Progression-free survival 2 (PFS2) as a surrogate endpoint for overall survival (OS) in breast cancer randomized controlled clinical trials

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria-based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials.Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS, and OS were evaluated at individual and trial levels. Patient-level responder analysis was performed for PFS and OS.Results: The coefficient of determination (R²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. At the trial level, the association between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio (OR) of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. HRs of PFS and OS for responders versus nonresponders were 0.129 [95% confidence interval (CI), 0.11-0.15] and 0.118 (95% CI, 0.11-0.13), respectively.Conclusions: Although responders exhibited longer survival and PFS than nonresponders, the trial-level and individual-level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations. Clin Cancer Res; 24(10); 2268-75. ©2018 AACRSee related commentary by Korn and Freidlin, p. 2239.

Association between progression-free survival and overall survival in mantle cell lymphoma: A trial-level surrogate endpoint analysis

e13089 Background: The use of surrogate endpoints can help reduce the trial duration and cost which is important for aggressive diseases such as TNBC. Previous studies suggest progression-free survival (PFS) may serve as a surrogate for OS in metastatic TNBC. We aim to evaluate PFS and additional surrogate endpoints for their correlation with OS in localized and advanced TNBC. Methods: TNBC phase 3 trials and pooled analysis as well as trials including TNBC subgroups, were identified through a systematic search using LARVOL CLIN, PubMed, clinicaltrials.gov, and conference proceedings. Out of these, trials reporting median survival and hazard ratios (HR) for both OS and surrogate endpoints were considered for further statistical analysis. Surrogate endpoints reported by fewer than 4 trials were excluded from the study. Pearson correlation (r) and determination coefficient (R2) were calculated to assess surrogacy between Median OS and Median PFS, HR OS and HR PFS, HR disease-free survival (DFS), and invasive disease-free survival (IDFS). Weighted regression analysis was conducted controlling for sample size among trial arms. Results: 26 TNBC cohorts and 2 pooled analyses evaluating PARP, PD-1, PD-L1 inhibitors, and chemotherapies were included. The association analysis results are shown. There was a significant correlation between median OS and median PFS (r = 0.73, p value = 1.026×10−6) as well as between HR OS and HR PFS (r = 0.61, p value = 0.009). There was also a significant correlation between HR DFS and HR IDFS with HR OS (r = 0.92, p value = 0.003; r = 0.99, p value = 0.014). Conclusions: PFS is significantly correlated with OS in TNBC across diverse therapies. Also, HR PFS, HR DFS, and HR IDFS are significantly correlated with HR OS. Overall, these results illustrate that PFS could be used as a surrogate for OS in TNBC. Subsequent studies should include early-phase trials to increase association robustness and enable correlation comparison between the diverse mechanism of actions and other surrogate endpoints. [Table: see text]

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and chemotherapy is known to improve overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC). ICIs have different response patterns and survival kinetics characteristics from those of the traditional chemotherapy. In first-line treatment for ES-SCLC, there is an urgent need for surrogate endpoints for the early and accurate prediction of OS. This study aimed to assess progression-free survival (PFS), milestone OS rate, milestone restricted mean survival time (RMST), overall response rate (ORR), and disease control rate (DCR) as proposed surrogate endpoints for OS in ES-SCLC for first-line immunotherapy trials.MethodsBetween January 1, 2013, and December 2020, published articles on randomized clinical trials of ICIs plus chemotherapy in patients with ES-SCLC as first-line therapy were searched in PubMed. s from the ESMO, ASCO, and WCLC, reported from 2018 onwards, were also searched. A weighted regression analysis based on the weighted least squares method was performed on log-transformed estimates of treatment effect, and the determination coefficient (R2) was calculated to evaluate the association between treatment effect on the surrogate endpoint and OS.ResultsSeven trials, representing 3,009 patients, were included to make up a total of 16 analyzed arms. The ratio of the 12-month OS milestone rate (r = −0.790, P = 0.011, R2 = 0.717) and 12-month OS milestone RMST (r = 0.798, P = 0.010, R2 = 0.702) was strongly correlated with the hazard ratio (HR) for OS. The strongest association was observed between the ratio of the 24-month OS milestone RMST and the HR for OS (r = 0.922, P = 0.001, R2 = 0.825). No associations were observed between the HR for OS and PFS and the RR for ORR and DCR.ConclusionsThe results suggested a strong correlation among the ratio of OS milestone rates at 12 months, ratios of OS milestone RMSTs at 12 and 24 months, and HR for OS. The results indicate that OS milestone rates and OS milestone RMSTs could be considered surrogate endpoints of OS in future first-line immunotherapy trials for ES-SCLC.

