBCFS. Secondary analyses evaluated the correlation of OS with other STEEP v2.0 endpoints (distant disease-free survival [DDFS], distant relapse-free survival [DRFS], recurrence-free survival [RFS], recurrence-free interval [RFI] and distant recurrence-free interval [DRFI]) and explored the surrogacy between OS and all endpoints in specific groups of patients (pts) according to their risk of relapse: hormone receptors positive (HR+)/HER2-negative (HER2-) pts with intermediate/high and high-risk and triple negative (TN) pts. Results: A total of 14,473 pts were included. Median age was 50 years (range, 20–82). All were female, and 51.8% were postmenopausal. With a median follow-up of 115 months (range, 0.0–188) we found 2,504 OS events, 4,146 IDFS events (60.9% being distant recurrences) and 3,810 IBCFS events (62.4% being distant recurrences). For each trial, HR of OS, IDFS and IBCFS indicated same conclusions. If HR< 1 for OS, it was also for IDFS and IBCFS and the same was true when HR >1. R2 results of the weighted linear correlations between the ln HR of OS versus (vs) IDFS and OS vs IBCFS were 0.86 and 0.89, respectively. Confidence intervals (CI) at 95% were both overlapping. All other efficacy endpoints showed strong correlation with OS in the overall analysis. R2 values for HR+/HER2- intermediate/high and high-risk pts were 0.89 (OS vs IDFS) and 0.84 (OS vs IBCFS). For TN pts the correlations were weaker, being 0.63 (OS vs IDFS) and 0.73 (OS vs IBCFS). All WLS R2 values are described in the table. Conclusions: All tested STEEP v2.0 endpoints were strongly correlated with OS (R2 close to 1), meaning that their use as surrogate endpoints for adjuvant CT trials is appropriate. Notably, no differences were found between them in this multi-trial analysis. Therefore, none of them is more appropriate than other to discriminate the value of a new intervention vs comparator in adjuvant CT studies with mature data and long-term follow-up. Table: Citation Format: Sara López-Tarruella, Marina Pollan, Ander Urriticoechea, Eva Carrasco, Gonzalo Spera, Miguel Martín, Begoña Bermejo, Linnea Chap, Manuel Ruíz - Borrego, John Crown, Jose Angel García-Sáenz, Arlene Chan, Angel Guerrero, Valerie Bee, Lourdes Calvo, Rodrigo Fresco, Andrea Blasco, Andrés Hernando, Dennis Slamon. STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-03.

Abstract PO1-17-07: Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis

Abstract Background: Although the goal of treatment is to improve overall survival (OS), in the adjuvant setting, disease-free survival (DFS) is an important endpoint because DFS risk reduction may reduce mortality risk. After introduction of the STEEP criteria, invasive DFS (iDFS) was adopted as an objective, well accepted primary endpoint in early breast cancer (EBC) trials. This analysis evaluated iDFS as a surrogate for OS in the HR+/HER2− EBC adjuvant treatment setting using real-world data. Methods: This retrospective analysis of the ConcertAI Patient360 database contains deidentified electronic medical records of patients (pts) treated at US academic and community oncology clinics from Jan 1, 1995 to Apr 30, 2021. The cohort included pts with AJCC (8th ed.) stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status; pathological and/or clinical staging [pathological stage was prioritized if both existed in the record]) HR+/HER2− EBC who had surgery and initiated adjuvant endocrine therapy (ET); ovarian function suppression was permitted. iDFS (disease recurrence, metastasis, second primary tumor, or death) and OS (death due to any cause) were defined as time between ET start and first qualifying event. Pts not experiencing an event were censored at data cutoff or maximum follow-up (whichever was first) for iDFS and maximum follow-up for OS. Correlation analyses between individual iDFS and OS times were performed using Pearson and Spearman correlations and an iterative multiple imputation (IMI) algorithm. Subgroup analyses were conducted by first ET, menopausal status (imputed as 50 years if missing), stage, nodal status, prior (neo)adjuvant chemotherapy, and prior radiation. Results: In total, 3133 pts were analyzed. Mean (SD) age (index or ET initiation date) was 58.4 (12.4) years; 98.8% of pts were female, 29.9% were premenopausal, 80.9% had stage II disease, 57.1% had nodal involvement, and 41.6% and 48.8% had received (neo)adjuvant chemotherapy and radiation therapy. Overall, 1854 and 653 pts received nonsteroidal aromatase inhibitors and tamoxifen only. The median follow-up time was 55.1 months for iDFS and 68.2 months for OS. The iDFS (1103 events [35.2%]) rates were 88.9% and 73.9% at 2 and 5 years. The OS (554 events [17.7%]) rates were 97.4% and 90.5% at 2 and 5 years. There was a significant and high correlation ( >0.85 based on IQWiG 2011 guidelines) between iDFS and OS in the overall cohort (Pearson 0.91, P< .001; Spearman 0.88, P< .001) with 82% of OS variation explained by iDFS (least square R2=0.82; Table). Results were confirmed by IMI rho (0.83, P< .001), which is interpreted as very strong ( >0.8). Results were consistent among all reported subgroups; Pearson and Spearman correlations exceeded 0.85 and IMI exceeded 0.8, except for pts with stage III disease where correlation remained high (Pearson 0.88, P< .001) or medium/strong (Spearman 0.84, P< .001; IMI 0.79, P< .001) and where most censoring was observed (38.2% of pts). Conclusions: This retrospective cohort analysis demonstrates a very strong pt-level surrogacy between iDFS and OS among pts with HR+/HER2− EBC treated in a real-world, US-based, academic and community setting. The findings complement the trial-level surrogacy from prior analyses using data from randomized controlled trials and support iDFS as a surrogate endpoint for OS in HR+/HER2− EBC trials. Citation Format: Stephanie Graff, Sara Tolaney, Lowell Hart, Pedram Razavi, Wolfgang Janni, Lee Schwartzberg, Andrii Danyliv, Juan Carlos Mora Payan, Ilia Ferrusi, Rishi Rajat Adhikary, Joyce O'Shaughnessy. Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-07.

Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma.

The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Two bibliographic databases (PubMed and Embase, 1970-2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010-2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P < 0.0001) and 0.79 (P < 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26-2.17) increase in median OS. Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM.

A preliminary study of optimal treatment response rates in patients undergoing hepatic arterial infusion chemotherapy combined with molecular targeting and immunotherapy.

This study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy. This study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stage C comprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximum selection. Survival curves of patients in the high rating and low rating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results. The median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was -0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR. BRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR.

Pathological response in resectable non-small cell lung cancer: a systematic literature review and meta-analysis.

Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival. A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard ratio [HR] for overall survival or event-free survival by pathological complete response or major pathological response status, yes vs no) and at the trial level using weighted least squares regressions (hazard ratio for overall survival or event-free survival vs pathological complete response, by treatment arm) were performed. In both meta-analyses, pathological complete response yielded favorable overall survival compared with no pathological complete response (frequentist, 20 studies and 6530 patients: HR = 0.49, 95% confidence interval = 0.42 to 0.57; Bayesian, 19 studies and 5988 patients: HR = 0.48, 95% probability interval = 0.43 to 0.55) and similarly for major pathological response (frequentist, 12 studies and 1193 patients: HR = 0.36, 95% confidence interval = 0.29 to 0.44; Bayesian, 11 studies and 1018 patients: HR = 0.33, 95% probability interval = 0.26 to 0.42). Across subgroups, estimates consistently showed better overall survival or event-free survival in pathological complete response or major pathological response compared with no pathological complete response or no major pathological response. Trial-level analyses showed a moderate to strong correlation between event-free survival and overall survival hazard ratios (R2 = 0.7159) but did not show a correlation between treatment effects on pathological complete response and overall survival or event-free survival. There was a strong and consistent association between pathological response and survival and a moderate to strong correlation between event-free survival and overall survival following neoadjuvant therapy for patients with resectable non-small cell lung cancer.

Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma

BackgroundThe 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.MethodsWe 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.ResultsThirty-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).ConclusionsOne-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.

