Use Of Progression-free Survival Research Articles

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.

Are the Radiological and Molecular Features of Pediatric Medulloblastomas Valuable Prognostic Indicators? A 10-Year Retrospective Review in the Middle East

Medulloblastomas are the most common malignant brain tumors in the pediatric population. Based on the idea that tumors with identical radio-genomic features should behave similarly, the four molecular subtypes are now widely accepted as a guide for the management and prognosis. The radiological features of medulloblastomas can predict the molecular subtype; thus, anticipating the subsequent disease progression. However, this has not been evaluated comprehensively. We aim to thoroughly study the association between the molecular subtypes and radiological features of medulloblastomas. Moreover, we aim to investigate the efficacy of this correlation with the use of progression-free survival (PFS) and five-year survival rates. A retrospective analysis was conducted for all histopathological confirmed medulloblastomas in pediatric patients (<16 years old) that were operated on in Kuwait over the past ten years (n=44). The radiological, histological, and molecular characteristics were justifiably evaluated and analyzed in our sample. The overall progression-free survival after one year was noticed among 27 cases (≈44%) and the non-specific five-year survival was seen in 31 cases (≈70%) after a five-year follow-up. SHH and WNT had the best outcomes, while group 3 showed the worst outcomes. Our findings did not support the association between most of the typical MRI characteristics and survival rate. We further established that SHH and WNT biological types have a better prognosis. There was no association observed between the radiographic features, specifically the location, and the molecular subtype.

Endpoint Surrogacy in Chronic Lymphocytic Leukemia: A Pooled Analysis of the German CLL Study Group

Introduction Overall survival (OS) is generally considered the most patient-relevant endpoint in oncology trials, however, its implementation can entail several challenges in the context of chronic lymphocytic leukemia (CLL): 1) The competing survival risk due to comorbidities in the mostly elderly CLL patient population; 2) the high efficacy of targeted therapies warrant longer observation periods or extensive patient recruitment, which can be operationally challenging; 3) the interference with increasingly potent relapse therapies, which can neutralize differences of efficacy of first line regimen. Hence, surrogate endpoints, such as progression-free survival (PFS), overall response or complete response rate (ORR, CR) or minimal residual disease (MRD), are commonly used in CLL research. However, data supporting a correlation between surrogate endpoints and OS in the treatment for CLL is scarce. Here, we present a large, systematic analysis of over 4000 patients (pts) treated in studies of the German CLL Study Group (GCLLSG) to determine the adequacy of surrogate endpoints in clinical trials for pts with CLL. Methods We analysed twelve phase II and phase III trials of the GCLLSG spanning from 1999 to 2022. Only pts receiving first-line therapy were included in the analysis. To determine correlation, the Kaplan-Meier survival function was estimated for both OS and PFS for each study separately. From these functions, the probability of survival (OS and PFS) was estimated at different time points. These pairs of time points were then correlated across the studies, with each pair of probabilities weighted by the number of pts in each corresponding study using Spearman's correlation coefficients. Additionally, we compared OS according to MRD and iwCLL response status at end-of-treatment (for fixed-duration regimens) or end-of-induction-treatment (for MRD-guided treatments) (EO[I]T) using Kaplan-Meier functions calculated from the time point of MRD assessment in peripheral blood. EO(I)T ranged from month 9 to month 15 after treatment initiation, depending on the study protocol. Results The full analysis set comprised 4237 pts. The median observation time was 67 months. Median age was 64 years (range 27 - 90). 45.1% of pts were older than 65 years. 3159 pts (74.6%) had received chemo/chemoimmunotherapy (C/CIT), whereas 1078 (25.4%) were treated with targeted therapies. There were 2114 progressive disease (PD) events and 1211 deaths captured within the trial data. The Spearman's Rho of the estimated survival probabilities for the time points 12/24, 24/36, 36/48 and 60/72 months (PFS/OS) was 0.95, 0.96, 0.94 and 0.92, respectively ( Panel A). Focussing on pts with confirmed OS event (n=1211), the Spearman's Rho between PFS and OS in months was 0.66 for pts receiving chemo/chemoimmunotherapy and 0.88 for pts receiving targeted treatment. ORR and CR rate was 89.8% and 31.5%, respectively. Pts with a CR had a significantly longer PFS (HR 0.38, 95% CI 0.34-0.42, p &amp;lt;0.001) and OS (HR 0.39, 95% CI 0.33- 0.46, p &amp;lt;0.001) compared to pts with non-CR. MRD measurements at the EO(I)T were available for 2521 pts (59.5%), of which 39% were treated with targeted agents. Rates of undetectable (&amp;lt;10 -4), intermediate (≥10 -4 and &amp;lt;10 -2) and high MRD (≥10 -2) were 59.1%, 21.7%, 19.3%, respectively, across treatment groups. The median OS for undetectable and intermediate MRD was not reached and 60.7 months for high MRD status ( Panel B). The estimated 60-month OS was 84.6%, 71.3% and 51.1%, respectively. Accordingly, median PFS for uMRD was 61.8 months and 60-month PFS was 52.6%. In pts ≤65 years of age, median OS was not reached with undetectable or intermediate MRD and 70.5 months in pts with high MRD status. In pts &amp;gt;65 years, median OS was not reached for uMRD and was 75.2 and 58.8 months, respectively, for pts with intermediate or high MRD. The corresponding hazard ratios for high versus uMRD status at EO(I)T were 3.33 (95% CI 2.57 - 4.3) in older and 5.89 (4.15 - 8.35) in younger pts. Conclusion In this large analysis of 12 prospective CLL trials, we found a robust correlation between PFS and OS, thereby supporting the use of PFS as a surrogate endpoint in clinical studies. More importantly, the MRD status at EO(I)T was associated with OS across all treatment modalities, demonstrating its utility in identifying pts with potentially dismal outcomes and providing a rationale for MRD-guided treatment strategies.