Earlier studies suggest progression-free survival (PFS) may be used as a surrogate endpoint for overall survival (OS) in metastatic breast cancer, which could shorten follow-up duration and speed up assessment of treatment effects. However, to our knowledge, the association between them is still unclear in advanced or metastatic triple-negative breast cancer (TNBC). A literature-based meta-analysis followed by correlation analysis was conducted in advanced or metastatic TNBC. Weighted multiple regression analysis was then used to test the strength of the association between medians of PFS and OS, and the association between HRPFS and HROS. Fourteen randomized clinical trials published between January 2007 and August 2019, 31 median pairs for PFS and OS, and 17 pairs for HRPFS and HROS from 3,880 patients were selected. The Pearson correlation coefficient between medians of PFS and OS was 0.84 (95% confidence interval (CI) 0.68-0.92, p < 0.001), and the correlation coefficient between HRPFS and HROS was 0.86 (95% CI 0.63-0.95, p < 0.001). Weighted multiple regression analysis showed HRPFS was the most significant predictor of HROS among covariates analyzed (p < 0.001). Both the medians of PFS and OS correlation, and the HRPFS and HROS correlation were 0.79 (p < 0.001), 0.80 (p = 0.001), respectively, in the 11 trials excluding immunotherapy and bevacizumab-based therapy trials. Our analysis suggests PFS can be strongly correlated with OS and considered a valid surrogate endpoint for OS in advanced or metastatic TNBC.

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&amp;lt; 1 for OS, it was also for IDFS and IBCFS and the same was true when HR &amp;gt;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.

BackgroundOverall survival is the true endpoint for most randomized controlled trials (RCTs) of malignant tumors, whereas progression-free survival (PFS) is considered the most reliable surrogate endpoint for overall survival (OS). The present study aimed to evaluate the correlation between surrogate endpoints and OS in randomized trials of first-line chemotherapy with doxorubicin (DOX), the standard treatment for advanced and metastatic soft tissue sarcomas (ASTS), using a meta-analytic approach.MethodsIn a systematic review, we identified RCTs of first-line chemotherapy for ASTS that compared single-agent doxorubicin (DOX) with other chemotherapy regimens, and were published in English during January 1974–December 2017. A meta-analysis was performed to evaluate the efficacy of first-line treatments for ASTS. Surrogacy of the intermediate endpoints for OS was investigated using weighted linear regression analysis. Correlation strength was examined using the coefficient of determination (R2).ResultsTwenty-seven randomized trials, comprising 6156 patients (3371 patients in the experimental arm and 2785 patients in the DOX arm) were identified. The hazard ratios for OS and PFS showed that the efficacy of treatment for ASTS was not significantly different between standard DOX and experimental treatments. The median OS was significantly prolonged in RCTs published after 2012 when pazopanib was approved for treating ASTS. The median PFS, however, did not differ significantly. The correlation between PFS and OS was moderate (R2 = 0.557), but better than that between OS and 3-month PFS, 6-month PFS, and response rate (R2 = 0.200, 0.073, and 0.278, respectively). The correlation between PFS and OS tended to be more favorable in RCTs published after 2012 (R2 = 0.586 and 0.459, respectively).ConclusionsThe trial-level correlation between PFS and OS was only modest; it tended to be better in RCTs published after 2012. While the effective lines of chemotherapy and the introduction of new drugs prolonged OS but not PFS, PFS is a better surrogate than other intermediate endpoints in the first-line ASTS trials even in the post-pazopanib era. Although this does not negate the need for more reliable surrogate endpoints for OS.