Correlation between surrogate endpoints and overall survival in unresectable hepatocellular carcinoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

This study aimed to assess the therapeutic effect of immune checkpoint inhibitors (ICIs) in patients with unresectable hepatocellular carcinoma (uHCC) and investigate the correlation between surrogate endpoints and overall survival (OS). A systematic literature search included phase I, II, and III clinical trials comparing ICIs to placebo or other therapies for uHCC treatment. Correlations between OS and surrogate endpoints were evaluated using meta-regression analyses and calculating the surrogate threshold effect (STE). The correlation analysis showed a weak association between OS and progression-free survival (PFS), with an R2 value of 0.352 (95% CI: 0.000–0.967). However, complete response (CR) exhibited a strong correlation with OS (R2 = 0.905, 95% CI: 0.728–1.000). Subgroup analyses revealed high correlations between OS and PFS, CR, stable disease (SD), and DC in phase III trials (R2: 0.827–0.922). For the ICI + IA group, significant correlations were observed between OS and SD, progressive disease (PD), and grade 3–5 immune-related adverse events (irAEs) (R2: 0.713–0.969). Analyses of the correlation between survival benefit and risk of mortality across various time points showed a strong association within the first year (R2: 0.724–0.868) but a weak association beyond one year (R2: 0.406–0.499). In ICI trials for uHCC, PFS has limited utility as a surrogate endpoint for OS, while CR exhibits a strong correlation with OS. Subgroup analyses highlight high correlations between OS and PFS, SD, and DC in phase III trials. Notably, the ICI + IA group shows significant associations between OS and SD, PD, and grade 3–5 irAEs. These findings offer valuable insights for interpreting trial outcomes and selecting appropriate endpoints in future clinical studies involving ICIs for uHCC patients.

Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.

Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined. We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS. Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS. NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma.

Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Surrogate endpoints for overall survival in randomized clinical trials testing immune checkpoint inhibitors: a systematic review and meta-analysis.

There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs). We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS. 61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HRPFS and HRmPFS both had a strong surrogacy value (R2 = 0.74 and R2 = 0.81, respectively). In comparisons testing ICI as monotherapy, HRPFS was the best surrogate, although having a moderate correlation (R2 = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R2 ranging from 0.01 to 0.22. In RCTs testing ICIs, the value of potential surrogates for HROS was strongly affected by the type of treatment(s) tested. The evidence available supports HRPFS as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST.

Surrogate endpoints for overall survival in advanced hepatocellular carcinoma: A meta-analysis.

563 Background: Recent advances in systemic therapies have resulted in improved overall survivals (OS) for patients with advanced hepatocellular carcinoma (aHCC). The most commonly utilized primary endpoint for phase III trials in aHCC is OS. A robust surrogate endpoint (SEP) can reduce time and financial costs of future trials and accelerate regulatory approvals of new therapies. We conducted a literature-based meta-analysis to evaluate SEPs for OS in aHCC. Methods: Randomized controlled trials evaluating systemic therapies in aHCC published 2007 - 2023 were identified through a systemic literature search of Cochrane and Medline databases as well as of abstracts presented at ASCO and ESMO meetings. Hazard ratios (HR) for OS and progression-free survival (PFS) and time to progression (TTP) were extracted. ΔORR was calculated as the difference in overall response rates (ORR) between control and experimental arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Surrogate threshold effect (STE) was determined for each comparison when possible. A p &lt; 0.05 was considered to be statistically significant. Results: 26 trials were identified in the first-line setting with 14,827 patients and 11 trials in the subsequent-line setting with 5,316 patients. In first-line trials, immunotherapy (IO) is associated with higher ORR than other agents (p=0.003). There are statistically significant correlations between HRs of PFS/TTP/ΔORR and OS (Table). The relationship between HR-PFS and HR-OS persists in trials with or without IO, but only in trials enrolling &lt; 30% patients of non-viral aetiologies. In subsequent-line trials, there are statistically significant correlations between HRs of PFS/TTP and OS (Table). STE for HR PFS is 0.68 and 0.87 respectively for 1st and subsequent line trials. Conclusions: There are moderate to strong correlations between PFS and OS in aHCC in first-line and subsequent line trials. STE for HR-PFS of 0.68 in first-line and 0.87 in subsequent-line settings can guide sample size calculation in future clinical trials. [Table: see text]

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials. We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE). IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively. Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.