Randomised controlled trials evaluating anticancer therapies in haematological cancers: an overview of global research activity.

Design, results, and interpretation of oncology randomised controlled trials (RCTs) have changed substantially over the past decade. In this study, we describe all RCTs evaluating anticancer therapies in haematological cancers published globally during 2014-2017 with comparisons with solid tumours RCTs. A PubMed literature search identified all phase 3 RCTs of anticancer therapy for haematological cancers and solid tumours published globally during 2014-2017. Descriptive statistics, chi-square tests and the Kruskal-Wallis test were used to compare RCT design results, and output between haematological cancers and solid tumours as well as for different haematological cancer subtypes. 694 RCTs were identified; 124 in haematological cancers and 570 in solid tumours. Overall survival (OS) was the primary endpoint in only 12% (15/124) of haematological cancer trials compared to 35% (200/570) in solid tumours (p < 0.001). Haematological cancer RCTs evaluated the systemic novel therapy more often than the solid tumour RCT (98% versus 84%, p = 0.002). Use of surrogate endpoints like progression-free survival (PFS) and time to treatment failure (TTF) were more common in haematological cancers than solid tumours (47% versus 31%, p < 0.001). Within haematological cancers, the use of PFS and TTF was more prevalent in chronic lymphocytic leukaemia and multiple myeloma as compared to others (80%-81% versus 0%-41%, p < 0.001). Seventy-eight percent of haematologic trials were funded by industry as compared to 70% of solid tumour trials. Only 4% (5/124) of haematologicalcancer trials were led by investigators in upper-middle and lower-middle-income countries as compared to the 9% of solid tumour trials. The fact that only 12% of haematological cancer RCTs are designed to show improvements in OS is of grave concern for the field and the care of future patients. This is further compounded by the highly prevalent use of alternative primary endpoints that are rarely valid surrogates for OS in haematological cancers.

Progression-free survival as a surrogate endpoint of overall survival in advanced biliary tract cancer: A meta-analysis of randomized trials and individual-patient level correlation.

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.

Progression-free survival and quality of life in metastatic breast cancer: The patient perspective