BackgroundPatients with small cell lung cancer (SCLC) face a poor prognosis and have limited treatment options, which has prompted the initiation of clinical trials. Overall survival (OS) is the gold-standard endpoint in clinical trials, reflects the benefits patients derive from interventions. Nevertheless, utilizing OS as an endpoint in clinical trials requires large sample sizes and greater financial supports than using progression-free survival (PFS). This study aims to evaluate whether PFS can serve as a surrogate endpoint for OS, thereby conserving human and financial resources in SCLC clinical trials.MethodsWe conducted a systematic review of randomized controlled trials (RCTs) from online databases (PubMed, EMBASE, and the Cochrane Central Library) and international conferences up to January 1, 2025. Hazard ratios (HRs) for PFS and OS, as well as PFS and OS rates, were collected. Weighted linear regression analyses were performed to assess the correlation between PFS benefit and OS benefit, with subgroup analyses based on treatment lines and the trial phase.ResultsA total of 43 RCTs involving 15,119 patients with SCLC were analyzed, including 28 trials focusing on treatment-naïve patients and 15 trials evaluating non-first-line therapies. PFS exhibited a moderate correlation with OS benefit in treatment-naïve patients, particularly for those receiving first-line immunotherapy. Moreover, the 1-year PFS rate showed a strong association with the 1.5-year OS in first-line trials and 2-year OS in subsequent-line trials. No significant correlation was observed in patients who had received prior treatments.ConclusionsThis study supports the utilization of PFS as a surrogate endpoint for OS in clinical trials involving treatment-naïve SCLC patients, especially receiving first-line immunotherapy. This finding can enhance the efficiency of clinical trial design and facilitate the evaluation of novel therapeutic interventions in this challenging patient population.

4101 Background: Biliary tract cancer (BTC) is a heterogeneous group of diseases commonly diagnosed at advanced stages. Overall survival (OS) is the gold-standard primary endpoint in randomized controlled trials (RCT). However, the increasing use of subsequent lines of therapies and cross-over designs may confound the treatment effect. We therefore explored the use of progression free survival (PFS) as a surrogate endpoint of OS both at the trial-level and at the patient-level. Methods: For the trial-level correlation, we conducted a systematic review of RCTs in advanced BTC following the PRISMA guidelines. We searched PubMed, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from database inception to June 2022 and identified all randomized phase II/III trials testing systemic therapies for advanced BTC. We used a weighted linear regression to measure the correlation of log-transformed hazard ratios (HR) of OS and PFS based on trial size and calculated the surrogate threshold effect (STE). We used the IQWiG framework to define the strength of evidence. For the individual-level analysis, we included patients with advanced BTC treated with first and second line chemotherapy in the real-world RETUD registry. We estimated the correlation via the iterative multiple imputation method. Results: From a total of 1992 studies, we identified 32 RCTs including 70 treatment arms and 5140 patients that fulfilled the inclusion criteria. Twenty-three trials were performed in the first line setting and most were phase II RCTs (N = 23). We found a moderate correlation between OS and PFS ( R= 0.79, 95% CI 0.61-0.89). The slope of the regression line was 0.62±0.08, indicating that a 10% risk reduction in PFS will result in a 6.2%±0.8% improvement in OS. The STE was 0.69, suggesting that in a hypothetical trial of 400 patients, a PFS HR of 0.69 will likely result in a significant improvement on OS. Regarding the individual-level correlation, a total of 593 patients with advanced BTC were included. The median age of patients was 68y (IQR 59-74), most were males (54%) and received platinum-based chemotherapy (73.1%). In the first line setting, the median OS was 9.7 months (95% CI 8.7-10.5) and median PFS was 5 months (95% CI 4.5-5.5). We observed a strong correlation between PFS and OS ( r= 0.84, 95% CI 0.81-0.86). In the second line setting (N = 259), a similar correlation was observed to the first-line setting ( r= 0.76, 95% CI 0.72-0.8). Conclusions: At the trial-level, in this analysis treatment effects on PFS were moderately correlated with OS. A HR &lt; 0.69 in PFS suggested that it would likely lead to a significant OS benefit in a hypothetical trial including 400 patients. At the individual-level, PFS and OS were strongly correlated in a real-world cohort. Future validation in patients treated in the context of randomized trials is warranted.