Unsalvageable recurrence-free survival: a new surrogate endpoint for overall survival in patients with resected colorectal liver metastasis - an analysis from the LiverMetSurvey

Unsalvageable recurrence-free survival: a new surrogate endpoint for overall survival in patients with resected colorectal liver metastasis - an analysis from the LiverMetSurvey

Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer

Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

CO56 Radiographic Progression Free Survival as a Surrogate Endpoint for Overall Survival Among Men With Metastatic Castration-Resistant Prostate Cancer

CO56 Radiographic Progression Free Survival as a Surrogate Endpoint for Overall Survival Among Men With Metastatic Castration-Resistant Prostate Cancer

Impact of Progression-Free Survival at 24 Months on Subsequent Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Supplementary Analysis of JCOG0601

Introduction The impact of progression-free survival status at 24 months (PFS24) or event-free survival status at 24 months (EFS24) on subsequent survival has been evaluated in patients with various lymphoma subtypes. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve PFS24 or EFS24 generally have excellent outcomes. It has been observed that the overall survival (OS) after achieving EFS24 was not significantly different from that of the general population (M.J. Maurer. J Clin Oncol, 2014). However, the OS after achieving PFS24 was significantly worse than that of the general population (M.J. Maurer. Ann Oncol, 2018). Consequently, the impact of achieving PFS24 for DLBCL patients remains controversial. In this supplementary analysis, we evaluated the impact of achieving PFS24 on the subsequent survival of untreated DLBCL patients by using data from JCOG0601, a randomized phase2/3 study assessing the schedule of rituximab administration in combination with tri-weekly CHOP (Ohmachi K. Blood Adv, 2021). Methods Among 422 patients enrolled between Dec 2007 and Dec 2014 in JCOG0601, 409 patients were eligible for this analysis (Data cutoff date: Dec 19, 2017). PFS24 was defined as being alive without progression or relapse for 24 months from randomization. The protocol treatment was initiated within 7 days after randomization. OS from PFS24 was defined as the time from achieving PFS24 or the date of progression or relapse to death from any cause. We compared OS from PFS24 with that of age-, sex-, and calendar period-matched Japanese general population using standardized mortality ratios (SMRs). Similarly, PFS12 and PFS60, as well as OS from PFS12 and PFS60, were defined in the same manner as PFS24 and OS from PFS24. The log-rank P-values for OS were calculated. Results The baseline characteristics of the 409 patients were as follows: a median age of 62 years (range, 20-79), with males accounting for 56% (n=227) of the patients. At diagnosis, 46% (n=188) of the patients were Ann Arbor stage III or IV. The majority of patients (82%; n=335) were classified as international prognostic index low or low-intermediate risk. Based on the Hans algorithm for cell-of-origin, 51% (n=210) of the patients were categorized as non-germinal center B-cell type (non-GCB). At a median follow-up of 5.3 years among all patients, a total of 334 patients (82%) achieved PFS24, while 66 patients (16%) failed to achieve PFS24. Five patients died without progression within 24 months, and four patients were lost to follow-up within 24 months. Multivariable analysis revealed that risk factors for failing to achieve PFS24 included serum LDH levels higher than the upper normal limit and two or more extranodal lesions. Patients who achieved PFS24 had a significantly better OS than those who failed to achieve PFS24 (median OS, not reached vs. 1.3 years; P &amp;lt; 0.001). Similar results were observed when using PFS12 and PFS60, regardless of the cell-of-origin. Among the patients who failed to achieve PFS24, non-GCB type patients more frequently had relapsed or refractory diseases in extranodal sites (72%: n=26/36) compared to GCB type patients (43%; n=6/14). The OS after achieving PFS24 or PFS60 was not remarkably different from that of the general population (PFS24: SMR 1.29, 95% confidence interval [CI] 0.72-2.12, P = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, P = 0.55). However, the OS after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95%CI 1.59-3.22, P &amp;lt; 0.001). The primary cause of death for patients achieving PFS12 was DLBCL with the cumulative incidence of more than 5% at 5 years, while the incidence of death due to DLBCL was less than 5% for those achieving PFS24. The primary cause of death for the patients achieving PFS24 was other diseases except for DLBCL and treatment-related toxicity, including secondary malignancies (n=4/7) and pneumonia (n=3/7). Conclusion Newly diagnosed DLBCL patients treated with R-CHOP who achieved PFS24 exhibited an excellent subsequent outcome, which did not differ from those of age-, sex-, calendar-period matched individuals in the general population. Our findings suggest that PFS24 achievement could serve as a surrogate endpoint for OS in DLBCL patients. Further research is warranted to establish the utility of PFS24 achievement as a reliable milestone in clinical practice.