IntroductionTreatment advances for metastatic breast cancer (mBC) have improved overall survival (OS) in some mBC subtypes; however, there remains no cure for mBC. Considering the use of progression-free survival (PFS) and other surrogate endpoints in clinical trials, we must understand patient perspectives on measures used to assess treatment efficacy. ObjectiveTo explore global patient perceptions of the concept of PFS and its potential relation to quality of life (QoL). Materials and methodsVirtual roundtables in Europe and the United States and interviews in Japan with breast cancer patients, patient advocates, and thought leaders. Discussions were recorded, transcribed, and analyzed thematically. ResultsLengthened OS combined with no worsening or improvement in QoL remain the most important endpoints for mBC patients. Time when the disease is not progressing is meaningful to patients when coupled with improvements in QoL and no added treatment toxicity. Clinical terminology such as “PFS” is not well understood, and participants underscored the need for patient-friendly terminology to better illustrate the concept. Facets of care that patients with mBC value and that may be related to PFS include relief from cancer-related symptoms and treatment-related toxicities as well as the ability to pursue personal goals. Improved communication between patients and providers on managing treatment-related toxicities and addressing psychosocial challenges to maintain desired QoL is needed. ConclusionWhile OS and QoL are considered the most relevant endpoints, patients also value periods of time without disease progression. Incorporation of these considerations into the design and conduct of future clinical trials in mBC, as well as HTA and reimbursement decision-making, is needed to better capture the potential value of a therapeutic innovation.

Biased Evaluation in Cancer Drug Trials—How Use of Progression-Free Survival as the Primary End Point Can Mislead

This Viewpoint discusses whether the use of progression-free survival as the primary end point in cancer drug trials can result in misleading interpretations of improved overall survival and quality of life.

Progression-free survival: it is time for a new name.

Progression-free survival refers to the time from randomisation or initiation of treatment to the occurrence of disease progression or death. Disease progression is defined by the Response Evaluation Criteria in Solid Tumors as an increase in the sum of maximum tumour diameters of at least 20%, the development of any new lesions, or an unequivocal increase in non-measurable malignant disease. 1 Eisenhauer EA Therasse P Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247 Google Scholar These criteria were originally developed to categorise the outcomes of new cancer treatments in phase 2 studies and facilitate the advancement of promising therapies to phase 3 trials. As an endpoint that is subject to several sources of bias 2 Gutman SI Piper M Grant MD Basch E Oliansky DM Aronson N Progression-free survival: what does it mean for psychological well-being or quality of life? Methods Research Report No. 13-EHC074-EF. Agency for Healthcare Research and Quality, Rockville, MD2013 Google Scholar and that does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. 3 Booth CM Eisenhauer EA Progression-free survival: meaningful or simply measurable?. J Clin Oncol. 2012; 30: 1030-1033 Google Scholar However, over the past two decades, it has become the most common primary endpoint in oncology clinical trials. 4 Del Paggio JC Berry JS Hopman WM et al. Evolution of the randomized clinical trial in the era of precision oncology. JAMA Oncol. 2021; 7: 728-734 Google Scholar From a clinical perspective, a distinction between a patient with a tumour that grows by 21% and a patient with a tumour that grows by 19% seems unlikely. However, in most contemporary randomised controlled trials, these patients would be classified differently. We are concerned that progression-free survival has been widely accepted by the oncology community as an endpoint, without consideration of its limitations as a measure of meaningful impact for patients. 5 Gyawali B Hey SP Kesselheim AS Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine. 2020; 21100332 Google Scholar As described elsewhere, in addition to many methodological concerns about the use of progression-free survival as a primary endpoint, 3 Booth CM Eisenhauer EA Progression-free survival: meaningful or simply measurable?. J Clin Oncol. 2012; 30: 1030-1033 Google Scholar we are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.

A Survey of Survival Outcomes for Targeted Cancer Drugs Approved by the US Food and Drug Administration.