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

Evaluation of Progression-Free Survival (PFS) As a Surrogate Endpoint for Overall Survival (OS) in First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): Findings from the Surrogate Endpoint in Aggressive Lymphoma (SEAL) Analysis of Individual Patient Data from 7507 Patients

The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)-log HROS and log HRPFS-measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8-3.5 months) and the median OS was 7.2 months (95% CI, 6.5-8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:189-198Implications for Practice: For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.

The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.

Disease-free survival as a surrogate endpoint for overall survival in adults with resectable esophageal or gastroesophageal junction cancer: A correlation meta-analysis

7062 Background: In lymphoid malignancies, the strength of association between progression-free survival (PFS) and overall survival (OS) varies by disease aggressiveness. More-indolent malignancies such as multiple myeloma and follicular lymphoma have a weak correlation between PFS and OS, while more aggressive diseases like Hodgkin lymphoma have a stronger association. PFS has been validated as a surrogate for OS in first-line DLBCL, but its utility in R/R DLBCL in the era of CAR T-cell therapy has not been explored. This analysis is the first assessment of PFS as a surrogate endpoint for OS in DLBCL after the introduction of CAR T-cell therapy. Methods: A systematic review of ClinicalTrials.gov was conducted to identify phase 3 trials in DLBCL that reported hazard ratios (HR) for both PFS and OS. Trials initiated after 2015 were included to reflect the post-CAR T-cell therapy era, acknowledging that CAR T-cell therapy was approved in 2017 and most patients experience disease progression within two years. First-line trials were excluded from final analysis, resulting in an analysis focused exclusively on R/R DLBCL. Weighted linear regression analysis was performed, with the number of participants as the weighting factor. The strength of the association was evaluated using the coefficient of determination (R²), with predefined thresholds: R² &gt; 0.80 indicating a strong association, 0.60–0.80 indicating a moderate association, and R² &lt; 0.60 indicating a weak association. Results: A total of 101 randomized clinical trials were identified. Upon screening, 20 trials reported rates for both PFS and OS. Of these, 4 trials, encompassing 1,139 patients, reported HRs and were included in the final analysis. The weighted regression analysis demonstrated a strong correlation between PFS and OS, with a correlation coefficient (r) of 0.98 and a coefficient of determination (R²) of 0.98, indicating that 98% of the variance in OS could be explained by PFS (p = 0.012). Conclusions: This study provides the first surrogate endpoint analysis of PFS in R/R DLBCL in the post-CAR T-cell therapy era, excluding first-line trials. The findings suggest that PFS remains a strong surrogate for OS in this population. While the analysis is limited by the small number of available trials, the results highlight the need for ongoing surrogate validation as treatment landscapes evolve. Trial Name Participants PFS* HR (95% CI) OS HR (95% CI) STARGLO 274 0.40 (0.28 - 0.57) 0.62 (0.43 - 0.88) ZUMA-7 359 0.51 (0.38 - 0.67) 0.73 (0.54 - 0.98) TRANSFORM 184 0.41 (0.25 - 0.66) 0.51 (0.26 - 1.00) BELINDA 322 1.07* (0.82 - 1.40) 1.24 (0.83 - 1.85) Total 1,139 - - Correlation Coefficient (r) - 0.98 (p &lt; 0.001) - Coefficient of Determination (R²) - 0.98 -