Correlation between PFS and OS in FL: Implications for Clinical Trial Endpoint Selection

Introduction: Follicular lymphoma (FL) comprises 15% of all lymphoma cases and 70% of indolent lymphomas. Cytotoxic, targeted, and novel treatments lead to prolonged remission periods, with a median overall survival (OS) of greater than 10 years. For this reason, surrogate endpoints for OS are frequently used in clinical trials of FL to allow for quicker results and shorter time to drug approvals, as well as to offset the likely cost and difficulty in funding long term trials with OS as a primary endpoint. A frequently used surrogate endpoint is progression free survival (PFS); however, PFS has not been previously validated as a surrogate endpoint for OS in the treatment of FL. Previous systematic reviews of multiple trials did not have mature enough data to draw definitive conclusions (Zhu et al, AAPS J 2017). Methods: To evaluate the correlation between PFS and OS in FL trials, we conducted a comprehensive systematic review. We included all completed phase 2 or 3 clinical trials with posted results on ClinicalTrials.gov from the inception of the database until July 2023. Additionally, we manually added trials that were completed before the database inception in February 2000 culled from HemOnc.org. For inclusion, randomized controlled trials reporting a hazard ratio for both PFS and OS were considered. We performed statistical analyses, utilizing unadjusted linear regression weighted by sample size to evaluate the association between hazard ratios for PFS and OS. Results: A total of 169 randomized controlled trials for FL were initially identified. Upon screening, 74 randomized trials reported rates for both PFS and OS. 20 trials with 22 interventional arms that included hazard ratios were eligible for inclusion in final analysis. 21 (96%) phase 3 trials and 1 (4%) randomized phase 2 trial were included, encompassing 10,729 participants. Among the included interventional arms, 12 (55%) were in the first-line setting and 10 (45%) were in the refractory or relapsed setting. 14 (64%) arms demonstrated a PFS benefit, and 4 (18%) demonstrated both a PFS and OS benefit. Disease characteristics and treatment outcomes are included in Table 1. The correlation coefficient between PFS and OS was 0.558 (95% CI 0.545-0.571), indicating a weak association. The coefficient of determination was 0.311 (95% CI: 0.08-0.52) suggesting 31.1% of OS variance could be explained by changes in PFS (Figure 1). Discussion: PFS showed a weak correlation with OS in FL trials, challenging its role as a surrogate endpoint. Factors such as patient heterogeneity, treatment regimens, subsequent therapies, and treatment-related complications may contribute to the discrepancy. While PFS aids regulatory approval and drug development, our study suggests that PFS may not be an appropriate surrogate endpoint for OS in the treatment of FL, and alternative surrogate endpoints should be pursued. Possible alternative endpoints though will need to be validated using similar systematic methods given often contradictory findings between individual studies. For example, progression within 24 months of initial treatment (POD 24) was a valid surrogate endpoint for OS in the PRIMA study, however this was not the case in the GALLIUM study (Bachi et al., Blood Adv 2021). Other surrogate endpoints such as complete response rate at 30 months (CR30) have demonstrated strong correlation with PFS however their association with OS has yet to be established (Shi el, JCO 2016).

894P Is pathological complete response (PCR) a surrogate endpoint of overall survival in patients with technically unresectable oral cavity cancers? A real-world data study of 900 plus patients

894P Is pathological complete response (PCR) a surrogate endpoint of overall survival in patients with technically unresectable oral cavity cancers? A real-world data study of 900 plus patients

Evaluation of progression-free survival as a surrogate endpoint in primary CNS lymphoma: a systematic review and meta-analysis.

Purpose: To evaluate progression-free survival (PFS) as early surrogate endpoints for overall survival (OS) in primary CNS lymphoma (PCNSL). Methods: PubMed, Embase and Cochrane Central Library were searched up to 7June 2022. Trial-level analyses were performed by weighted linear regression of logarithmic hazard ratios for PFS and OS. Treatment arm-level analyses were performed between PFS rates and 3- or 5-year OS rates. Results: 1471 PCNSL patients in ninerandomized control trials were included. PFS was associated with OS (r=0.750; 95% CI: 0.228-0.937). Strong linear correlations existed between 1-, 2- and3-year PFS and 3-year OS (r =0.896-0.928), moderate or weak correlations existed between 3- to 6-month PFS and 3-year OS, 3-month to 5-year PFS and 5-year OS. Conclusion: Short-term PFS can validly substitute forlong-term OS in PCNSL.

1102P Evaluation of surrogate endpoints for overall survival within the RELATIVITY-047 trial

1102P Evaluation of surrogate endpoints for overall survival within the RELATIVITY-047 trial