The last two decades have witnessed the vigorous development of targeted cancer drugs and the potent therapeutic effects of these drugs have been validated by various true and surrogate end points. Overall survival (OS) and progression-free survival (PFS) outcomes were two important end points used in targeted cancer drugs clinical trials but investigation on which was rare as a consequence of inherent heterogeneity and complexity. Here, we present the review and analysis of OS and PFS outcomes of all targeted cancer drugs approved by the U.S. Food and Drug Administration (FDA) through December 31, 2019, in the setting of clinical studies. The targeted cancer drug directory was accessed via NCI website. The survival outcomes of those drugs in the setting of clinical trials were collected from publicly available Package Inserts and ClinicalTrials.gov. Median overall (OS) and progression-free survival (PFS) outcomes were summarized for targeted cancer drugs that were evaluated as monotherapies in clinical trials, contributions of targeted drugs to combination therapies in terms of survival benefit were analyzed, survival outcomes of FDA-approved first-line targeted therapies in different cancers were investigated, and the correlation between the absolute OS gain (ΔOS) and PFS gain (ΔPFS) as well as the hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms of available randomized clinical trials was evaluated. A total of 223 indications for 126 targeted cancer drugs have been approved by the FDA through December 31, 2019, among which 28 indications of 23 drugs have been approved for first-line therapies. Eighty indications for leukemia, lymphoma, and rare cancer types without survival data were excluded in the investigation of survival outcomes. For the remaining 143 indications, 99 were approved as monotherapies and 72 were approved as combination therapies. Among monotherapy subset, 18 of 72 (25%) indications with available OS outcomes have maximum median OS less than 12months, 55 of 72 (76%) drug indications have maximum median OS less than 24months, and 67 of 72 (93%) have maximum median OS less than 36months. Regarding PFS, 38 of 88 (43%) drug indications have maximum median PFS less than 6months, 69 of 88 (78%) drug indications have maximum median PFS less than 12months, and 84 of 88 (95%) drug indications have maximum median PFS less than 24months. The addition of targeted drugs to combination regimens under FDA's approval provided notable survival benefit, but the median value of OS gain rate of the available combination regimens was lower than that of PFS. The univariate Spearman Rank correlation coefficient suggested a significant positive correlation between ΔOS and ΔPFS (R = 0.62) but a weak correlation between HROS and HRPFS (R = 0.11) in 46 randomized clinical trials that investigated contributions of targeted cancer drugs to combination therapies with available data. A moderate correlation between ΔOS and ΔPFS (R = 0.43) and a rather weak correlation between HROS and HRPFS (R = 0.07) were also found in other randomized clinical trials that included in our study with available data. The survival benefit provided by targeted cancer drugs varied a lot among cancer types. Though targeted cancer drugs showed improvements in both OS and PFS in approved combination regimens, the median value of OS gain rate was lower than that of PFS. As only weak correlation was found between HRPFS and HROS, the evidence supporting the use of PFS as a surrogate to OS in the setting of targeted cancer drugs might also be limited.

A novel, more reliable approach to use of progression-free survival as a predictor of gain in overall survival: The Ottawa PFS Predictive Model.

Progression-free survival (PFS) hazard ratios and gain in median PFS are suggested predictors of overall survival (OS) gain (with gain defined as experimental arm minus control arm values). We assessed use of half-lives (time to progression/death of half remaining patients). We reviewed randomized trials from Journal of Clinical Oncology and New England Journal of Medicine, 01/2012-06/12/2017 (discovery series) and 01/01/2007-12/31/2011 (first validation series). If PFS or OS gains were significant, we used PFS/OS curve nonlinear regression analysis to estimate half-lives and defined "half-life gain" as experimental minus control arm half-life. With low crossover and significant PFS differences, PFS half-life gains ≥1.5 months had positive-predictive-values for OS gains ≥2 months of 79 % and 86 % and PFS half-life gains <1.5 months had negative-predictive-values for OS gains <2 months of 95 % and 75 %, in discovery and validation series, respectively. PFS half-life gains more reliably predicted OS gains than PFS hazard ratios or gains in median PFS. Findings were confirmed in a second validation series.

PF389 PROGRESSION‐FREE SURVIVAL PREDICTS OVERALL SURVIVAL IN FRONTLINE CLL

Background:Many phase II and III trials in oncology utilise the surrogate endpoint progression‐free survival (PFS) as the primary endpoint; however, the relationship between a surrogate endpoint and true clinical benefit in terms of overall survival (OS) or quality of life must be demonstrated.Aims:This research aimed to explore and quantify the relationship between PFS and OS in frontline CLL using two independent modelling approaches.Methods:A systematic literature search was conducted March 2017 to identify data on efficacy and safety outcomes of treatments for frontline CLL. PFS and OS Kaplan‐Meier curves were manually digitised using GetData Graph Digitizer (version 2.26). Potential treatment modifying variables were also extracted. Seventeen publications included data for PFS at 24 months (PFS24) and OS at 36 (OS36) and 60 months (OS60). Each treatment arm of each trial was considered as an independent observation. Pearson's correlation was used to calculate the correlation between OS36 or OS60, and treatment modifying variables and PFS24. Significantly correlated variables were then utilised in the robust ordinary least squares (OLS) regression analyses to develop models that could predict OS from PFS. Using the same data, a second analysis was performed with Cox semi‐parametric models. First patient‐level OS and PFS data were recreated using the Guyot algorithm. Next, to inform the modelling strategy, the validity of proportional hazards (PH) assumptions were checked using three methods: log log plot graphical observation, Cox model check, and Schoenfeld's residuals from the Cox model. Hazard ratios (HRs) were then derived from the models.Results:Using the seventeen identified publications, OS36 was found to be significantly correlated with elevated B microglobulin (R2 = −0.65; p = 0.064), del17p (R2 = −0.50; p = 0.016), and PFS (R2 = 0.38; p = 0.021). Similarly, OS60 was found to be significantly correlated with elevated B microglobulin (R2 = −0.71; p = 0.033), del17p (R2 = −0.48; p = 0.085), and PFS (R2 = 0.39; p = 0.062). Eight publications (16 treatment arms) included OS36, del17p, and elevated B2 microglobulin data, whilst five publications (nine treatment arms) included OS60, del17p, and B2 microglobulin data. The OLS regression models incorporating PFS24 and the additional covariates del17p and elevated B microglobulin were significant predictors of OS36 and OS60, with #R2 values of 79.7% and 90.8%, respectively. To assess regression model accuracy, PFS24, del17p, and elevated B2 data were identified from recent phase II/ III publications and entered into the models. Six of the seven OS36 regression model predictions were conservative, with differences between observed and predicted values ranging from −5.78 to 0.09%. Four of the seven OS60 regression model predictions were conservative, with differences between observed and predicted values ranging from −12.69 to 7.65%. PH assumptions were deemed acceptable in all treatment arms. HRs (OS vs. PFS) derived from the Cox models (mean: 0.25; range: 0.10 to 0.49) were significant (p &lt; 0.05) in all treatment arms except one.Summary/Conclusion:The regression models and Cox model‐derived HRs can predict OS from PFS in this dataset of frontline CLL trials. These models, therefore, support the use of PFS as a surrogate endpoint for OS.image

Progression-free survival as a predictor of overall survival in patients with advanced breast cancer: A real-world study from the China National Cancer Center.

e12590 Background: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with advanced breast cancer is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). Methods: From January 2003 to December 2012, 1851 patients with advanced breast cancer at start of first-line therapy were enrolled in this real-world study. An independent cohort of patients hospitalized in 2013 was used for external validation. All data were collected from the Database of China National Cancer Cancer. Results: The correlation coefficient (Pearson’s r) between PFS and OS was 0.807 in patients only receiving endocrine therapy as first-line treatment, 0.643 in those treated with chemotherapy, and 0.642 in the whole cohort. Receiver operating characteristic curve indicated that PFS = 12 months was the optimal cutoff value for predicting patient’s survival. The median OS was 30.0 months (95% CI 27.8-32.2) in the PFS &lt; 12 months group, and 69.0 months (95% CI 60.8-77.2) in the other group (P &lt; 0.0001). Multivariate analysis revealed that compared with patients who did not progress at 12 months, the adjusted hazard ratio (HR) for death was 2.681 (95% CI, 2.301-3.124; P &lt; 0.0001) for patients with PFS &lt; 12 months. Subgroup analysis based on patient’s age, molecular subtype, visceral metastasis and types of first-line treatment further confirmed that PFS &lt; 12 months was associated with significant poor prognosis in all these subgroups. In patients with luminal type of breast cancer, the HR for death was 2.567 (95%CI 2.147-3.069; P &lt; 0.0001) for patients with PFS &lt; 12 months. Notably, for these patients with luminal type breast cancer who had progressed within 12 months after first-line treatment, addition of chemotherapy in the second-line therapy would surprisingly have adverse effects on patients’ survival when compared with endocrine therapy alone (HR = 1.627, 95%CI 1.016-2.604, P = 0.043). The findings were externally validated in the independent cohort. Conclusions: To our knowledge, this is the first real-world study revealed that PFS at 12 months in first-line therapy predict OS of patients with advanced breast cancer.

Estimation of Study Time Reduction Using Surrogate End Points Rather Than Overall Survival in Oncology Clinical Trials

Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life. To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS). This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018. The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS. In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months). From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.

FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen.

On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44-0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448-53. ©2017 AACR.

Sample size determination for the current strategy in oncology Phase 3 trials that tests progression-free survival and overall survival in a two-stage design framework

ABSTRACTThe selection of progression-free survival (PFS) or overall survival (OS) as the most suitable primary endpoint (PE) in oncology Phase 3 trials is currently under intense debate. Because of substantial limitations in the single use of PFS (or OS) as the PE, trial designs that include PFS and OS as co-primary endpoints are attracting increasing interest. In this article, we report on the formulation of determining the sample size for a trial that sequentially tests PFS and OS by treating them as co-PEs. Using a three-component model of OS, the proposed method overcomes the drawbacks of an existing method that requires unreasonable assumption of the exponential distribution for OS, although the hazard function is nonconstant because effective subsequent therapy has prolonged postprogression survival in recent oncology trials. Alternative estimation method of hazard ratio for OS under a three-component mode is also discussed by checking the appropriateness of assuming proportionality of hazards for OS. In order to examine the performance of our proposed method, we performed three numerical studies using both simulated and actual data of cancer Phase 3 trials. We find that the proposed method preserves a prespecified target value of power with a feasible increment of trial scale.

Combining drugs and extending treatment - a PFS end point is not sufficient.

In studies investigating the combination of two or more anticancer drugs that are already approved for independent use, or 'maintenance' regimens, the use of progression-free survival as the end point for approval is inadequate; sequential treatment with the same agents or existing salvage therapies, respectively, might provide an equivalent survival benefit, with lower toxicity, cost, and treatment burden, therefore, the use of an overall survival end point is essential to justify such interventions.

Title: Progression-Free Survival 2 in Hematological Cancer Treatment Choices: Challenges to Routine Use

Background: In 2012, the European Medicines Agency (EMA) recommended the use of progression-free survival (PFS) 2 as a secondary endpoint in trials evaluating maintenance treatment in hematology oncology trials. PFS2 is defined by the EMA as time from randomization to objective tumor progression on next-line treatment or death from any cause. Potential benefits of PFS2 may be found in cases where experimental treatments appear to improve PFS but not overall survival (OS), particularly in situations with improved survival but where measurement of OS is confounded, for example when drugs are trialed in early lines of therapy and subsequently coupled with improved salvage treatments. However, in practice the utility of this endpoint may seem unclear in cases where tumor cells undergo molecular or microenvironment changes without obvious clinical progression. Currently, the US Food and Drug Administration (FDA) does not recognize this end point and in our experience, healthcare providers are unsure of its definition or value.Objective: To understand the current definitions and limitations of PFS2 from a review of the literature and registered clinical trials in the context of PFS.Methods: We undertook a pragmatic literature review relating to PFS and PFS2. Sources investigated included peer-reviewed literature, clinicaltrials.gov, horizon scanning and health technology appraisal (HTA) activities, and 'grey literature' sources. After review of the search hits, information was grouped according to the therapy area and type of information and the main themes and questions identified.Results: We identified a range of specific challenges and issues regarding each endpoint. For PFS, we noted ongoing debates across disease areas. These principally related to the interpretation of clinical trial evidence: expert clinical opinion routinely highlighted concerns about statistical issues and bias arising from censoring, missing data, subjectivity and assessment time. Two other common issues were the need for adequate sample size to detect differences in OS and a lack of evidence relating prolonged PFS to better health-related quality of life (HRQoL).For PFS2, more basic challenges and needs were identified than for PFS. Only the EMA provides a clear definition; the US Food and Drug Administration (FDA) and other regulatory agencies do not appear to have a definition or policy regarding PFS2 at this time. On the other hand, PFS2 is increasingly incorporated into oncology trials as a secondary endpoint in both hematologic and solid tumors. As of 1 August 2016, there were 41 oncology trials registered on clinicaltrials.gov where PFS2 is included. Of these, 20 trials have been registered or updated since January 2015. The implications of routinely generating and using PFS2 data for regulatory and market access purposes therefore are currently unclear. Most of the current information is related to PFS2 data in trials of lenalidomide in multiple myeloma.Based on commentaries and discussions in the literature, there is an ongoing need to understand the clinical and economic rationales for using PFS2 data to support benefit-risk assessments (e.g. relating effect sizes to clinical outcomes) and to determine how best to communicate these potential benefits meaningfully. There is also a need to understand how PFS2 may relate to patient-centered benefits, such as HRQoL, which may help to identify patient preferences in the context of treatment choice.This information has been used to develop a physician questionnaire that would help identify insights and opinions about PFS2 in the following areas: (1) use of surrogate endpoints, (2) treatment choice in relapsing cancers, (3) implications of PFS2 for clinical practice and (4) future needs for PFS2. Results from this primary research will be presented subsequently.Conclusions: PFS2 is increasingly included as a secondary endpoint in oncology trials assessing the benefits of maintenance or sequential treatments. However, there is limited guidance from regulatory bodies on using and interpreting PFS2 data even though there are post-approval implications regarding potential positioning of drugs within treatment pathways. To date, the EMA is the only regulatory agency that has considered the relevance of PFS2 as a clinical endpoint. The clinical importance of PFS2 needs greater understanding to help physicians apply the data in patient management. DisclosuresSolaman:Celgene: Consultancy. Walker:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Trends in endpoint selection in clinical trials of advanced breast cancer.

The selection of appropriate endpoints is crucial for the evaluation of clinical benefits and approval of novel anticancer agents. To our knowledge, this is the first study to evaluate endpoint selection and the shift in trends in phase II and phase III trials of advanced breast cancer treatment. All phase II and phase III trials of advanced breast cancer registered in the ClinicalTrials.gov registry between October 2000 and September 2012 were included in our study. Two study periods were considered for comparison: October 2000 to September 2007 (cohort A) and October 2007 to September 2012 (cohort B). Information on primary and secondary outcome measures, as well as trial characteristics, was extracted by two independent reviewers. Of the 398 phase II and 120 phase III trials, the most frequently intended primary endpoint was progression-free survival (phase II: 28.1%; phase III: 50.0%). For phase II trials, a shifting trend in primary outcome was observed from cohort A to cohort B: the use of objective response rate, the most frequently intended primary outcome, significantly declined (cohort A: 60.6%; cohort B: 39.0%; P<0.001), while the use of progression-free survival significantly increased (cohort A: 35.9%; cohort B: 66.1%; P<0.001). Progression-free survival is the most frequently intended primary outcome measure in phase II and phase III trials of advanced breast cancer treatment, with a shifting trend observed from objective response rate to progression-free survival in phase II trials.

Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis.

Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31% (i.e., model R (2)) of the variability between the PFS-OS association was accounted for. When trials were limited to ≥2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R (2) increased to 55%. However, the HRPFS-HROS association was no longer significant when only 1st-line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the ≥2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended.

Evaluating Expected Costs and Benefits of Granting Access to New Treatments on the Basis of Progression-Free Survival in Non-Small-Cell Lung Cancer.

Surrogate end points may be used as proxy for more robust clinical end points. One prominent example is the use of progression-free survival (PFS) as a surrogate for overall survival (OS) in trials for oncologic treatments. Decisions based on surrogate end points may expedite regulatory approval but may not accurately reflect drug efficacy. Payers and clinicians must balance the potential benefits of earlier treatment access based on surrogate end points against the risks of clinical uncertainty. To present a framework for evaluating the expected net benefit or cost of providing early access to new treatments on the basis of evidence of PFS benefits before OS results are available, using non-small-cell lung cancer (NSCLC) as an example. A probabilistic decision model was used to estimate expected incremental social value of the decision to grant access to a new treatment on the basis of PFS evidence. The model analyzed a hypothetical population of patients with NSCLC who could be treated during the period between PFS and OS evidence publication. Estimates for delay in publication of OS evidence following publication of PFS evidence, expected OS benefit given PFS benefit, incremental cost of new treatment, and other parameters were drawn from the literature on treatment of NSCLC. Incremental social value of early access for each additional patient per month (in 2014 US dollars). For "medium-value" model parameters, early reimbursement of drugs with any PFS benefit yields an incremental social cost of more than $170,000 per newly treated patient per month. In contrast, granting early access on the basis of PFS benefit between 1 and 3.5 months produces more than $73,000 in incremental social value. Across the full range of model parameter values, granting access for drugs with PFS benefit between 3 and 3.5 months is robustly beneficial, generating incremental social value ranging from $38,000 to more than $1 million per newly treated patient per month, whereas access for all drugs with any PFS benefit is usually not beneficial. The value of providing access to new treatments on the basis of surrogate end points, and PFS in particular, likely varies considerably. Payers and clinicians should carefully consider how to use PFS data in balancing potential benefits against costs in each particular disease.